Chemical Insights into Antibacterial N-Halamines - Chemical Reviews

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Chemical Insights into Antibacterial N‑Halamines Alideertu Dong,*,† Yan-Jie Wang,*,‡ Yangyang Gao,† Tianyi Gao,† and Ge Gao*,§ †

College of Chemistry and Chemical Engineering, Inner Mongolia University, Hohhot 010021, People’s Republic of China Department of Chemical and Biological Engineering, University of British Columbia, 2360 East Mall, Vancouver, BC, Canada V6T 1Z3 § College of Chemistry, Jilin University, Changchun 130021, People’s Republic of China ‡

ABSTRACT: Microbial contamination arising from pathogens poses serious threats to human health and in recent decades has presented an unprecedented challenge to antibacterial research. Of the various antibacterial agents that effectively kill pathogens, halogen-based antibacterial compounds have been successful in eliminating harmful pathogen-associated diseases and are becoming the most popular disinfectants. As a significant subcategory of halogen antibacterial agents, N-halamines have drawn increasing research interest into their chemistry and practical applications. N-Halamines have many advantages over other antibacterial agents, including effectiveness against a broad spectrum of microorganisms, long-term physicochemical stability, high structural durability, and the regenerability of their functional groups, with corresponding renewal of their antibacterial properties. This review examines recent progress and research trends in both theoretical and experimental studies of N-halamines, with the aim of providing a systematic and comprehensive survey and assessment of the significant advances in our understanding of antibacterial N-halamines. This review serves as a practical guide to developing N-halamines through both broad and in-depth basic research and offers suggestions for their potential future applications.

CONTENTS 1. Introduction 2. Synthesis of N-Halamines 2.1. Cyclic N-Halamines 2.1.1. Hydantoin-Containing N-Halamines 2.1.2. Imidazolidinone-Containing N-Halamines 2.1.3. Oxazolidinone-Containing N-Halamines 2.1.4. Succinimide-Containing N-Halamines 2.1.5. 4-Piperidinol-Containing N-Halamines 2.1.6. 1,3,8-Triazaspiro[4.5]-Decane-2,4-DioneContaining N-Halamines 2.1.7. 1,3,5-Triazinane-2,4-Dione-Containing N-Halamines 2.1.8. Barbituric Acid-Containing N-Halamines 2.1.9. Cyanuric Acid-Containing N-Halamines 2.2. Acyclic N-Halamines 2.2.1. Inorganic N-Halamines 2.2.2. Amine N-Halamines 2.2.3. Amide N-Halamines 2.2.4. Amino Acid- and Peptide-Containing NHalamines 2.2.5. Aromatic Compound-Containing N-Halamines 2.2.6. Melamine-Containing N-Halamines 2.2.7. Polysaccharide-Containing N-Halamines 2.3. Combinations of Cyclic and Acyclic N-Halamines

© XXXX American Chemical Society

3. Identification of N−X Bond 3.1. Within Inorganic N-Halamines 3.1.1. Specific Methods 3.1.2. Semispecific and Nonspecific Methods 3.2. Within Organic N-Halamines 3.2.1. Chemical Methods 3.2.2. Physical Techniques 4. Stability of N-Halamines 4.1. Structure 4.2. Heat 4.3. Light 4.4. pH 4.5. Water 4.6. Chemicals 4.7. Bacteria 5. Antibacterial Action of N-Halamines 5.1. Antibacterial Activity 5.1.1. Inherent Properties 5.1.2. Antibacterial Assay 5.2. Factors Affecting Antibacterial Activity 5.2.1. Effect of Type 5.2.2. Effect of Size 5.2.3. Effect of Substitution 5.2.4. Effect of Hydrophilic−Hydrophobic Properties 5.2.5. Effect of Solution pH

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DOI: 10.1021/acs.chemrev.6b00687 Chem. Rev. XXXX, XXX, XXX−XXX

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with contact antibacterial properties. With the development of insoluble polymeric N-halamines, many research groups, especially both Ren’s group37 and Liang’s group,38 tended to introduce novel chemical structure into their designed polymeric N-halamines for developing better antibacterial properties in wide and potent applications. Interestingly, Jang and Kim39 utilized nanotechnology in the synthesis of polymeric N-halamines to fabricate N-halamine-based nanoparticles in antibacterial applications, using colloidal silica as a template. Recently, nanosized N-halamines, resulting from the combination of advanced nanotechnology and effective polymeric methods, have attracted increasing attention in the antibacterial field due to their enhanced antibacterial efficiency.40,41 N-Halamines can be inorganic or organic compounds in which oxidative halogens are chemically bonded to nitrogen (see Figure 1).42 Generally, N-halamines can effectively stabilize

1. INTRODUCTION Certain recent, comprehensive literature surveys have demonstrated that due to a lack of safety consciousness and control, numerous emerging and re-emerging pathogens have caused widespread human disease and deaths, raising global fears of pandemics.1,2 To prevent and control emerging infectioninduced diseases, numerous researchers have been focusing on the development of highly effective antibacterial techniques so that pathogens can be eliminated or neutralized before they become hazardous.3−12 Of the new antibacterial agents that effectively kill a wide spectrum of pathogens, halogen-based antibacterial agents are known to prevent lethal diseases from infectious pathogens and therefore have attracted significant research interest, as they can play an effective role in protecting human health and improving environmental hygiene.13 Used predominantly as disinfectants, halogen-based antibacterial agents have been adopted throughout the world because of their cost-effectiveness and ability to kill the majority of microorganisms rapidly.14 Most of the halogen-based antibacterial agents are composed of strong oxidants, such as gaseous Cl2, salt of hypochlorite, chlorine dioxide, and Nhalamines.15,16 Among the available halogen-based biocides, Nhalamines have become some of the most popular.17−30 After N-halamines were defined as halogen derivatives of nitrogen in the coverage of inorganic chemistry as early as 1927,31 Berliner32 revealed an important effect of inorganic Nhalamines (i.e., chloro derivatives of ammonia) on water purification. Later, Drago’s group33 and Wegner’s group34 reviewed and discussed different synthesis routes, analytical detections, chemical structures, physical properties, and chemical reactions of N-halamines in a long period of 1950− 1960. In 1970, Kovacic and coauthors35 discussed the early chemistry of N-halamines mainly in synthetic methods and physicial/chemical properties, with their important emphasis on both N-bromamines and N-chloramines. Then, Worley36 started to focus on the design and synthesis of N-halamines in the early 1990’s, using chlorine or bromine to stabilize the surface of insoluble polymeric N-halamines, and endow them

Figure 1. Structural illustration of N-halamine compound. R1, R2 = H, X, inorganic group and/or organic group. X = Cl, Br, or I. Reproduced from ref 42. Copyright 2013 American Chemical Society.

5.2.6. Effect of Bacteria Species 5.3. Mechanism of Antibacterial Action 5.3.1. Contact Killing 5.3.2. Release Killing 5.3.3. Transfer Killing 5.4. Biological Effect on Bacteria 6. Applications of N-Halamines 6.1. Water Treatment 6.2. Air Purification 6.3. Textile Products 6.4. Medical and Healthcare Products 6.5. Dyes and Paints 6.6. Silica Materials 6.7. Other Applications 7. Conclusions and Perspectives Author Information Corresponding Authors ORCID Notes Biographies Acknowledgments Abbreviations References

and store halogen atoms in N−X covalent bonds. Thanks to the strong oxidative state (+1) of halogen atoms in these bonds, Nhalamines have been reported to show powerful antibacterial activity against pathogens.17 Specifically, their structure, which includes the stabilization of free halogen, not only allows Nhalamines to effectively destroy a broad spectrum of microorganisms without causing multidrug-resistant superbugs but also confers other advantages, such as long-term stability in aqueous solution and dry storage, high durability, regenerability, lower corrosion than free halogens, good human and environmental safety, and low cost.18−20 Interestingly, once oxidative halogen is consumed, N-halamines are easily recharged through exposure to dilute household bleach or halogen-releasing agents, indicating that N-halamines have renewable antimicrobial properties and activity.22 As a result of their unique antibacterial qualities, N-halamines have been used in a broad range of applications, such as water treatment, air purification, textile products, medical and healthcare products, dyes, paints, and food processing.23 Unlike other halogen-based antibacterial agents, the Nhalamines tend to be significantly more diverse in their molecular structure. The halogen in N-halamines can include chlorine, bromine, or iodine, with chlorine being the most popular.24,25 The N-halamines are divided into three types: amine N-halamines, amide N-halamines, and imide N-halamines, based on whether they involve the halogenation of amine, amide, or imide compounds.43 Interestingly, when the effects that electron withdrawal and electron donation had on the N−X bond were investigated, the hierarchy of structural stability for these three categories was found to be amine Nhalamines > amide N-halamines > imide N-halamines.42 NHalamines can also conveniently be classified as cyclic or acyclic, with both classes having good antibacterial activity against a broad range of microorganisms. However, the latter B


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Table 1. Classification, Structure, Antibacterial Property, and Application for Some Typical N-Halamines

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Table 1. continued

indicates that N-halamines can be classified as cyclic, acyclic, or a combination of the two. They may be further subdivided based on the structure of the precursors used in the synthesis process. Table 1 summarizes the antibacterial properties and applications of different synthetic N-halamines.

decompose in the presence of water, light, and heat more easily than the former. To date, other published reviews of N-halamines have focused on only one or a few aspects of synthesis, characterization, antibacterial properties, and applications.35,42−52 To thoroughly understand and develop N-halamines in terms of both broad and in-depth basic research and potential applications, we have taken a new, important approach by comprehensively focusing upon the chemistry of antibacterial N-halamines. Through examining the recent progress and research trends in both theoretical and experimental studies of antibacterial N-halamines, this review provides a systematic and thorough survey and assessment of the great advances that have been made with antibacterial N-halamines. We review material selection, synthesis methods, structural characterization, and activity performance, and we emphasize their interrelatedness.

2.1. Cyclic N-Halamines

Cyclic N-halamines have one or more N−X bonds in primarily five- or six-membered rings. The most common contain hydantoin, imidazolidinone, oxazolidinone, succinimide, 4piperidinol, 1,3,8-triazaspiro[4.5]-decane-2,4-dione, 1,3,5-triazinane-2,4-dione, barbituric acid, or cyanuric acid. Table 1 presents schematic illustrations for typical cyclic N-halamines. The absence of α-hydrogen next to the N−X bond(s) can prevent the formation of hydrochloric acid, as a result of an elimination reaction between the α-hydrogen and the halogen in the N−X bonds. 2.1.1. Hydantoin-Containing N-Halamines. As the most familiar in the cyclic class, hydantoin-containing N-halamines can often be synthesized via the facile halogenation of hydantoin using positive halogen-containing compounds. We summarize the relevant techniques here.

2. SYNTHESIS OF N-HALAMINES Debiemme-Chouvy’s reported that N-halamines could be synthesized via the halogenation of N−H bond-containing precursors.42 As noted above, structural characterization D


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Bucherer-Bergs synthesis can produce 5-substituted hydantoins from carbonyl precursors via the actions of potassium cyanide and ammonium carbonate;53 this method has been widely used for preparing hydantoin-containing N-halamines.54−58 For instance, Worley’s group54 synthesized 5methyl-5-(4′-methylphenyl)hydantoin (2.2) via a typical Bucherer-Bergs synthesis process (Figure 2) in which 4-

Figure 3. Synthesis of 1-chloro-3-alkyl-5,5-dimethylhydantoin (CADMH). Reproduced from ref 59. Copyright 2006 American Chemical Society. Figure 2. A typical Bucherer-Bergs synthesis for PEG-N-halamine.

containing N-halamines by exposure to dilute hypochlorite solutions. Similarly, Sun’s group used 11-bromoundecanoic acid (BUA) and a potassium salt of DMH to produce an Nhalamine precursor, dimethylhydantoin undecanoic acid (DMH-UA).61 After chlorination with dilute bleach, the DMH-UA was transformed into 3-chloro-4,4-dimethylhydantoin undecanoic acid (Cl-DMH-UA). Liang et al.62 prepared a series of new N-halamine epoxide precursors to obtain hydantoin-containing N-halamines via a very facile and economical method. A typical preparation of 3-glycidyl-5,5dialkylhydantoin involved the following. First, 5,5-dialkylhydantoin was converted to its sodium or potassium salt using NaOH or KOH, and then the material was reacted with the same molar concentration of epichlorohydrin without actual isolation of the salt. Next, the cellulose surfaces were treated with 3-glycidyl-5,5-dialkylhydantoin to generate biocidal functionality in the resulting hydantoin-containing N-halamines through exposure to halogen solutions. In addition to these four routes for synthesizing hydantoincontaining N-halamines, click chemistry has been used to attach DMH-based N-halamines.63,64 A typical example is the work of Agarwal’s group,63 which involved synthesizing 3-(2′-azidoethyl)-5,5-dimethylhydantoin (DMH-N3) in the first step and then anchoring it on alkyne-based polymers using click chemistry. Chlorination then yielded antimicrobial hydantoingrafted polymeric N-halamines. Unlike these modes of synthesizing hydantoin-containing Nhalamines, hydantoinyl siloxanes can be used as intermediate precursors to obtain a class of hydantoin-containing Nhalamines siloxanes by alkyl substitution. It has been reported58,70−74 that a series of hydantoinyl siloxane-containing reactions took place via alkyl substitution at the N3 position of the hydantoin rings when the sodium salts of the hydantoin reacted with (3-chloripropyl)triethoxysilane. In Worley’s report,72 the hydantoin-containing N-halamine siloxanes (4.5) typically were accessed after DMH (4.1) reacted with (3chloripropyl)triethoxysilane, followed by chlorination (Figure 4). To strengthen the chemical bonds and thereby provide high stability as well as good activity, Barnes et al.58 utilized the Bucherer-Bergs method to synthesize 5,5-(1,2-ethanediyl)bis[5methylhydantoin] from acetonylacetone and attached it onto cotton fibers by siloxane covalent bonding. The fibers were rendered biocidal by forming hydantoinyl siloxane-containing N-halamines after exposure to oxidative halogen solutions. In the presence of DMH, the Gabriel reaction75−78 is often used to prepare cyclic N-halamine monomers. According to

methylacetophenone (2.1) was used as a starting material in the initial reaction, followed by the attachment of poly(ethylene glycol)-terminated amine (PEG-NH2) and chlorination in the presence of sodium hypochlorite to yield PEG-hydantoincontaining N-halamines (2.5). Broughton’s group used mnitroacetophenone instead of 4-methylacetophenone when implementing the Bucherer-Bergs process to synthesize maminophenylhydantoin-based N-halamines.55 Subsequently, the as-prepared hydantoin-containing N-halamines were grafted onto cellulosic fibers to yield antibacterial properties. Worley’s group employed a modified approach to achieve a strong chemical attachment between the fibers and the hydantoinbased N-halamines; the 5-methyl-5-(3′-aminophenyl)hydantoin resulting from the Bucherer-Bergs synthesis was initially bound to s-triazine and then reacted with cellulose, followed by bleaching to yield antimicrobial cellulosic fibers.56 Ren et al.57 explored a new method for modifying fibers with hydantoincontaining N-halamines using an electrospinning technique. In their study, 3-(5′-methyl-5′-hydantoinyl)acetanilide, obtained via the Bucherer-Bergs synthesis of 3-acetamidoacetophenone, was loaded tightly onto electrospun polyacrylonitrile (PAN) fibers. After the N−H → N−Cl transformation of the hydantoin moiety from exposure to household bleach, the hydantoin-containing N-halamines rendered the PAN fibers excellent antibacterial agents. The Bucherer-Bergs synthesis method is regarded as most suitable for obtaining hydantoin-containing N-halamines when the starting materials are carbonyl compounds. However, most N-halamine synthesis methods use 5,5-dimethylhydantoin (DMH) as a starting material to produce hydantoin-containing N-halamines via a substitution reaction.59−69 Sun’s group59 prepared a series of 3-alkyl-5,5-dimethylhydantoin derivatives (3.3) by reacting DMH (3.1) with alkyl bromides, attaching different alkyl chain lengths (C2−C22) (Figure 3). Upon chlorination, these hydantoin derivatives were facilely transformed into a hydantoin-containing N-halamine: 1-chloro-3alkyl-5,5-dimethylhydantoin (CADMH, 3.4). In contrast, Ren et al.60 synthesized an N-halamine diol precursor, 3-(2,3dihydroxypropyl)-5,5-dimethylhydantoin, using DMH and 3chloropropanediol as the N-halamine precursor and diol reagent, respectively. They coated the N-halamine diol precursor onto cotton fabrics using 1,2,3,4-butanetetracarboxylic acid (BTCA) as the cross-linking agent, and the coated cotton was rendered biocidal after forming hydantoinE


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reactions, such as alkyl substitution and Gabriel reaction, can be performed facilely by a one-step reaction between sodium (or potassium) salts of hydantoin and the substituents, while the method of click chemistry is always performed via a simple reaction of azido-hydantoin with alkynyl-based polymers to obtain the hydantoin-containing N-halamines. 2.1.2. Imidazolidinone-Containing N-Halamines. Imidazolidinones are a basic moiety of cyclic N-halamines. After Worley’s group83 first described their synthesis in 1987, imidazolidinone-containing N-halamines quickly became the most extensively used N-halamines because of their superior efficacy in inactivating many species of bacteria.83−90 Two important precursors in their preparation are 2,2,5,5-tetramethyl-4-imidazolidinone and 4,4,5,5-tetramethyl-2-imidazolidinone, which have significant structural differences. The former has one amide and one amine group, while the latter has two amide groups. Selecting 1,3-dihalo-2,2,5,5-tetramethyl-4-imidazolidinones as typical examples of imidazolidinone-containing Nhalamines, Worley’s group84 prepared them via a facile method involving a reaction between 2,2,5,5-tetramethyl-4-imidazolidinones and sodium hydroxide in the presence of liquid bromine and/or chlorine gas. They also were the first to synthesize other types of imidazolidinone-containing N-halamines, the 1,3dihalo-4,4,5,5-tetramethyl-2-imidazolidinones, which are isomers of 1,3-dihalo-2,2,5,5-tetramethyl-4-imidazolidinone. Basically, 1,3-dihalo-4,4,5,5-tetramethyl-2-imidazolidinones include three different types: 1,3-dichloro-4,4,5,5-tetramethyl-2-imidazolidinone, 1,3-dibromo-4,4,5,5-tetramethyl-2-imidazolidinone, and l-bromo-3-chloro-4,4,5,5-tetramethyl-2-imidazolidine. The former two were synthesized in a one-step reaction83 after the introduction of chlorine gas and liquid bromine, respectively, into a 4,4,5,5-tetramethyl-2-imidazolidinone aqueous system. However, the third was synthesized using a complex method in which 4,4,5,5-tetramethyl-2-imidazolidine reacted first with tertbutyl hypochlorite to form 1-chloro-4,4,5,5-tetramethyl-2imidazolidine and, subsequently, continued to react with Nbromosuccinimide to obtain l-bromo-3-chloro-4,4,5,5-tetramethyl-2-imidazolidine.83 Clearly, the synthesis procedures for the former two are simpler. It has to be mentioned that N-bromamines are not as stable as their N-chloramine analogues because N−Br has a lower bond strength than N−C1.83,84 Thereby, compared to 1,3dichloro-4,4,5,5-tetramethyl-2-imidazolidinone and 1,3-dibromo-4,4,5,5-tetramethyl-2-imidazolidinone, l-bromo-3-chloro4,4,5,5-tetramethyl-2-imidazolidine is a more suitable disinfectant because the bromine moiety rapidly kills bacteria, and the chlorine moiety can provide long-term disinfecting action to prevent further growth of microorganisms. Although there have been significant advances in creating l-bromo-3-chloro-4,4,5,5tetramethyl-2-imidazolidine for use in antibacterial applications, its synthesis is not easy and cost-effective because it is difficult and expensive to create N-halamines from 4,4,5,5-tetramethyl2-imidazolidinone.83,84 To solve this problem, Elrod and Worley85 developed a novel route for obtaining 1,3-dichloro2,2,5,5-tetrasubstituted-4-imidazolidinones (5.8) via a five-step process (Figure 5): (1) formation of 2,2,5,5-tetrasubstituted-4imidazolidinthiones (5.2) with identical substituents at the 2 and 5 positions; (2) hydrolysis of the cyclic thione to acyclic aminothioamide (5.3); (3) preparation of 2,2,5,5-tetrasubstituted-4-imidazolidinthiones (5.4) with different substituents at the 2 and 5 positions; (4) oxidation to form 2,2,5,5tetrasubstituted-4-imidazolidinones (5.7); and (5) chlorination to obtain 1,3-dichloro-2,2,5,5-tetrasubstituted-4-imidazolidi-

Figure 4. Synthetic routes for biocidal silica. Reproduced with permission from ref 72. Copyright 2005 Wiley Periodicals.

Sun and co-workers,75 the Gabriel reaction of DMH with allyl bromide was used to prepare 3-allyl-5,5-dimethylhydantoin (ADMH), which was copolymerized with acrylonitrile (AN), vinyl acetate (VAC), and methyl methacrylate (MMA), respectively. After chlorination, the corresponding polymeric hydantoin-containing N-halamines were obtained, and these exhibited high antibacterial activity. Similarly, Xi et al.76 prepared ADMH using the Gabriel reaction. They then coated their N-halamine on polyester fabrics to enable antibacterial activity via vapor-phase-assisted polymerization coupled with chlorination. Notably, 3-(4′-vinylbenzyl)-5,5-dimethylhydantoin (VBDMH) can usually be used as a monomer for synthesizing N-halamine.79−82 For example, Chen et al.79,80 synthesized VBDMH by reacting DMH with 4-vinyl benzyl chloride, and then copolymerizing the resulting material with nbutyl methacrylate (BMA) using benzoyl peroxide (BPO) as the initiator. After treatment with two different halogenation agents, tert-butyl hypochlorite and sodium hypochlorite, respectively, they obtained the final hydantoin-containing Nhalamines. Worley’s group81,82 formed VBDMH the same way, and then coated it on polymers through admicellar polymerization with a cationic surfactant. Subsequent chlorination treatment conferred biocidal properties on the coated polymers and yielded hydantoin-containing N-halamines. All the methods above to synthesize the hydantoincontaining N-halamines can be summarized as Bucherer-Bergs synthesis, substitution reaction, alkyl substitution, Gabriel reaction, and click chemistry, in which substitution reaction includes alkyl substitution and Gabriel reaction. For these methods, on the one hand, their reaction yields of hydantoincontaining N-halamines ranged from 50% to 96%, indicating a good feasibility in the synthesis. On the other hand, these synthesis methods present a significant difference in the substituted position of hydantoin ring. Bucherer-Bergs synthesis is located at the C5 position on hydantoin ring, offering two kinds of N−X bonds, such as imide N−X bond (N3 position) and amide N−X bond (N1 position), while both substitution reaction and click reaction are carried out at the N3 position on hydantoin ring, which resulting in an only amide N−X bond (N1 position). On the basis of the fabrication of N−X bond, Bucherer-Bergs synthesis is inclined to provide a high content of halogen, but its synthesis route is not easy and cost-effective due to an additional step to prepare hydantoin ring from carbonyl compounds. In contrast to Bucherer-Bergs synthesis, both substitution reaction and click chemistry directly use hydantoin ring to fabricate hydantoincontaining N-halamines, suggesting that these two reaction methods should be simpler and more convenient than the Bucherer-Bergs synthesis. Usually, two types of substitution F


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via a facile reaction of 2-amino-2-ethyl-1,3-propanediol (6.1) with diethyl carbonate (Figure 6). Using acryloyl chloride,

Figure 5. Synthetic routes for the production of 1,3-dichloro-2,2,5,5tetrasubstituted-4-imidazolidinones. Reproduced from ref 85. Copyright 1999 American Chemical Society.

Figure 6. Synthesis of acylated 3-chloro-4-(hydroxymethyl)-4-ethyl-2oxazolidinones. Reproduced from ref 101. Copyright 1998 American Chemical Society.

nones (5.8). The product’s stability and antibacterial efficacy are well-established. Imidazolidinones are usually involved in the preparation of antibacterial N-halamine polymers and coatings.91−94 Sun et al.91 reacted acryloyl chloride with 2,2,5,5-tetramethyl-4imidazolidinone to synthesize 1-acryloyl-2,2,5,5-tetramethyl-4imidazolidinone (ACTMIO) as an imidazolidinone-containing monomer. They then grafted ACTMIO onto textile fabrics via copolymerization with several monomers, such as acrylonitrile (AN), methyl methacrylate (MMA), and vinyl acetate (VAC), under ordinary conditions. After chlorine bleach treatment, imidazolidinones were transformed into imidazolidinonecontaining N-halamines, conferring biocidal activity upon the fabrics. The direct attachment of imidazolidinones onto polymers has been reported as a way to synthesize imidazolidinone-containing N-halamines.92−94 Using an epoxide tethering method, Cerkez et al.92 deposited imidazolidinone-based N-halamines onto cotton fabrics via a reaction between a sodium salt of imidazolidinone and the fabrics, using a chlorination treatment. Chen et al.93 used cross-linked chloromethylated polystyrene to react with 2,2,5,5-tetramethyl4-imidazolidinone to directly form functionalized polymers; after treatment with free chlorine or bromine, imidazolidinonebased N-halamines were formed. These two synthesis methods demonstrate the direct attachment of imidazolidonone to achieve imidazolidinone-containing N-halamines. 2.1.3. Oxazolidinone-Containing N-Halamines. In accordance with Bodor’s work,95 oxazolidinone compounds are one of the intermediate precursors in the preparation of cyclic N-halamines. In 1976, Bodor’s group95 developed two oxazolidinone-containing N-halamines, 3-chloro-4,4-dimethyl2-oxazolidinon and 3-bromo-4,4-dimethyl-2-oxazolidinon, as agents in bactericidal applications. Subsequently, oxazolidinonecontaining N-halamines quickly became the most extensively studied class of N-halamines in antibacterial fields due to their stability in aqueous solution and solid form, their straightforward synthesis, and their effectiveness against a broad spectrum of microorganisms.96−100 To obtain effective intermediate precursors of cyclic Nhalamines, chemical methods were used to develop oxazolidinone derivatives such as 4-(hydroxymethyl)-4-ethyl-2-oxazolidinone.101−106 Using a one-step procedure, Eknoian et al.101 synthesized 4-(hydroxymethyl)-4-ethyl-2-oxazolidinone (6.2)

crotonyl chloride, 2-methylacryloyl chloride, and 3,3-dimethylacryloyl chloride, they also derivated 4-(hydroxymethyl)-4ethyl-2-oxazolidinone to obtain four acylated precursors (6.3): 4-[(acryloxy)methyl]-4-ethyl-2-oxazolidinone, 4-(crotonoxymethyl)-4-ethyl-2-oxazolidinone, 4-[[(2′-methylacryl)oxy]methyl]-4-ethyl-2-oxazolidinone, and 4-[[(3′,3′-dimethylacryl)oxy]methyl]-4-ethyl-2-oxazolidinone. These oxazolidinones can generate polymeric N-halamines (6.4) after emulsion polymerization combined with halogenation using tert-butyl hypochlorite or sodium hypobromite. These oxazolidinone-containing Nhalamines have potential for commercial applications because high yield is feasible, and the starting materials are all relatively inexpensive. To extend Eknoian’s work in textile applications, Xing’s group105,106 coated oxazolidinone-containing N-halamines onto cellulose fibers using 4-(hydroxymethyl)-4-ethyl2-oxazolidinone as the starting material to achieve N-halaminegrafted cellulose fibers, which displayed powerful and rapid antibacterial capability. 2.1.4. Succinimide-Containing N-Halamines. Succinimide is regarded as an important resource in the preparation of cyclic N-halamines because it has an immobilized imide group in its 5-membered ring. According to Postma and Albericio,107 succinimide-containing N-halamines were easily synthesized by reacting succinimide with trichloroisocyanuric acid. However, there is a dearth of studies on the antibacterial properties of succinimide-containing N-halamines, possibly because of the instability of the N−X bonds in the succinimide ring. Yu and co-workers108 used N-chlorosuccinimide (NCS) as an antimicrobial additive in reverse osmosis (RO)-based membranes. They found that NCS effectively inactivated bacteria on the surface without damaging the RO membranes. Most excitingly, NCS was found to be nontoxic, easy to use, readily soluble in water, and relatively inexpensive, all of which make it a candidate for use in water treatment.108 Generally, NCS is considered an alternative to free chlorine in the synthesis of N-halamines because it is less aggressive yet has greater activity in the presence of other contaminants. NCS is a chlorinating agent, donating chlorine (+1) to synthesize other N-halamines. Pastoriza’s report109 showed that the reaction of NCS with nitrogenous compounds resulted in the formation of the corresponding N-halamines. They believed G


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as the reagents. In contrast, Chen’s group114 carried out a transesterification reaction between chlorinated TMP and methyl acrylate to prepare chlorinated 2,2,6,6-tetramethylpiperidinyl acrylate, using tetraisopropyl orthotitanate as a catalyst. These two synthesized amine N-halamines containing modified CC bonds are easily homopolymerized or copolymerized with other monomers (acrylic acid potassium salt or trimethyl2-methacryloxy ethylammonium) and can even be grafted onto cellulose using a polymerization approach.115,116 A systematic review of previous reports indicates that most polymeric N-halamines have been obtained by a “posthalogenation” approach,75,91,102,115 in which the precursors were first incorporated into the target polymers, and then the resultant polymers were halogenated to transform the precursors into N-halamines using conventional methods. Interestingly, Cao and Sun117 developed a novel “prechlorination” approach to prepare polymeric N-halamines. First they prepared N-chloro-2,2,6,6-tetramethyl-4-piperidinyl methacrylate (Cl-TMPM) after the simple chlorination of TMPM with dichlorisocyanurate sodium, and then they performed seed emulsion polymerization to produce poly(ClTMPM). Preparing an alkyl derivative of TMP-based N-halamine has also been considered an effective way to synthesize 4piperidinol-containing N-halamines. Sun’s group118 reacted 2,2,6,6-tetramethyl-4-piperidinol hydrochloride (TMP·HCl) with lauroyl chloride then chlorinated the result with sodium dichloroisocyanurate, yielding N-chloro-2,2,6,6-tetramethyl-4piperidinol laurate (Cl-TMPL) as an additive for use in antimicrobial applications. 2.1.6. 1,3,8-Triazaspiro[4.5]-Decane-2,4-Dione-Containing N-Halamines. Among the various N-halamines, those containing 1,3,8-triazaspiro[4.5]-decane-2,4-dione have the most powerful antibacterial properties; these materials feature three kinds of N−X bonds, allowing a high chlorine loading because they have more nitrogen sites for chlorination. In most cases, 7,7,9,9-tetramethyl-1,3,8-triazaspiro[4.5]-decane2,4-dione (TTDD, 9.2) is considered an important intermediate precursor; it can be prepared via the Bucherer-Bergs method,119 which involves the reaction of 2,2,4,4-tetramethyl-4piperidone (9.1), potassium cyanide, and ammonium carbonate in a molar ratio of 1:2:6, as shown in Figure 9. The final 1,3,8-

that the chlorination reactions of 2,2,2-trifluoroethylamine and benzylamine with NCS led to N-chloramines via the disruption of the N−H bond and the formation of the N−Cl bond. 2.1.5. 4-Piperidinol-Containing N-Halamines. A derivative of 4-piperidinol, 2,2,6,6-tetramethyl piperidinol (TMP), has one amine group in its structure, which can be converted into N-halamine via a reaction related to chlorine bleaching.110 Indeed, TMP is the most popular candidate for synthesizing cyclic amine N-halamines.110−112 As shown in Figure 7, Ren’s

Figure 7. Production of 4-piperidinol-containing N-halamine-coated cotton fabric. Reproduced with permission from ref 110. Copyright 2014 Springer.

group110 bonded TMP (7.2) onto cotton fabric using 1,2,3,4butanetetracarboxylic acid (BTCA, 7.1) as a cross-linking agent. With a bleaching treatment, the amine was transformed into Nhalamine (7.4) and showed excellent antibacterial properties. Similarly, bis(N-chloro-2,2,6,6-tetramethyl-4-piperidinyl) sebacate (Cl-BTMP) can be used as an additive to generate potent antimicrobial activity with good thermal stability and photostability. Interestingly, Sun’s group111 fabricated electrospun cellulose acetate (CA) nanofiber fabrics containing Cl-BTMP using an electrospinning technique. They verified the product’s superior antimicrobial activity in several contexts, including biomedicine and hygiene. In contrast, Luo and coauthors112 chlorinated poly[(6-morpholino-s-triazine-2,4-diyl)-[2,2,6,6-tetramethyl-4-piperidyl]-imino]-hexamethylene[(2,2,6,6-tetramethyl-4-piperidyl)-imino]] (HA-1, 8.1) using sodium hypochlorite solution, obtaining poly[(6-morpholino-s-triazine-2,4diyl)-N-chloro-[2,2,6,6-tetramethyl-4-piperidyl)imino]-hexamethylene-[(2,2,6,6-4-piperidyl) imino]] (APA-1, 8.2), as shown in Figure 8. In the synthesis procedure, HA-1 is a hindered amine polymeric additive, while APA-1 has abundant amine N−Cl bonds in its structure.

Figure 9. Synthesis of chlorinated 7,7,9,9-tetramethyl-1,3,8-triazaspiro[4.5]-decane-2,4-dione (TTDD-Cl). Reproduced with permission from ref 119. Copyright 2013 Wiley Periodicals.

Figure 8. Preparation of poly[(6-morpholino-s-triazine-2,4-diyl)-Nchloro-[2,2,6,6-tetramethyl-4-piperidyl)imino]-hexamethylene[(2,2,6,6−4-piperidyl) imino]] (APA-1). Reproduced with permission from ref 112. Copyright 2006 Wiley Periodicals.

triazaspiro[4.5]-decane-2,4-dione-containing N-halamines (9.3) are then easily obtained by chlorinating TTDD with aqueous sodium hypochlorite. With the assistance of electrospinning, the N-halamines can be formed into nanosized polyacrylonitrile fibrous mats with biocidal properties.119 N-Halamines synthesized as derivatives of TTDD have also been identified as significant candidates for antibacterial applications.120,121 By combining KOH-pretreated 7,7,9,9-

In the preparation of new 4-piperidinol-containing Nhalamines, TMP has been reported to be connected with carbon−carbon double bonds after a reaction with acryloyl chloride. Liu and coauthors113 synthesized 2,2,6,6-tetramethylpiperidinyl acrylate (TMPA) as a 4-piperidinol-containing Nhalamine precursor monomer, using acryloyl chloride and TMP H


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tetramethyl-1,3,8-triazaspiro[4.5]-decane-2,4-dione with an equivalent molar quantity of (3-chloropropyl)triethoxysilane, Worley’s group120 synthesized 3-(3′-triethoxysilylpropyl)7,7,9,9-tetramethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione (TTDD siloxane, 10.1), as seen in Figure 10, and coated this

Figure 11. A four-step reaction procedure to synthesize poly(1,3,5trichloro-6-methyl-6-(4′-vinylphenyl)-1,3,5-triazine-2,4-dione) (polyCTD). Reproduced with permission from ref 123. Copyright 1996 Elsevier.

triazine-2,4-dithione) (11.3). In the third step, a reaction involving hydrogen peroxide was conducted under alkaline conditions to prepare poly(triazinedione) (11.4). In the last step, chlorination resulted in the formation of poly-CTD (11.5) when chlorine gas was bubbled into the alkaline poly(triazinedione) suspension. The poly-CTD displayed more active N−Cl bonds as well as better insolubility than comparable materials, making it an excellent biocidal candidate for water filter applications. Worley’s group also created 1,3,5-triazinane-2,4-dionecontaining N-halamines using a modified synthesis route.124 A substitution occurred at position 6 on the 1,3,5-triazinane2,4-dione ring, resulting in two products: 6-phenyl-3-(3′triethoxysilylpropyl)-1,3,5-triazinane-2,4-dione (MTPTD) and 6,6-dimethyl-3-(3′-triethoxysilylpropyl)-1,3,5-triazinane-2,4dione (DMTPTD). In the synthesis of the former, benzylaldehyde (12.1) first reacted with biuret (12.2) to achieve 6-phenyl-1,3,5-triazinane-2,4-dione (12.3). The attachment of a propyltriethoxysilane group at position 3 under alkaline conditions was done to obtain MTPTD (12.5), as shown in Figure 12A. In contrast, a three-step procedure was used to prepare DMTPTD (Figure 12B). First, 6,6-dimethyl1,3,5-triazinane-2,4(1H,3H)-dithione (12.8) was synthesized via a reaction between dithiobiuret (12.7) and acetone (12.6) under the bubbled chlorine hydride. Next, the 6,6-dimethyl1,3,5-triazinane-2,4(1H,3H)-dithione was transformed in an alkaline hydrogen peroxide solution into 6,6-dimethyl-1,3,5triazinane-2,4-dione (12.9). Finally, again under alkaline conditions, the propyltriethoxysilane group was fixed at the 3 position in 6,6-dimethyl-1,3,5-triazinane-2,4-dione to obtain DMTPTD (12.11). Importantly, both MTPTD and DMTPTD were coated onto the surface of either silica gel particles or cellulose as the substrate, and chlorination was performed to generate N-halamines on the surface, resulting in antimicrobial properties. 2.1.8. Barbituric Acid-Containing N-Halamines. The subcategory of cyclic N-halamines containing barbituric acid are generally known as antibacterial additives in polymers for antimicrobial applications because the barbituric acid offers two imide N−X bonds that enable antimicrobial activity.125 Ahmed and coauthors have made significant contributions to

Figure 10. Production of 1,3,8-triazaspiro[4.5]-decane-2,4-dionecontaining N-halamine-coated polyester. Reproduced with permission from ref 120. Copyright 2008 Wiley Periodicals.

onto polyester (PET) fiber surfaces via covalent bonding. Chlorination yielded 1,3,8-triazaspiro[4.5]-decane-2,4-dionecontaining N-halamine-modified PET (10.4) with excellent biocidal activity.120 Liang et al.121 also prepared TTDD siloxane and then coated its polymerized derivative onto silica gel and cellulose to produce an antimicrobial 1,3,8-triazaspiro[4.5]decane-2,4-dione-containing N-halamine. Notably, with the loss of oxidative chlorine, the coatings not only were quite stable but also tended to recharge.120,121 In addition to TTDD siloxane-based N-halamines, Worley’s group122 has developed a new TTDD derivative, 3-(2,3dihydroxypropyl)-7,7,9,9-tetramethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione (TTDD diol), as another intermediate precursor for preparing different 1,3,8-triazaspiro[4.5]-decane2,4-dione-containing N-halamines by combining TTDD and 3chloropropanediol under alkaline conditions. During this synthesis process, several different concentrations of TTDD diol were bound to cotton fabric and then subjected to chlorination. Significantly, cotton fabrics modified with the assynthesized 1,3,8-triazaspiro[4.5]-decane-2,4-dione-containing N-halamine exhibited powerful antimicrobial activity. 2.1.7. 1,3,5-Triazinane-2,4-Dione-Containing N-Halamines. Cyclic N-halamines can be synthesized from 1,3,5triazinane-2,4-dione-containing compounds using a halogenation approach.123,124 Their structural characteristics make 1,3,5-triazinane-2,4-dione-containing N-halamines very popular in the field of antimicrobial development thanks to their three nitrogen sites, the halogenation of which gives them higher antibacterial activity than other cyclic N-halamines. In a four-step reaction (Figure 11), Sun et al.123 synthesized poly(1,3,5-trichloro-6-methyl-6-(4′-vinylphenyl)-1,3,5-triazine2,4-dione) (poly-CTD), which can also be called a 1,3,5triazinane-2,4-dione-containing polymeric N-halamine. In the first step, poly(4-vinylacetophenone) (11.2) was synthesized via the Friedel−Crafts acylation of polystyrene (11.1). In the second step, poly(4-vinylacetophenone) was reacted with dithiobiuret to achieve poly(6-methyl-6-(4′-vinylphenyl)-1,3,5I


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to react with two modified silica gels, 2-cyano-functionalized silica gel and 3-(isocyanato)propylfunctionalized silica gel, to produce different antibacterial silica gels containing barbituric acid-based N-halamines. To make the insoluble particles larger, the barbituric acid-bearing N-halamines were blended with sodium alginate, and a subsequent cross-linking reaction was conducted using calcium chloride. The final as-prepared products were found to exhibit powerful antimicrobial activity due to the N-halamine components.129 Unlike Ahmen’s group, Elrod and Worley130 synthesized antibacterial barbituric acid-containing N-halamines starting from diethyl methyl malonate rather than from the barbituric acid ring. They demonstrated that in the presence of sodium methoxide, diethyl methyl malonate (14.1) can react with urea (14.2) to produce 5-methylbarbituric acid salt (14.3), as seen in Figure 14. Next, a two-day reaction between 5-

Figure 12. Synthesis of (A) 6-phenyl-3-(3′-triethoxysilylpropyl)-1,3,5triazinane-2,4-dione (MTPTD) and (B) 6,6-dimethyl-3-(3′-triethoxysilylpropyl)-1,3,5-triazinane-2,4-dione (DMTPTD). Reproduced with permission from ref 124. Copyright 2009 Elsevier.

developing barbituric acid-based N-halamines for antibacterial applications, using various synthesis methods.125−129 In their foundational work,125 barbituric acid-containing N-halamines were bonded covalently to cellulosic parts of rice straws and then employed in columns as model water filters, owing to their good antimicrobial action. Interestingly, 5-aminobarbituric acid (uramil) was reported to consist of a derivative of barbituric acid, also used in the synthesis of new N-halamines.126−129 On the basis of reactions related to uramil, Ahmed’s group126−129 reported the synthesis of several barbituric acid-containing polymers (13.4 and 13.7) by reacting uramil (13.2) with polyacrylonitrile (13.1) and polyethyl acrylate (13.5), respectively (Figure 13), and by copolymerizing uramil-based heterocyclic monomers with tolylene-2,6-diisocyanate and toluene-2,4-diisocyanate. These synthesized polymers provide rich amide and imide bonds that are easily converted to their quaternary salts and N-halamine forms after halogenation. The same research group used uramil

Figure 14. Synthesis of poly[acrylonitrile-co-(1,3-dichloro-5-methyl-5(4′-vinylbenzyl)-barbituric acid)] (poly-AN-barb-Cl).

methylbarbituric acid salt and p-vinylbenzyl chloride (14.4) resulted in the formation of 5-methyl-5-(4′-vinylbenzyl)barbituric acid (MVBBA, 14.5). Finally, poly[acrylonitrile-co(1,3-dichloro-5-methyl-5-(4′-vinylbenzyl)-barbituric acid)] (Poly-AN-Barb-Cl, 14.8) was obtained after combining the copolymerization of acrylonitrile (14.6) with MVBBA and a chlorination treatment. The final copolymer, Poly-AN-Barb-Cl, displayed not only an excellent antibacterial activity but also long-term stability. 2.1.9. Cyanuric Acid-Containing N-Halamines. Similar to barbituric acid-containing N-halamines, those containing cyanuric acid present excellent antibacterial action because of their three imide N−X bonds within each 6-membered ring; indeed, they are more effective than other cyclic N-halamines.131−136 In particular, Ahmed’s group131 demonstrated that chlorinated cyanuric acids bonded onto cellulose extracted from rice straw worked against bacteria and viruses in singlestage and multistage filtration systems. To some extent, their facile preparation of cyanuric acid-containing N-halamines using waste rice straw can significantly decrease synthesis costs. The same group132 prepared a new cross-linked Nhalamine polymer (chlorinated polyepicyanuriohydrin (15.4), see Figure 15) and incorporated it into a multifiltration system to study its ability to produce water free of bacteria, viruses, and halide ions. After a laboratory scale test, the synthesized

Figure 13. (A) Preparation of poly(N-iminouramil)ethylene and its halogenation. (B) Preparation of 5-polyacrylamidobarbituric acid and its halogenation. Reproduced with permission from ref 126. Copyright 2008 Elsevier. J


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Figure 15. Preparation of cross-linked polyepicyanuriohydrin and its halogenation.

(PET)136 by grafting cyanuric acid-containing N-halamines onto them using a modified pad-dry-cure route. Unlike the method for grafting GTT onto cotton fabrics, NaOH was employed before grafting GTT onto PET, to hydrolyze some of the ester linkages on the surface of the PET fibers; this enhanced the reaction efficiency between PET and GTT because PET fibers have fewer reactive groups (e.g., hydroxyls). The PET fabrics decorated with the cyanuric acid-containing N-halamines showed good durability and stability when subjected to washing and storage, suggesting their potential application in healthcare-associated industries.

chlorinated polyepicyanuriohydrin was successful. Significantly, using metabolomic profiling,133 they continued to differentiate the bactericidal effects of chlorinated polyepicyanuriohydrin and free halogen and investigated their effects on the E. coli metabolome. Furthermore, the corresponding metabolic profiles implied that in addition to direct contact between the N-halamines and the bacterial cells, the mode of action of Nhalamines can be initiated by the release of halogen ions into the aqueous environment. Unlike Ahmed’s group, Ren’s group134−136 developed cyanuric acid-containing N-halamines for antimicrobial finishing, using pad-dry-cure approaches. Typically, they synthesized two new N-halamine precursors,134,135 such as 1-glycidyl-striazine-2,4,6-trione (GTT, 16.1) and 1-(2,3-dihydroxypropyl)s-triazine-2,4,6-trione (DTT, 16.2), after reacting cyanuric acid with epichlorohydrin and 3-chloropropanediol, respectively. Then, they grafted the two precursors onto cotton fibers to achieve antibacterial fabrics (16.5) (see Figure 16) using a regular pad-dry-cure method coupled with chlorination treatment. In the two synthesis procedures, 1,2,3,4-butanetetracarboxylic acid (BTCA) was employed as a cross-linking agent134 to firmly attach the two precursors onto the cotton fibers. In addition to antimicrobial cotton fabrics, Ren’s group also developed biocidal synthetic polymer fibers such as polyester

2.2. Acyclic N-Halamines

In contrast to cyclic N-halamines, acyclics are defined as compounds with one or more N−X bonds in which the bond(s) cannot be located in cyclic rings. Some of the typical acyclic N-halamines are summarized and tabulated in Table 1. On the basis of their structural features, acyclic N-halamines are generally classified as inorganic N-halamines, amine N-halamines, amide N-halamines, amino acid- and peptidecontaining N-halamines, aromatic compound containing Nhalamines, melamine-containing N-halamines, and polysaccharide-containing N-halamines. 2.2.1. Inorganic N-Halamines. It has been reported that halogens such as chlorine, bromine, and iodine can be used to form inorganic N-halamines,137−139 with chlorine being more popular than the latter two.42 For instance, researchers have found NH2Cl (monochloramine, MCA), NHCl2 (dichloramine, DCA), and NCl3 (trichloramine, TCA) to be attractive for water purification.137 These typical chlorine-based inorganic N-halamines are generally synthesized using a substitution reaction between chlorine in the +1 oxidation state and ammonia, via a chloroamination process. The corresponding equations (eqs 1−3) are as follows: NH3 + HClO → NH 2Cl + H 2O

(1)

NH 2Cl + HClO → NHCl 2 + H 2O

(2)

NHCl 2 + HClO → NCl3 + H 2O

(3)

Notably, inorganic N-halamines have always been found in mixtures rather than singly.49,137 The existence of the three kinds of chlorine-based inorganic N-halamines noted above basically depends on certain factors in the synthesis process: pH, temperature, and chlorine-to-nitrogen ratio (Figure 17). As

Figure 16. Coating 1-glycidyl-s-triazine-2,4,6-trione (GTT) or 1-(2,3dihydroxypropyl)-s-triazine-2,4,6-trione (DTT) onto cotton fabrics, with subsequent halogenation. Reproduced with permission from ref 134. Copyright 2014 John Wiley and Sons. K


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Figure 17. Distribution of inorganic chloramines as a function of (A) molar ratio of N/Cl or (B) pH. Reproduced with permission from ref 137. Copyright 2015 Elsevier.

reported previously,137 MCA is the predominant material and is relatively stable in neutral conditions (pH 7.5−9), while the DCA and TCA predominate at a pH of ∼4.5 or below 4.5, respectively. As a subset of inorganic N-halamines, the mixed inorganic Nhalamines, such as NHBrCl, NBr2Cl, and NBr2I, are generally synthesized by an aqueous halogenation process. For instance, Haag’s group reported on inorganic N-halamines containing both N−Cl and N−Br bonds.138 The researchers definitely demonstrated that hypobromous acid can brominate MCA to obtain N-bromo-N-chloramines (eq 4) or N,N-dibromo-Nchloramines (eq 5) in aqueous solution: NH 2Cl + HOBr → NHBrCl + H 2O

(4)

NHBrCl + HOBr → NBr2Cl + H 2O

(5)

Figure 18. Structures for four β-blockers: atenolol, metoprolol, propranolol, and nadolol. Reproduced with permission from ref 140. Copyright 2004 American Chemical Society.

2.2.2. Amine N-Halamines. The preparation methods for organic amine N-halamines differ from those for inorganic and traditionally result from one of three paths (eqs 6−8):42 RR′NH + X 2 → RR′NX + HX

(6)

RR′NH + HOX → RR′NX + H 2O

(7)

RR′NH + OX− → RR′NX + OH−

(8)

Figure 19. General equation for the reaction of (A) NCNMPT, (B) N-chlorosuccinimide (NCS), and (C) tert-butyl hypochlorite (tBuOCl) with nitrogenous compounds.

benzylamine109 were used as the reactants (see Figure 19B). They found a chlorine transfer process in both cases, from NCS to a nitrogenous compound, generating the corresponding Nhalamines. Interestingly, when the same group142 examined the effect of a chlorination reaction involving nitrogenous organic compounds using tert-butyl-hypochlorite (tBuOCl), they selected 2,2,2-trifluoroethylamine, benzylamine, glycine, and dimethylamine to produce the corresponding homologous Nhalamines after chlorination treatment (see Figure 19C). Haag138 also explored the synthesis conditions required to form N,N-dihalamines when methylamine was used as a model amine. In his synthesis, N,N-dichloromethylamine (CH3NCl2) and N,N-dibromomethylamine (CH3NBr2) were prepared via a reaction of methylamine (CH3NH2) with sodium hypochlorite or sodium hypobromite, respectively. Comparative evaluation indicated that CH3NBr2 tends to form faster, decompose faster, and have greater antibacterial effectiveness than CH3NCl2. He also tried to synthesize N-bromo-N-chloromethylamine (CH3NBrCl) using two different approaches, the bromination reaction of CH3NHCl to yield CH3NBrCl (eq 9), and the halogen exchange reaction (eq 10):

where R is an organic substituent, R′ is either an organic substituent or H, and X is a halogen. Pinkston and Sedlak140 confirmed that amine-bearing pharmaceuticals can react with free chlorine (i.e., HOCl/OCl−), resulting in the formation of amine N-halamines. A reaction between a β-blocker (e.g., atenolol, metoprolol, propranolol, or nadolol, as shown in Figure 18) and a free chlorine can be performed to obtain different products under different pH conditions. Significantly, the synthesized amine N-halamines are easily converted back to their parent compound by one or more reactions related to strong nucleophiles, while in the absence of strong nucleophiles, the synthesized amine N-halamines can be decomposed to produce stable products. To understand and discover new methods for synthesizing organic amine N-halamines, Pastoriza’s group141,142 tried reacting organic amine with oxidative halogen-containing organic compounds rather than free chlorine and found that a reaction between nitrogenous organic compounds and one Nhalamine can form alternative N-halamines. For example, using a transformation reaction involving N-chloro-N-methyl-ptoluenesulfonamide (NCNMPT) with nitrogenous organic compounds at 25 °C, they obtained corresponding amine Nhalamine products, as seen in Figure 19A.141 Subsequently, a similar transformation reaction was used to investigate Nchlorosuccinimide (NCS) when 2,2,2-trifluoroethylamine and

CH3NHCl + HOBr → CH3NBrCl + H 2O CH3NCl 2 + CH3NBr2 → 2CH3NBrCl

(9) (10)

In both of these reactions, the as-prepared N-halamine (CH3NBrCl) was less persistent in the reaction environment; L


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To find effective amide N-halamines for antibacterial applications, Ding’s group155 created core−shell structured amide N-halamines in which silica nanoparticles acted as a core while amide N-halamines were the shell. Their synthesis route (see Figure 21) was first to functionalize silica nanoparticles with polyacrylamide via a layer-by-layer (LBL) electrostatic selfassembly method. A chlorination treatment was used as the subsequent step to form the amide N-halamines. In the core− shell structured product, the amide N-halamines offered antibacterial action while the silica nanoparticles acted as supports to enhance the activated surface area. Owing to the coordinated effect of silica and amide N-halamines, the product had high, stable antibacterial activity. Ren’s group used the LBL deposition method156 to coat a cationic acyclic amide Nhalamine and an anionic acyclic amide N-halamine onto cotton separately. The two ionic amide N-halamines were prepared from two precursors, the cationic homopolymer poly[(3acrylamidopropyl) trimethylammonium chloride] and the anionic homopolymer poly(2-acrylamido-2-methylpropanesulfonic acid sodium salt), which were supported on the cotton fabrics and exhibited antimicrobial properties. In addition to poly(acrylic derivative)s-based precursors being used to synthesize acyclic amide N-halamines, carboxylic derivatives-based polymers (e.g., carboxylic acid, ester, anhydride, etc.)157−163 have also been used, by combining an amination reaction and chlorination. A typical example is the work of Kim and Lee,157 who employed an amination reaction to prepare antimicrobial amide N-halamines via a reaction of 1,2,3,4-butanetetracarboxylic acid (BTCA) with m-phenylenediamine (m-PDA) using sodium hypophosphite as catalyst, coupled with chlorination. The as-prepared N-halamine products were suitable for the modification of a cellulose filter to disinfect water. By the aid of a simple pad-dry-cure method, Cerkez et al.158 ran a reaction of 2-amino-2-methyl-1-propanol (AMP) with BTCA as a cross-linker, using cotton as a substrate. The N-halamine product’s antibacterial functionality was achieved after treatment with household bleach. Liang’s group159 prepared poly(styrene-co-N-(t-Bu)-N-chloro-acrylamide) (22.5) using a combined approach that involved the copolymerization of styrene (22.1) and acrylic acid (22.2), amination with tert-butylamine, and chlorination (see Figure 22). Using the LBL deposition method, Goddard’s group160−163 coated polypropylene, polyethylene, and stainless steel with acyclic amide N-halamines containing bilayers of cross-linked polyethylenimine and poly(acrylic acid) to achieve antimicrobial functionality. Using an ester as a reactant, Chen et al.164−166 carried out an amination reaction and chlorination to prepare their amide N-halamines (see Figure 23), providing a new way to synthesize acyclic amide N-halamines. Specifically, the aminating tert-butyl ester was hydrolyzed to carboxyl groups for conjugation with tert-butylamine via amide bonds,

it was stable for only 10 days in the dark, then possible disproportionation was observed. To obtain amine N-halamines, some cation amine-containing compounds have been used to good effect in the transformation reaction. Bedner and MacCrehan143 investigated the reactivity of two key cation-containing compounds, fluoxetine and metoprolol (see Figure 20), in the presence of

Figure 20. Structures of fluoxetine and metoprolol. Reproduced with permission from ref 143. Copyright 2006 Elsevier.

hypochlorite. The reactions were carried out in pure water under conditions that simulated wastewater disinfection, including neutral pH (7.0), a range of reaction time (2−60 min), and a molar excess of hypochlorite relative to the cation amine-containing compound concentration (5.7 times). Both compounds rapidly reacted with hypochlorite to generate two new neutral amine N-halamines. This confirmed that the cation amine-containing compound could be transformed into its corresponding neutral N-halamine. 2.2.3. Amide N-Halamines. Most acyclic amide Nhalamines exist as polymers and are always obtained via the polymerization of acyclic vinyl amide monomers and chlorination treatment. 144−154 Generally, poly(acrylic derivative)s,144 resulting from acrylamide (AAM), methacrylamide (MAA), N-tert-butylacrylamide (NTAAM), and N-tertbutylmethacrylamide (NTMAM), have been the most popular precursors for preparing acyclic amide N-halamines. Several research groups144−154 have made significant efforts to develop poly(acrylic derivative)s-based N-halamines in various antibacterial applications. These poly(acrylic derivative)s-based Nhalamines can be grafted onto the surfaces of cotton or synthetic polymers to produce biocidal activity. Sun’s group144 performed radical graft polymerization of polypropylene (PP) in the presence of AAM, MAA, NTAAM, and NTMAM, respectively; after chlorine bleaching, the amide groups were totally transformed into the corresponding amide N-halamines. Occasionally, certain cross-linkers,145,146 N-(hydroxymethyl) acrylamide (NMA) and N,N′-methylenebis(acrylamide) (MBA), have been used to generate stable, polymeric network-contained N-halamines. Due to their amide structure, the two cross-linkers noted above often served as precursors in producing new amide N−X bonds by attaching to tether polymers via copolymerization.

Figure 21. Schematic illustration for the synthesis of N-halamine-functionalized core−shell nanoparticles. Reproduced with permission from ref 155. Copyright 2015 Royal Society of Chemistry. M


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butanediamide (TSHB), N-(3-triethoxysilylpropyl)-N′-cyclohexylbutanediamide (TSCHB), and N-(3-triethoxysilylpropyl)-N′-phenylbutanediamide (TSPB). These precursor compounds were then tethered to the surface of cotton fabrics through covalent ether linkages, followed by exposure to dilute sodium hypochlorite solutions to confer antibacterial properties. Goddard’s group169 also used the amination of an anhydride to prepare an antimicrobial N-halamine coating on PP. In a series of procedures presented in Figure 24, alternating layers of branched PE and styrene maleic anhydride copolymers were formed on the surface of PP; these conferred an antimicrobial quality upon the material after the amide Nhalamine groups were exposed to household bleach. All of the synthesis reactions discussed above are strongly related to the formation of acyclic amide N-halamines. Using certain carboxylic derivatives, such as carboxylic acid, esters, or anhydrides, acyclic amide N-halamines can be obtained via a combined procedure involving an amination reaction and chlorination treatment. In comparison with synthesis using poly(acrylic derivative)s, the generation of N-halamines using carboxylic derivatives is somewhat more complicated due to the additional amination procedures. 2.2.4. Amino Acid- and Peptide-Containing N-Halamines. N-Halamines containing amino acids or peptides have become attractive to many researchers because they have amino acid-based structural features that are useful in disinfection for microbial control.170−175 Some of the typical structures are presented in Table 1. Generally, amino acids and peptides facilely react with free chlorine to produce organic N-halamines after chlorine transfers from free chlorine to the nitrogen of the amine.170 Bodor’s group170,171 synthesized amino acid-containing N-halamines from α-aminoisobutyric acid simply by treating it with sodium hypochlorite. Careful examination found that the chlorinated α-aminoisobutyric acid offered good antibacterial activity. Both Selk’s group172 and Ahearn’s group173 improved our understanding of amino acid-bearing N-hal-

Figure 22. Route for synthesizing chlorinated poly(styrene-co-N-(tBu)-N-chloro-acrylamide) (PSA−N−Cl). Reproduced with permission from ref 159. Copyright 2014 Elsevier.

Figure 23. Strategy for designing an antibacterial surface using polystyrene as the substrate. Reproduced with permission from ref 166. Copyright 2011 Elsevier.

and then further chlorinated into biocidal N-halamine moieties. The amination of an anhydride is another plausible route for synthesizing acyclic amide N-halamines.167−169 By the amination reaction of succinic anhydride with 3-aminopropyl triethoxysilane, followed by derivatization, Li’s group167,168 synthesized several siloxane-based N-halamine precursors: N(3-triethoxysilylpropyl)-N′-(N‴-heptylcarbamido-N″-ethyl)-butanediamide (TSHCEB), N-(3-triethoxysilylpropyl)-N′-hexyl-

Figure 24. Illustration of antimicrobial coating. Reproduced from ref 169. Copyright 2015 American Chemical Society. N


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Figure 25. Chemical structures of Kevlar, Nomex, Kermel, and polybenzimidazole. Reproduced with permission from ref 183. Copyright 2003 Wiley Periodicals.

final product exhibited good biocidal activity against bacteria, fungi, viruses, and spores. Compared to p-aramids, m-aramids have better stability during bleaching, favoring the formation of aromatic compound-containing N-halamines. N-Halamines made from maramids are widely used as additives in antibacterial applications.179−182 For example, Lee’s group179−182 coated m-aramid N-halamines onto poly(vinyl alcohol), PET, and cotton fabric surfaces. The final modified N-halamine products had potent, durable, and rechargeable biocidal activity against both Gram-positive and Gram-negative bacteria. The same group179 used an electrospinning technique to fabricate an maramid-containing N-halamine nanofibrous membrane. When the product was used for nonpressure-driven filtration, bacteriafree water was obtained. Unlike aramids, which require certain techniques to render them useful, functional polymers such as poly(aromatic imideamide) (Kermel) and polybenzimidazole (PBI) (see Figure 25) can be used directly to produce aromatic compound-containing N-halamines. Sun’s group183 developed a continuous pad-drycure process to graft 3-allyl-5,5-dimethylhydantoin (ADMH) onto Kermel and a PBI/Kevlar blend, respectively. After chlorination, two aromatic compound-containing N-halamines were obtained, and they demonstrated powerful, durable, and renewable antibacterial activity. 2.2.6. Melamine-Containing N-Halamines. On the basis of their structural characteristics, melamine-containing Nhalamines belong to a subcollection of amine N-halamines due to the presence of amine N−X bonds.186−191 However, the former have quite similar chemical properties to the latter, even though their strong electron-withdrawing effects result from different functional groups.191 According to Sun’s report,189 the biocidal activity and stability of melamine-containing Nhalamines fall between those of amine N-halamines and amide N-halamines because the melamine-containing Nhalamines combine the advantages of both. Generally, 2,4-diamino-6-diallylamino-1,3,5-triazine (NDAM) is used in biocidal functionalization as the precursor of melamine-containing N-halamines.186−188 For example, Sun’s group186,187 grafted PP with NDAM via a reactive extrusion method using either 2,5-dimethyl-2,5-(tertbutylperoxy)hexyne (DTBHY) or dicumyl peroxide (DCP) as the initiator; after chlorination, chloromelamine-based PP was obtained and demonstrated antibacterial properties. The same group188 developed novel composite membranes with poly(vinyl alcohol-co-ethylene-g-diallylmelamine) (PVA-co-PE-

amines, focusing on how their materials’ antimicrobial activity compared with that of other typical biocides, such as 3-chloro4,4-dimethyl-2-oxazolidinone, chlorhexidine, and diazolidinyl urea. After comparative antimicrobial evaluations, the two groups found that the chlorinated amino acids were more potent bactericides than the selected others. To conduct a systematic investigation into the synthesis of amino acidcontaining N-halamines, Fayyad and Al-Sheikh174 tried a protocol whereby the addition of an amino acid such as histidine, glycine, or phenylalanine into a sodium hypochlorite solution could preferentially generate the corresponding Nhalamines. They proved that the chlorine bonded more quickly to amino acids than to ammonia, so the hypochlorite preferred to form amino acid-containing N-halamines rather than inorganic N-halamines when amino acids were present with ammonia. Their subsequent study demonstrated that the synthesized amino acid-containing N-halamines were considerably less effective for inactivating bacteria than free chlorine. Interesting, Amiri et al.175 synthesized N-halamines by combining sodium hypochlorite with amino acids and peptides that included glycine, Ala-Ala, and Arg-Gly-Asp-Ser in a N:Cl molar ratio of 1:0.4, and then used them to combat E. coli. Their antibacterial investigation demonstrated that the disinfection effectiveness of the as-synthesized amino acidcontaining N-halamines could be controlled in a pH-dependent manner. The lower the pH value, the faster the inactivation rate of the as-synthesized N-halamines and the higher their antibacterial function. 2.2.5. Aromatic Compound-Containing N-Halamines. As is well-known, aramids (i.e., aromatic polyamides) are the main intermediate precursors in the preparation of aromatic compound-containing N-halamines because they contain an amide group between two aromatic rings, favoring a transformation reaction into new N-halamines.176−185 According to Lee’s report,179 the aramids can be divided into p-aramids (such as Kevlar) and m-aramids (such as Nomex) (see Figure 25). To obtain aromatic compound-containing N-halamines, p-aramids are not ideal precursors because they can decompose during chlorination in bleach;176 Worley’s group177 confirmed the decomposition mechanism of p-aramids during bleaching. Given that the direct transformation of a p-aramid amide group into the N−Cl structure is very difficult, Luo and Sun178 created a new method by anchoring amide N-halamines onto paramid fabrics after two combined reactions involving the in situ polymerization of methacrylamide and chlorination. The O


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g-DAM) nanofibers layered on poly(propylene-g-diallylmelamine) (PP-g-DAM) meltblown nonwoven fabric. With chlorination, the final nanofibrous membranes had powerful and rapid biocidal effects against bacteria. These materials could be widely used in various fields related to biological decontamination. Another melamine derivative, 2-amino-4-chloro-6-hydroxy-striazine (ACHT), is also a suitable intermediate precursor for preparing melamine-containing N-halamines due to its aminoterminated triazine ring.189,190 In Sun’s group,189 ACHT was synthesized by controlling a hydrolysis reaction of 2-amino-4,6dichloro-s-triazine (ADCT). Next, the ACHT was immobilized on cotton cellulose via a simple pad-dry-cure approach. Finally, the covalently bound ACHT moieties were transformed into chloromelamines after chlorination treatment. The final chloromelamine-grafted products were found to display potent, durable, and rechargeable biocidal functions against bacteria, yeasts, viruses, and bacterial spores. Melamine formaldehyde (MF) fibers have also been used to obtain new melamine-containing N-halamines. Kocer et al.191 reported that to prepare melamine-containing N-halamines, they used melamine formaldehyde (MF) fibers in a hydrolysis reaction with sulfuric acid aqueous solution, followed by chlorination with household bleach. They found that when some of the formaldehyde had been released from the fibers after acid treatment, the fibers became more accessible to chlorine absorption. The biocidal performance of the hydrolyzed chlorinated-treated fibers was further improved by a hydrophilic N-halamine surface coating.191 2.2.7. Polysaccharide-Containing N-Halamines. Chitin consists of 2-acetamido-2-deoxy-D-glucose based on a β (1−4) linkage. Unlike cellulose, chitin, the second most abundant biopolymer, is a naturally occurring polysaccharide.192 To study the acetamide group of chitin so as to develop new Nchlorination methods, Ifuku’s group193 prepared polysaccharide-containing N-halamines by reacting chitin nanofiber film with sodium hypochlorite, yielding a material with antibacterial and antifungal activity (see Figure 26A). They demonstrated that although the active chlorine content of the prepared polysaccharide-containing N-halamines gradually decreased due to disassociation of the N−Cl bond, chlorine could be recharged into the chitin by another sodium hypochlorite solution treatment. In addition to polysaccharide-containing N-halamines being synthesized from chitin, chitosan has been developed as a precursor because chitosan can be obtained by the deacetylation of chitin.194−196 Although chitosan itself is antimicrobial, many researchers have chlorinated it to boost antimicrobial functionality. According to Cao et al.,194 amino groups of chitosan can be transformed into an N-halamine structure after a chlorine bleach treatment, with the resulting material showing antibacterial activity and even preventing the formation of bacterial biofilms (see Figure 26B). Using a nitrogen-plasma treatment, Zhou and Kan195 coated chitosan onto cotton fabric and found that introducing chlorine into the amino groups inhibited bacteria. Kim and Park196,197 prepared chlorinated cross-linker chitosan salt/cotton knit composites, further showing that chitosan-derived N-halamines can have antimicrobial properties and rechargeability. However, while the chitosan-containing N-halamines were found to inhibit the growth of bacteria and yeasts, their activity was limited in moderate environments, hindering their widespread application. To widen and enhance their antibacterial activities, Ren’s

Figure 26. Preparation of N-halamines from (A) chitin, (B) chitosan, and (C) chitosan-3-glycidyl-5,5-dimethylhydantoin (GH).

group used a novel modification approach by combining chlorinated chitosan with hydantoin-bearing N-halamines.198,199 As seen in Figure 26C, they chemically bonded hydantoin rings onto chitosan and then used chlorination to produce N-halamines containing both chitosan and hydantoins, which were effective against bacteria. In addition to chitin and chitosan, starch can be the parent polysaccharide for preparing new N-halamines.200 In Moustafa’s work,200 as seen in Figure 27, new polysaccharides (27.3) were

Figure 27. Grafting reaction for polysaccharide-containing N-halamines in water-soluble starch.

prepared by grafting acrylonitrile onto starch (27.1), and then combining the result with bioactive heterocyclic rings. Chlorination using sodium hypochlorite yielded polysaccharide-containing N-halamines (27.4) with high disinfecting power against bacteria. With starch being used in the preparation of biocidal Nhalamines, its derivatives, such as β-cyclodextrin (β-CD), have also received increasing attention for their use in antibacterial applications, due to their hydrophilicity, nontoxicity, and biodegradability.201 Ren’s group201 synthesized antimicrobial P


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nanofibers by electrospinning β-CD-based N-halamine copolymers mixed with cellulose acetate (CA). In the N-halamine copolymers, β-CD improved the biocompatibility of the obtained materials because it has a large number of cavities in which to trap organic molecules resulting from dead bacteria and thus prevent environmental contamination; CA is a cellulose-derived polymer with many advantages, such as good mechanical properties, good hydrolytic stability, low toxicity, environmental friendliness, and relatively low cost. Importantly, CA can more easily than natural cellulose be electrospun into nanoscale fibers that yield antimicrobial functionality. 2.3. Combinations of Cyclic and Acyclic N-Halamines

To develop novel approaches for preparing antibacterial Nhalamines, some researchers have combined the structural characteristics of cyclic and acyclic N-halamines to jointly enhance the active N−X sites, forming new N-halamines with cyclic and acyclic structures (see Table 1). Ren et al.57 used the Bucherer-Bergs method to synthesize 3-(5′-methyl-5′hydantoinyl)acetanilide, which included an acyclic amide, a cyclic imide, and a cyclic amide in its structure, and loaded it onto electrospun polyacrylonitrile fibers. After exposure to household bleach, the as-prepared fibers showed powerful antibacterial activity. Similarly, Broughton’s group55 used the Bucherer-Bergs method in the synthesis of m-amino-phenyl hydantoin (m-APH). The m-APH, which included amine, amide, and imide groups in cyclic and acyclic forms, was immobilized on cotton fabric using poly(carboxylic acid) as a cross-linker. After a procedure related to chlorine bleaching, the final products had antibacterial activity. Another synthesis route for preparing N-halamines with a combined cyclic and acyclic structure features hydantoin acrylamide (HA) as an intermediate precursor, using N-(1,1dimethyl-3-oxobutyl)acrylamide as a starting agent via the Bucherer-Bergs method to form the final N-halamines.202−208 The amide moiety in the acrylamide structure and the amide and imide moieties in the hydantoin ring are more easily halogenated in comparison with the sterically hindered secondary amide. HA (28.1) can be copolymerized with many commercial monomers (see Figure 28), such as 3(trimethoxysilyl)propyl methacrylate (SL, 28.2),203 glycidyl methacrylate (GM, 28.8),204 2-acrylamido-2-methyl-1-propanesulfonic acid sodium (SA, 28.4),205 and trimethyl-2-methacryloxyethylammonium chloride (QM, 28.6);206 chlorination then generates cyclic/acyclic combined N-halamines. The resulting products of these combined N-halamines have been used as antimicrobial additives in various fields, such as water disinfection, textiles, and paints. Generally, the approaches to prepare the combined cyclic and acyclic N-halamines are very few, owing to the limited strategies to obtain the cyclic and acyclic structure only from hydantoin group and amide (or chitosan) group, respectively, while it is diverse to synthesize cyclic N-halamines and acyclic N-halamines. Compared with the cyclic N-halamines and acyclic N-halamines, the combined cyclic and acyclic Nhalamines can offer much more N−X sites to promote their antibacterial activities, although they had complicated synthesis routes and high material cost. So more simple and efficient methods should be proposed in the development of the combined cyclic and acyclic N-halamines in the future research. Besides, four acyclic N-halamines (i.e., MCA, DCA, TCA, and amino acid containing N-halamines) can importantly

Figure 28. Copolymerization of hydantoin acrylamide (HA) with (A) 3-(trimethoxysilyl)propyl methacrylate (SL), (B) 2-acrylamido-2methyl-1-propanesulfonic acid sodium (SA), (C) trimethyl-2-methacryloxyethylammonium chloride (QM), and (D) glycidyl methacrylate (GM), respectively.

produce their antibacterial effect in the field of disinfection. In comparison with other halogenating agents (e.g., NCS, tBuOCl, NCNMPT, etc.), sodium hypochlorite have been more popular halogenating agents to prepare most of acyclic N-halamines so far. Typically, polymeric amide N-halamines could be obtained facilely by polymerization followed with halogenation at the assist of sodium hypochlorite as a halogenating agent, but the popularization of these N-halamines was limited owing to their serious instability toward some factors, such as water, light, and temperature. Similar to the polymeric amide N-halamines, the polysaccharide-containing N-halamines, especially the chitosanbased N-halamines, could be prepared by a sodium hypochlorite-assisted halogenation of polysaccharides. However, considering that most of the acyclic N-halamines often presented a short lifetime during their experimental preparation, more and more researchers put their emphasis on the preparation and synthesis of more stable cyclic N-halamines, using some effective precursors (e.g., hydantoin, imidazolidinones, or 1,3,8-triazaspiro[4.5]-decane-2,4-diones). In the synthesis of cyclic N-halamines, the important target is to obtain amine/amide/imide-containing precursors in the final Q


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3.1.1. Specific Methods. Specific methods for analyzing the structure of inorganic N-halamines function in terms of the materials’ physicochemical properties. A popular method for characterizing all inorganic N-halamines is reverse-phase highperformance liquid chromatography (HPLC) on a C18 phase column with a water/acetonitrile (or water/methanol) eluting gradient. In the HPLC analysis of inorganic N-halamines, the detection system is divided into three types: (i) without chemical derivatization, (ii) with precolumn chemical derivatization, and (iii) with postcolumn chemical derivatization. At the first type, detection is carried out primarily by using a UV absorbance detector or an electrochemical detector. A sample of an inorganic N-halamine can be identified with UV photometry based on the strongest absorbance at 244 nm for MCA, at 210 nm for DCA, and at 221 nm for TCA. Electrochemical detection is related to the pH value of the solution and nature of the electrodes.209 In a comparison of UV absorbance detection and electrochemical detection, Ge et al.209 demonstrated that the latter is more sensitive, especially for DCA. However, despite its low specificity, UV absorbance detection has been used with the HPLC method to study the evolution of MCA concentration in the presence of organic Nhalamines.174 A second type of HPLC uses a precolumn chemical derivatizing agent to determine the structure of inorganic Nhalamines. Scully and Bempong210 developed sodium benzenesulfinate (PhSO2−, Na+) as a precolumn derivatizing agent. They also used 5-dimethylaminonaphtalene-1-sulfonic acid (or dansyl sulfinic acid, DANSO2H) to derivatize N-halamines prior to HPLC analysis.211 The derivatized products were fluorescent, suggesting that a fluorescence detector might give this method high selectivity and sensitivity. Interestingly, 5dimethylaminonaphtalene-1-sulfonic acid and DANSO2H can capture both MCA and DCA, whereas many other derivatizing agents are useful only for MCA. Carlson’s group212 used 2mercapto-benzothiazole (2-MBTZ) as a precolumn derivatizing agent, and the products were easily analyzed by either UV photometric detection or electrochemical detection. Unlike these two types of HPLC, the third type, which uses postcolumn chemical derivatization, is almost unaffected by interference from organic N-halamines. The main advantages of this approach are the sample preparation method and the rapid automated analysis that yields structural identification. To date, potassium iodide is the only postcolumn derivatizing agent used to identify inorganic N-halamines; the resulting triiodide ions (I3−) are captured by a UV spectrophotometric detector or an electrochemical detector (see Figure 29).213,221 Gas chromatography (GC) has also been reported as a specific method for characterizing inorganic N-halamines. Kosaka et al.214 used a headspace GC (HS-GC) method to analyze TCA in drinking water with the help of quadrupole mass spectrometry (MS) detection. This method has the advantages of injection automation, good specificity, and high sensitivity. HS-GC/MS analysis is more suitable for DCA than HS-GC. Interestingly, unlike DCA and TCA, MCA is too polar to be directly analyzed using GC. Instead, MCA has to be transformed into volatile derivatives via a two-step chemical derivatization: (i) MCA derivatization into indophenol, then (ii) silylation or acetylation of the indophenol. GC analysis of the derivatized indophenol can be performed using a capillary column with an apolar/weakly polar stationary phase and a MS detector. Both Clark’s group215 and Jü ttner’s group216 confirmed the chemical derivatization of MCA for GC analysis.

preparation of cyclic N-halamines rather than to build a subsequent halogenation. Interestingly, all the precursors above have been available on the market so that the important target of synthesis is changed as the achievement of polymeric cyclic N-halamines. Particularly, in the exploration of N-halamines for water treatment or textile production, some physical and/ chemical routes started to graft polymeric cyclic N-halamines onto cotton or synthetic fabrics (e.g., polyester, nylon, and polypropylene) to render them antimicrobial properties.

3. IDENTIFICATION OF N−X BOND 3.1. Within Inorganic N-Halamines

Although many analytical methods have been used to characterize the structure of inorganic N-halamines, these methods are difficult and have less than desirable sensitivity and specificity.49 Table 2 presents some typical analytical methods for identifying inorganic N-halamines in aqueous matrices.209−236 To date, the analytical methods can be classified mainly into two categories: (i) specific and (ii) semispecific or nonspecific. We will examine these in more detail. Table 2. Typical Analytical Methods to Identify Inorganic NHalamines in Aqueous Matricesa no.

analytes

analysis method

ref

1

MCA, DCA, and TCA MCA, DCA, and TCA MCA and DCA

drinking water

HPLC

209

water

211

MCA, DCA, and TCA DCA and TCA MCA MCA MCA, DCA, and TCA MCA MCA

municipal wastewaters

SECamperometry SECamperometry HPLC− photometry HS-GC GC/MS GC/MS MIMS

218 219

MCA, DCA, and TCA MCA, DCA, and TCA MCA MCA

drinking waters

MIMS HPLC− fluorimetry HPLC− amperometry HPLC− photometry GC-MS HPLCPhotometry colorimetry colorimetry HPLC− fluorimetry colorimetry colorimetry colorimetry colorimetry colorimetry colorimetry

2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

MCA MCA MCA, DCA, and TCA MCA MCA MCA MCA MCA MCA

matrices

water

drinking waters sea water freshwater lakes waters waters water

waters sea water wastewaters river waters waters waters from treatment plants drinking waters natural waters river waters river waters sea waters river waters

212 213 214 215 216 217

220 221 222 223 227 228 230 231 232 233 234 235 236

a

Reproduced with permission from ref 49. Copyright 2012 Elsevier. MCA = NH2Cl; DCA = NHCl2; TCA = NCl3; HPLC = highperformance liquid chromatography; SEC = size-exclusion chromatography; HS-GC = head space gas chromatography; GC/MS = gas chromatography/mass spectrometry; and MIMS = membrane introduction mass spectrometry. R


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Figure 29. Liquid chromatograph/postcolumn electrochemical detection system. Reproduced with permission from ref 221. Copyright 2008 Preston Publ Inc.

3.1.2. Semispecific and Nonspecific Methods. In contrast to specific methods, semispecific and nonspecific methods are not exclusive to inorganic N-halamines. They include the colorimetric, titrimetric, and flow-injection methods. In the identification of inorganic N-halamines, the colorimetric method is generally performed by the aid of redox reactions. N,N-Diethyl-p-phenylenediamine (DPD)224,225 is the most popular oxidizing reagent for characterizing inorganic Nhalamines, which oxidize iodide to iodine and then turn red when reacting with DPD. However, organic N-halamines can interfere by competing in the reaction with iodide because both organic and inorganic N-halamines can simultaneously react with iodide in the colorimetric method. A chemical derivatization reaction226 has been developed for use with the colorimetric method, to analyze inorganic N-halamines. Harp’s group227 and Tao’s group228 reported that MCA reacted with phenol in the presence of nitroferricyanide to form benzoquinone monoamine, which reacted with the excess phenol to produce indophenol, yielding a blue color. Unlike with the DPD colorimetric method, there was almost no interference from organic N-halamine or inorganic chlorine species. However, the high LOQs of this method may make it unsuitable for identifying trace levels of inorganic N-halamines. The titrimetric method can be used to identify inorganic Nhalamines. DPD is the color indicator and ammonium sulfate with ferrous iron (ASF) the reacting reagent. This approach is very good for differentiating MCA, DCA, and TCA. However, in most cases, it presents the same advantages and drawbacks as the colorimetric method. Compared to the titrimetry, colorimetry can be realized via flow-injection analysis (FIA) or continuous-flow analysis (CFA); these are considered variations of the colorimetric method because some of the same reagents are used (e.g., DPD). Saad’s group229 used a photometric detector during flow-injection analysis to identify inorganic N-halamines (see Figure 31), while Carlsson et al.230 developed a miniaturized continuous-flow method for analyzing inorganic N-halamines. Both studies showed that the flowinjection method is rapid, automatic, adaptable to in situ analysis, and economical.

The combination of MCA-specific derivatization and GC/MS analysis not only minimizes matrix interference but also increases sensitivity. However, this method suffers from the risk of sample contamination and/or MCA loss and is relatively complex and time-consuming, so it is not practical for the routine analysis of inorganic N-halamines. In addition to HPLC and GC, membrane introduction mass spectrometry (MIMS) (see Figure 30) has been used as a

Figure 30. Schematic representation of the membrane introduction mass spectrometry (MIMS) system. Reproduced from ref 217. Copyright 1999 American Chemical Society.

specific method for identifying inorganic N-halamines. Semipermeable membranes are introduced into a MS system. These membranes have a porous structure and are hydrophobic, facilitating the transport of nonpolar and moderately polar compounds in water and preventing interference from the matrix and water. The membranes allow the extraction and introduction of the sampled inorganic N-halamines into the MS with the aid of carrier gas. During the procedure, inorganic Nhalamines are usually ionized and detected using a quadrupole mass analyzer.217,218 Shang and Blatchley217 confirmed that the MIMS method is quick, easy, and offers relatively high limits of quantitation (LOQs) for inorganic N-halamines. MIMS is thus viewed as a very promising method, since it allows the characterization of inorganic N-halamines without prior sample treatment. S


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NCl + 2I− + H+ → NH + I 2 + Cl−

(11)

I 2 + 2S2 O32 − → 2I− + S4 O6 2 −

(12)

In a typical procedure, a N-halamine sample was added into acidic solution containing potassium iodide and starch. The iodide ions can be oxidized by N-halamine and then iodine was released to generate a chromogenic reaction in starch solution, resulting in the appearance of blue color in the solution (Figure 32A).237,238 When sodium thiosulfate was used as a titrant, the

Figure 31. Flow-injection analysis manifold for the determination of inorganic N-halamines. Reproduced with permission from ref 229. Copyright 2005 Elsevier.

For three analytical methods (i.e., specific, semispecific, and nonspecific methods) to identify inorganic N-halamines, it has been evidenced that different from two other methods such as semispecific method and nonspecific method, specific methods can effectively distinguish inorganic N-halamines from organic N-halamines, by preventing the interference from organic Nhalamines. Although some possible chemical derivatizations can be combined into the semispecific and/or nonspecific methods and to some extent enhance the specificity of inorganic Nhalamines during identification, the complication of derivatization reactions, as well as the high LOQs, can result in a big difficulty to trace levels of inorganic N-halamines. Moreover, different from some specific methods such as HPLC, GC, and MS, both semispecific and nonspecific methods are generally carried out at the assist of chemical reactions related to oxidative properties of inorganic N-halamines, while those specific methods tend to focus the specificity toward MCA, DCA, or TCA.

Figure 32. (A) The oxidation−reduction reactions (A−1 and A−2) and color changes during iodometric/thiosulfate titration (from A−3 to A−6). (B) Chemical characterization of N-halamines using 5,5′dithiobis(2-nitrobenzoic acid) (TNB).

iodine was exhausted with thiosulfate to achieve the color fading at the end point. The presence of N-halamines can be verified based on the resulting color evolution. In addition to qualitative identification, the oxidative chlorine content of organic N-halamines can be quantitatively analyzed using idometric/thiosulfate titration.239 Badrossamay and Sun239 demonstrated how to calculate the content of active chlorine in N-halamines using the following equation (eq 13):

3.2. Within Organic N-Halamines

Organic N-halamines account for the majority of N-halamines and exist mainly in polymeric forms. As is well-known, the N− X bond in organic N-halamines can be detected by chemical and/or physical methods. 3.2.1. Chemical Methods. As seen in Table 3, the N−X bond of organic N-halamines can be identified via various oxidation−reduction reactions related to different chemical methods, such as idometric/thiosulfate titration,237−240 thiol oxidation, 241−243 5-thio-2-nitrobenzoic acid-assisted approach,244 3,3′,5,5′-tetramethylbenzidine-assisted test, dihydrorhodamine-assisted test, or sodium hypochlorite-assisted test,245,246 and the chemical derivatization method.247 Idometric/thiosulfate titration is to date the most popular chemical method for identifying organic N-halamines.237,238 It primarily involves two oxidation−reduction reactions (eq 11 and eq 12, see Table 3).

active chlorine (ppm) = 35.45 × (V1 − V2) × N × 1000/2 × W

(13)

where V1 and V2 are the volume (mL) of the iodine solution consumed in titrations of blank sodium thiosulfate solution and the volume of the N-halamine, N is the normality of the iodine solution, and W is the weight (g) of the N-halamine. Ma et al.240 calculated the chlorine load of N-halamines using an alternative equation (eq 14):

Table 3. Typical Chemical Methods to Identify Organic N-Halaminesa chemical method

chemical reaction(s)

idometric/thiosulfate titration

N−Cl + 2I− + H+ → N−H + I2 + Cl− I2 + 2S2O32− → 2I− + S4O62− N−Cl + − CH2SCH3 + H2O → N−H + − CH2S(O)CH3 + Cl− + H+ N−Cl + 2TNB → N−H + DTNB + Cl− + H+ − − − R2N−Cl + Ph-SO2− → Ph-SO2NR2 + Cl−

thiol oxidation method TNB-assisted approach TMB-assisted method dihydrohodamine-assisted test sodium hypochlorite-assisted test chemical derivatization method a

qualitative analysis

quantitative analysis

√

√

237−240

√

×

241−243

√ √ √ √

× √ √ ×

243 and 244 245 245 246

√

×

210, 211, 219, and 247

ref

“√” = suitable and “×” = unsuitable. T


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carried out. Similar to the TMB-assisted test, a dihydrorhodamine-assisted test can be used in the qualitative and/or quantitative analysis of N-halamines. Specifically, a N-halamine sample was directly added into dihydrorhodamine in phosphate buffered saline (PBS) containing iodide, and then the dihydrorhodamine was oxidized to a fluorescent rhodamine. With the aid of λex 500 nm and λem 536 nm, the fluorescence of the formed rhodamine can be obtained to calculate the contents of N-halamines. An advantage of the TMB and/or dihydrorhodamine assay is that it can produce a signal rather than quenching, resulting in better sensitivity and accuracy for identification. In addition, the TMB and dihydrorhodamine assays are much easier than the TNB method because they use a microtiter plate format. Sodium hypochlorite assisted test has also been used to qualitatively distinguish organic N-halamines (see Table 3). According to the Van Urk’s test in Stoward’s report,246 a solution of N-halamines, such as chloamine T, can turn from green into yellow and red when mixed with a solution of resorcinol. However, a sodium hypochlorite solution turns purple when mixed with resorcinol solution and brown when it comes in contact with manganous chloride solution; organic Nhalamines do not. Sodium hypochlorite is being used to develop effective tests for distinguishing organic N-halamines. In the case of some organic N-halamines, such as Nchloropiperidine, N-chlorodiethylamine, and N-chlorodimethylamine, there is currently no special method for identifying them because no technique is suitable to isolate them. Usually, their chemical derivatization must be accomplished in an alternative way (see Table 3). In a typical chemical derivatization, sodium salts of arenesulfinic acids can act as derivatizing agents to react with organic N-halamines.210,211 For example, organic Nhalamines react rapidly with sodium benzenesulfinate or sodium toluenesulfinate to form arenesulfonamides (see eq 17, see Table 3).

(14)

where Cl+ (%) is the weight percent of oxidative chlorine in the samples, N and V are the normality (equiv/L) and volume (L), respectively, of the titrant sodium thiosulfate, and W is the weight (g) of the samples. Thiol oxidation is a favorable pathway for the qualitative identification of N-halamines. The reaction (eq 15) of methionine (HOOCCH(NH2)CH2CH2SCH3) with N-halamine241,242 is a typical example (see Table 3). NCl + −CH 2SCH3 + H 2O → NH + −CH 2S(O)CH3 + Cl− + H+

(15)

Specifically, methionine and N-halamines were mixed and reacted in a phosphate buffer system or a Tris-HCl buffer system because the use of methionine can result in the convertion of methionine into methionine sulfoxide, as well as the loss of active halogen from N-halamines. With respect to this transformation of methionine into methionine sulfoxide, Peskin and Winterbourn243 proposed an acid-catalyzed mechanism in which the transfer of positive chlorine to sulfur is promoted by the hydrogen ions so that the reaction rate increases with decreasing pH. This reaction between methionine and N-halamine has been recognized as a qualitative method to effectively identify N-halamines, while few reports were related to the methionine oxidation in the quantitative identification of N-halamines. The presence of N-halamines can also be detected qualitatively via a reaction (eq 16) related to 5-thio-2nitrobenzoic acid (TNB) (see Table 3).244 NCl + 2TNB → NH + DTNB + Cl− + H+

(16)

In a typical measurement, a N-halamine sample can be directly introduced into TNB solution, resulting in the formation of colorless 5,5′-dithiobis(2-nitrobenzoic acid) (DTNB) (see Figure 32B) due to the reaction between N-halamine and TNB. Importantly, this reaction can be justified using UV/ visible absorbance measurements. At 412 nm, the absorbance peak of TNB clearly decreases as the reaction proceeds, while the peak of DTNB increases at 324 nm. In a systematic study of the reaction between TNB and several amino acid containing N-halamines, Peskin and Winterbourn243 demonstrated that these N-halamines showed increasing reactivity with TNB in the order: taurine < glycine < N-acetyl-lysine. What is more, their study showed that N-halamines are less reactive with TNB than hypochlorous acid, but N-halamines can react preferentially with thiols. Also, Debiemme-Chouvy’s group244 confirmed that the quantification of N-halamines using TNB is impossible not only because TNB solution is not stable but also because it is very hard to determine the reaction end point of N-halamines at the assistant of TNB. To find a better method than the TNB-assisted approach, Dypbukt et al.245 developed a sensitive and selective assay for the qualitative detection of N-halamines using iodide to catalyze the oxidation reaction of either 3,3′,5,5′-tetramethylbenzidine (TMB) or dihydrorhodamine (see Table 3). In a typical TMBassisted test, a N-halamine sample was introduced into a mixture solution containing TMB, sodium iodide, and acetate buffer. After a certain period, TMB can be oxidized by Nhalamines to form a blue product that can strongly absorb visible light. By recording the absorbance of this blue product at 650 nm, the quantitative analysis of N-halamines could be

R 2NCl + PhSO2− → PhSO2 NR 2 + Cl−

(17)

Using different organic N-halamines prepared from different precursors, including primary and secondary aliphatic amines, aromatic amines, and amino acids, Scully’s group247 verified this reaction via different physicochemical methods. Later, the same group211 converted some organic N-halamines to highly fluorescent dansyl derivatives by reacting them with 5(dimethylamino)naphthalene-1-sulfinic acid (DANASO2H). Using an HPLC technique, mixtures of the obtained derivatized products were completely separated and systematically analyzed. Building upon that prior work, Jersey et al.219 examined the derivatization mechanism of organic N-halamines. They reported the potential limitations of the derivatization of organic N-halamines with dansylsulfinic acid due to a matrix effect, low yields at dilute concentrations of the N-halamines, and a marked dependence of yield upon the composition of the N-halamines. These restrictions make the dansylation method unsuitable for the quantitative detection of organic Nhalamines, but it can be used for their qualitative identification. 3.2.2. Physical Techniques. As has been widely reported, the identification of organic N-halamines is generally accomplished with the aid of physical techniques such as Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance spectroscopy (NMR), X-ray photoelectron spectroscopy (XPS), energy-dispersive X-ray spectroscopy (EDX), UV−vis spectroscopy (UV), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), zeta U


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Figure 33. FTIR spectra of 5,5-dimethylhydantoin (DMH), 1-bromododecane (BD), 3-dodecyl-5,5-dimethylhydantoin (DDMH), and 1-chloro-3dodecyl-5,5-dimethylhydantoin (Cl-DDMH). Reproduced from ref 59. Copyright 2006 American Chemical Society.

Figure 34. 1H NMR spectra of 1-bromododecane (BD), 5,5-dimethylhydantoin (DMH), 3-dodecyl-5,5-dimethylhydantoin (DDMH), and 1-chloro3-dodecyl-5,5-dimethylhydantoin (Cl-DDMH). Reproduced from ref 59. Copyright 2006 American Chemical Society.

potential analysis, contact angle measurement, X-ray diffraction (XRD), scanning electron microscopy (SEM), atomic force microscopy (AFM), gel permeation chromatography (GPC), liquid chromatography (LC), and mass spectrometry (MS). Usually, FTIR is considered an indispensable technique for identifying organic N-halamines. FTIR spectra are used to

differentiate the transformation of a N−H bond to a N−Cl bond, using the various signals of the organic N-halamines and their corresponding precursors. Three signals in the FTIR spectra59,248−260 are involved: the disappearance of the N−H peak, the appearance of the N−Cl peak, and a shift in the C O peak. A key criterion is that the N−H peak always disappears V


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Figure 35. (A) XPS survey spectrum, (B) Br 3d spectrum, and (C) Cl 2p spectrum from N-halamine-modified SnO2 film. Reproduced with permission from ref 262. Copyright 2011 Elsevier.

substitutions at position 3 on 1-chloro-5,5-dimethylhydantoin. The signal of the amide proton at position 1 on the hydantoin ring disappeared (see Figure 34). 1H NMR spectra have also been used to identify other organic N-halamines.112,118 For example, Luo et al.112 reported characterizing 4-piperidinolcontaining N-halamines. In the resulting 1H NMR spectra, the amino protons yielded a broad peak at 0.67 ppm, which disappeared after bleach treatment because the N−H group was transformed into N−Cl. When Sun et al.117 reported using 13C NMR to identify 4-piperidinol-containing N-halamines, they also found a peak shift from ∼51.5 to ∼62.9 ppm after chlorination, which they attributed to the replacement of the N−H structure with the N−Cl group because the latter has a stronger electron-withdrawing effect on the neighboring carbon. Interestingly, their results from 13C NMR were the same as those they obtained using 1H NMR and FTIR. XPS is an analytical technique drawing upon elemental and/ or chemical analysis to gain detailed information about the chemical composition at the surfaces of organic N-halamines. In addition to the two main signals from C 1s and O 1s, XPS scans of N-halamines also contain peaks for N 1s at about 400 eV and Cl 2p at about 200 eV (or Br 3d at about 66 eV), corresponding to the N−X group (X = Cl or Br), whose appearance is the most reliable evidence for the formation of organic N-halamines (see Figure 35, panels A− C).69,108,157,194,261−265 When checking for the N−X group, the Cl 2p (or Br 3d) signal is regarded as the main feature of interest in the XPS analysis of organic N-halamines. Jie et al.264 detected N 1s and Cl 2p in the XPS spectra of antibacterial polymeric resins, suggesting the presence of the N−X bond, while Jiang et al.265 used the appearance of Cl 2p at 198.7 eV to prove the conversion of N−H to N−Cl. To further determine actual bindings, N 1s and Cl 2p signals can be curve-fitted into

when the characteristic N−Cl peak appears, due to the transformation of N−H to N−Cl. On the basis of the signals in the FTIR spectra presented in Figure 33, Sun’s group59 confirmed the transformation of 1-chloro-3-dodecyl-5,5-dimethylhydantoin (Cl-DDMH) from 3-dodecyl-5,5-dimethylhydantoin (DDMH). In the DDMH spectrum, a broad peak around 3280 cm−1 can be assigned to N−H stretching vibrations; these disappeared in the spectrum of Cl-DDMH, while two new bonds appeared at 758 and 735 cm−1, providing evidence of the N−Cl bonds. As noted above, a shift in the C O peak is another significant piece of evidence, assignable to the breakage of N−H and CO hydrogen bonding during the transformation of N−H to N−Cl. The same group59 showed that the two peaks of the CO bond shifted from 1782 and 1707 cm−1 in DDMH to 1794 and 1728 cm−1 in Cl-DDMH. In addition to identifying small N-halamine-based organic molecules, FTIR can be used to examine some of the Nhalamine-based polymers, such as cyclic N-halamines and acyclic N-halamines.254,256 For example, Dong et al.254 confirmed the presence of hydantoin-containing N-halamines on the surface of magnetic silica nanoparticles by analyzing the characteristic N−Cl bond at 760 cm−1 in their FTIR spectra. Luo and Sun256 also used FTIR to differentiate chlorinated polymethacrylamides (PMAA) on polypropylene tubing from their precursor. NMR spectra can also be employed to identify the chemical structure of organic N-halamines. 1H NMR is regarded as an effective route for proving the presence of N−Cl derived from N−H, by displaying the N−H proton signal.59,61,79,112,117,118,253,258 In particular, 1H NMR can yield signals identifying hydantoin-containing N-halamines.59,61,79,253,258 Sun’s group59,61 used 1H NMR to characterize several organic N-halamines with different W


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several peak components, including N+, > N−, N−H, N−Cl, Cl−N, and Cl−.69,264 The weakest N−H and strongest N−Cl signals are very desirable for identifying organic N-halamines, as Liang’s group showed.69,264 They exploited the curve fitting of the N 1s and Cl 2p peaks and characterized several quaternarized N-halamines. However, it should be noted that Cl 2s is not as obvious as Cl 2p; the former commonly appears as a rather weak signal, acting as an alternative marker for the N−Cl group. Sometimes, a Cl 2s signal at 271.4 eV can be detected.108,157,194,263 To effectively analyze the N−X bond of organic Nhalamines, EDX has become an important tool because it can yield elemental characterization. On the basis of the elemental composition of N-halamines,253,262,266 the existence of a N peak and a Cl peak (or a Br peak) in EDX spectra is thought to prove the generation of N-halamines. Debiemme-Chouvy et al.262 checked the elemental signals of N, Cl, and Br in the EDX spectra of a SnO2 film, and then inferred the factual presence of N-halamines on the film’s surface after the SnO2 was modified with N-halamines (Figure 36). Besides its use in qualitative

Due to a lack of hydrogen bonding, organic N-halamines have lower melting points and endothermal points than their unhalogenated precursors, so two thermal analysis methods, TGA and DSC, have been used to verify the transformation of N−H to N−Cl in terms of those substances’ melting and/or edothermal points.57,59,118,147,183,201,253,260 Sun’s group59 tested an unchlorinated sample to characterize 1-chloro-3-alkyl-5,5dimethylhydantoins; they were found to have a sharp melting peak at 76.1 °C, whereas after chlorination, they presented a decreasing melting point, ending at 52.4 °C. An intensive exothermic peak was observed at 176.0 °C due to the decomposition of N−Cl bonds. These results confirm the effectiveness of TGA and DSC for analyzing the thermal behavior of organic N-halamines. Luo and Sun147 found that acyclic N-halamines grafted onto fabrics presented an exothermic peak at 171 °C, but the same peak was not detected for unchlorinated fabrics that resulted in the formation of acyclic N-halamines. Significantly, when Tan and Obendorf253 used DSC to conduct a quantitative analysis, they evaluated the loading of their organic N-halamines on the basis of the thermal properties of nylon-6. They discovered that increasing the loading of organic N-halamines on nylon-6 caused a downward shift in the melting point, suggesting that the thermal stability was inversely proportional to the Nhalamine content. The zeta potential method is not regularly used to identify organic N-halamines, but it can support other methods and confirm identification tests. Liang’s group69,159,264 used the zeta potential technique to characterize organic N-halamines by combining it with other chemical/physical techniques, such as idometric/thiosulfate titration, FTIR, and XPS. Water contact angle measurement can also be used to analyze hydrophilicity and has been employed as an adjunct approach to effectively identify organic N-halamines.113,162,163,252 Other methods, such as XRD, 7 4 , 1 1 9 , 1 7 6 , 2 0 1 , 2 5 3 , 2 5 7 SEM, 6 1 , 1 2 9 , 2 0 1 , 2 5 1 , 2 5 8 , 2 6 2 AFM,162,163,258 GPC,114 LC,268,269 and MS,270 can be used as auxiliary characterization tools to confirm the formation of Nhalamines. When physical methods are compared with chemical methods in the identification of N−X bond(s) for organic Nhalamines, it is obvious that researchers would like to use physical methods rather than chemical methods because the physical methods can provide more detailed information about N-halamines, such as chemical component, molecular structure, morphology, and size. However, the physical methods require the expensive and precise instruments, while the chemical methods may be accomplished in a low-cost manner related to oxidation−reduction reactions. On the basis of the qualitative and quantitative analysis explored for identifying organic Nhalamines, the qualitative methods seem much better than the quantitative methods because N-halamines are active and sensitive, resulting in their instability under certain circustance such as water, light, temperature, or microorganisms. Interestingly, the quantitation of N-halamines could be attained by using a combination of physical and/or chemical method(s). Typically, the idometric/thiosulfate titration has been a most effective method in the quantitative analysis of organic Nhalamines due to some significant advantages such as costeffectiveness, convenience, easy and fast operation, and high repeatability. Sometimes, the idometric/thiosulfate titration can be combined with several physical methods (e.g., FTIR, NMR, XPS, etc.) to present both qualitative and quantitative data in the identification of organic N-halamines.

Figure 36. EDX spectra of SnO2 films (A) before and (B) after modification with N-halamines. Reproduced with permission from ref 262. Copyright 2011 Elsevier.

identification, EDX analysis can also be employed to quantify organic N-halamine content based on elemental intensity. For example, Tan and Obendorf253 used Cl intensity in their EDX spectra as an indicator to determine the relative concentration of N-halamine on the surfaces of polyurethane membranes. They also used changes in the peak intensities of Cl to demonstrate the relative abundance and distribution of Nhalamines on the surfaces of nylon-6 membranes. Due to the broad absorption peak of the N−X bond within the UV region, UV−vis spectroscopy has also been developed to characterize organic N-halamines.59,61,92,117,138,193,267 Jensen and Helz267 used UV−vis absorptions to prove that the UV maximum absorption of N-chloropiperidine occurred at 262 nm and disappeared after dechlorination treatment. Worley’s group92 found the absorptions of hydantoin- and imidazolidinone-containing N-halamines to be around 270 and 287 nm, respectively. Sun’s group117 used UV−vis to verify the N−Cl bond in 4-piperidinol-containing N-halamines, at 282 nm. At the same time, they confirmed the maximum absorption of chitosan-based N-halamines to be around 320 nm, which was supported by Ifuku’s group.193 Haag’s group138 also used UV− vis to analyze dihalogenated N-halamines. They found that the synthesis of CH3NBrCl via the incremental addition of NaOBr to a CH3NHCl solution gave rise to peaks at 224 and 330 nm on the UV−vis spectra. X


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4. STABILITY OF N-HALAMINES The stability of N-halamines is strongly related to their antibacterial activity and has generated numerous theoretical and experimental studies. Their stability is significantly influenced by structure, heat, light, pH, water, chemicals, and bacteria. 4.1. Structure

Most structure analysis of N-halamines have focused on cyclic N-halamines, such as those containing hydantoin, imidazolidinone, or 1,3,8-triazaspiro[4.5]-decane-2,4-dione.271−279 Three N−Cl bonds, in amines, amides, and imides, are available in the use of cyclic N-halamines. Experimentally, the stability of the three bonds toward the release of free halogen58 has been shown to decrease in the order: amine > amide > imide. Interestingly, McKee’s group277 theoretically confirmed this order when they ran a conductor-like, polarizable continuum, aqueous solvation model with UAKS cavities at the level of B3LYP/6-31+G(d). They selected chlorinated 5,5-dimethylhydantoin (DMH) as a model N-halamine because it contains one amide N−Cl bond and one imide N−Cl bond, favoring their modeling and calculations. Their theoretical calculations found the imide N−Cl bond to be more labile than the amide one. They demonstrated that compared to the imide N−Cl bond, the amide N−Cl bond showed higher stability due to its stronger polarity, although the length of the imide N−Cl bond was shorter. Moreover, the imide N−Cl bond showed a more ionic character and more rapid dissociation by hydrolysis. Importantly, according to an analysis of Gibbs free energy,277 the computational method confirms that the formation of the amide N-halamines is more spontaneous and exothermic than the formation of the imide N-halamines, indicating that the stability of the imide N−Cl bond should be weaker than that of the amide N−Cl bond. The same research group277 compared the amine N−Cl bond and the amide N−Cl bond using chlorinated 2,2,5,5tetramethylimidazolidinone (TMIO) as a target N-halamine, since it possesses both bonds. Their theoretical calculations suggested that the amine N−Cl bound chlorine more strongly than the amide one, which agreed well with their experimental data. Their experiments also confirmed that the monohalogenation of TMIO transferred from a kinetically controlled product of an amide N-halamine to a thermodynamically controlled product of an amine N-halamine. To further investigate the stability issues of N-halamines, McKee’s group277 examined the effect of ring size on the stability of cyclic N-halamines by comparing chlorinated 7,7,9,9-tetramethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione (TTDD) with its five- or seven-membered ring analogs (Figure 37). Surprisingly, their calculations indicated an amine > imide > amide order for the stability of N-halamines. The steric effect of cyclic moieties at position 5 of the hydantoin ring can cause the amide N-halamine to be more labile than the imide Nhalamine; in addition, the change in ring size has no effect on the stability of the amine N-halamines. Interestingly, Kocer et al.271 used density functional theory (DFT) calculations at the restricted and unrestricted (U)B3LYP/6-311++G(2d,p) theory level to elucidate the mechanism for the stability of hydantoin-containing N-halamines toward UV light. To quantify the homolytic cleavage of the N− Cl bond, they computed the heats of formation (ΔfH°298) for radical Cl and N species, along with their corresponding bond dissociation enthalpies. The theoretical results matched their

Figure 37. Minimized structures at the B3LYP/6-31+G(d) level of A3, B3, and C3. Reproduced from ref 277. Copyright 2006 American Chemical Society.

experimental ones. The computations predicted that the Cl bound at the N1 position would be less stable than in systems where the Cl is bound to the alkyl chain substituted at the N3 position of hydantoin. This suggested that a large thermodynamic driving force was driving the rearrangements. According to Ren’s group,274 the bonds between N-halamine moieties and substrates, as well as N−X bonds, tend to decompose under UV light irradiation. To enhance their stabilities under this condition, titanium dioxide74,257 has been introduced as an effective additive into N-halamine systems; the results are presented in Table 4. Ren’s group274 further studied Table 4. Chlorine Stability of Cotton-PSPH-Cl without TiO2 and Cotton-TiO2/PSPH-Cl with TiO2, using UV Measurementa chlorine loading (wt %) time (h) 0 1 2 4 8 12 24 48 rechlorination (48 h)

cotton-PSPH-Cl 0.26 0.14 0.12 0.06 0.03 0.01 0.00 0.00 0.13

± ± ± ± ± ±

0.01 0.01 0.01 0.01 0.01 0.01

± 0.02

cotton-TiO2/PSPH-Cl 0.30 0.23 0.22 0.20 0.17 0.15 0.10 0.06 0.25

± ± ± ± ± ± ± ± ±

0.01 0.01 0.01 0.01 0.01 0.01 0.01 0.02 0.01

a

Reproduced from ref 74. Copyright 2014 American Chemical Society.

mechanisms for protecting the photolytic decomposition of a N-halamine siloxane. Their quantum mechanical calculations found that the addition of TiO2 would increase the activation barrier of the C−Si scission reaction, decreasing the loss of the biocidal hydantoin moiety and thus resulting in enhanced UV stability for N-halamines (see Figure 38). In addition to cyclic N-halamines, a few acyclic N-halamines have been successfully employed in structure analysis. Using two high-performance polymers (Kevlar and Nomex), Akdag et al.177 examined the decomposition of aramid-containing NY


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Figure 38. Calculated transition structure for the cleavage of a TiO2/ PSPH model system using UB3LYP/6-311++(2d,p). Distances given in angstroms. Reproduced from ref 274. Copyright 2016 American Chemical Society.

Figure 39. DSC curves for both 3-docosyl-5,5-dimethylhydantoin (DCSDMH) and 1-chloro-3-docosyl-5,5-dimethylhydantoin (ClDCSDMH). Reproduced from ref 59. Copyright 2006 American Chemical Society.

halamines in which two mimics of Kevlar and Nomex were synthesized to simulate the carboxylate and diaminophenylene components. They found that the p-diaminophenylene component of the Kevlar mimic was oxidized to a quinonetype structure after treatment with hypochlorous acid and then started to decompose, but this did not occur with the Nomex mimic. Their study indicated that based on the route using Kevlar to synthesize N-halamines, a similar Kevlar structure in aramid-containing N-halamines tended to decompose. Tarade and Vrček280 used theoretical computations to study the chlorination reactivity of alkyl-, cycloalkyl-, heterocyclic, and aromatic amines with hypochlorous acid. They employed density functional (B3LYP), double hybrid (B2PLYPD), and composite theoretical models (G3B3) to evaluate the steric, electronic, and solvent effects on the reactivity of different families of amines with hypochlorous acid to generate Nhalamines. Their theoretical results indicated that, in agreement with experiments, the heterocyclic amines have the highest reactivities, whereas the aromatic amines have relatively low reactivities.

Chylińska and Kaczmarek281 systematically studied the effect of thermal degradation on N-halamines. They demonstrated that the thermal degradation of hydantoin-containing Nhalamines followed a structure-dependent set of rules: (i) the total decomposition of N-halamines is generally preceded by breakage of the N−Cl bonds, suggesting that N-halamines undergo a more complex decomposition process than their precursors; (ii) the presence of aromatic rings can enhance the thermal stability of N-halamines; (iii) higher steric hindrances at position 5 in hydantoin rings can result in more stable Nhalamines; and (iv) polymeric N-halamines are more stable than low-molecular organic N-halamines. Also, according to Worley et al.,282 the stabilities of brominated N-halamines are much more affected by increasing temperature than their chlorinated analogs; they postulated that under that condition, the lability of the N−Br bond may be enhanced much more readily than that of the N−Cl bond. In general, the stability of N-halamines toward heat is an important factor related to their synthesis, structural identification, antibacterial properties, and applications. Studies of their melting points and exothermic processes indicate that the thermal properties of N-halamines may to some extent reflect their stability toward heat, and this often is a reliable guide to their synthesis procedures and practical applications.

4.2. Heat

The stability of N-halamines is dependent on temperature, as the N−Cl bond is very sensitive to temperature.57,115,157,167,207,251,258,260 Determining the thermal properties of N-halamines is important to check their stability in the presence of heat. To this end, two important points need to be reviewed and discussed. On the one hand, the N−Cl bonds of N-halamines have been regarded as more labile than their corresponding amine, amide, or imide-containing precursors because N-halamines lack intermolecular hydrogen bonding. Therefore, the introduction of chlorine atoms in the formation of N-halamines can reduce their thermal stability.120,129,136,183,189,193,201,253,265 N-Halamines synthesized in this way therefore always have lower melting points than their precursors. For example, Figure 39 shows that 1-chloro-3docosyl-5,5-dimethylhydantoin (Cl-DCSDMH) has a melting point of 52.4 °C,59 lower than that of 3-docosyl-5,5dimethylhydantoin (DCSDMH) (76.1 °C). This suggests that the melting point can become an effective indicator when comparing the thermal stability of N-halamines and their precursors. On the other hand, the appearance of an exothermic process can indicate the decomposition of the N−Cl bond.118,147 Most studies have reported that the N−Cl bond began to decompose below 200 °C, regardless of the type of N-halamine.61,79,111,117,155,168,176,194,198

4.3. Light

To date, it has been important to study the stability of Nhalamines under light, especially UV light, in practical applications. Upon exposure to UV light, N-halamines generally tend to decompose, whereas their unchlorinated precursors do not easily degrade. UV light might break the N−Cl bond.283−291 Worley’s investigation283 found that within 24 h of exposure to UV light, hydantoin-containing N-halamines almost completely lost their oxidative chlorine, but their unchlorinated counterparts showed no significant decomposition during 120 h of exposure, indicating that the presence of N−Cl functionality has an observable effect on the photodegradation process. Kocer’s group289 compared the stability of 4-piperidinol-containing N-halamines to their unchlorinated counterparts under UV irradiation. The unchlorinated samples were very stable, whereas the 4-piperidinol-containing Nhalamines lost all bound chlorine within 6 h. However, the lost chlorine could be recovered after exposure to an aqueous solution of sodium hypochlorite. Z


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Given the poor stability of N-halamines under UV light, Sandstrom and Sun273 started to design UV-resistant ones by varying their molecular structures. They postulated that an aromatic structure could absorb UV radiation and thus protect the N−Cl bond from dissociation. However, when they conducted their experiment in a weathering chamber under controlled conditions, a high degree of decomposition occurred and chlorine loss could not be prevented.273 The same phenomenon was observed by Worley’s group81 with hydantoin-based N-halamines bearing aromatic structures. Interestingly, Ren’s group134 synthesized novel N-halamine diol and epoxide and then coated them onto cotton. They found that the UV stability of the cotton coated with Nhalamine diol was significantly improved in comparison with the results from the cotton coated with N-halamine siloxanes. However, the chlorine on the coated cotton still decreased rapidly within the first hour of UV irradiation. The addition of proper UV absorbing substances to the N-halamine coatings improved the stability of the coated antimicrobial materials, suggesting an ideal way for extending the shelf life of Nhalamines. Notably, Ren et al.74,257,274 proved that titania in UV shielding can absorb UV light, thereby improving the stability of N-halamines. Ambient laboratory light stability has also been evaluated for its effect on antibacterial N-halamines. Kocer207 investigated the fluorescent light stability of hydantoin acrylamide-based Nhalamine copolymers by adding them into water-based latex paint. Under fluorescent lighting, the paints slowly lost their chlorine. However, they could be rechlorinated up to their initial loadings using halogenation treatment, and the rechlorinated paints offered the same antimicrobial activity as those not subjected to fluorescent light. To further study the ambient laboratory light stability of N-halamine, Ren et al.290 experimented with different N-halamine siloxanes bound to cotton. Unlike Kocer’s findings,207 they discovered that after decomposition under a laboratory light, the N−Cl bonds were not completely restored to their original loadings using a rechlorination treatment, due to the decomposition of siloxanes. Worley’s group124 also studied the decomposition of 1,3,5-triazinane-2,4-dione-containing N-halamine siloxanes under ambient light exposure. They found that after 28 days of exposure, the dissociation experienced by the N−Cl bonds was almost entirely reversed after rechlorination because the sixmembered rings have good stability under laboratory lighting. Generally, both UV and ambient photons can cause the dissociation of N−Cl, particularly the former because of their higher energy. Most of the dissociation process is related to a homolytic cleavage of N−Cl into radicals rather than a heterolytic cleavage of N−Cl into N− and Cl+, as the latter are unlikely to revert to the precursor N-halamine structures.

In addition to N−Cl breakage, the Hoffmann-Loeffler rearrangement (a type of intramolecular photolytic rearrangement) has been reported under UV light and can have a serious negative influence on the stability of N-halamines. Petterson et al.292 demonstrated the rearrangement of the chlorine atom on acyclic N-chlorimide or acyclic N-chloramide from the nitrogen atom onto the acyl chain under UV light. N-Halamides have three or more methylene units in their acyl/alkyl side chains, and these easily tend toward Hoffmann-Loeffler rearrangement under UV irradiation.292−294 The high selectivity for the halogenation of C-4 in the acyl chain requires that a 1,5hydrogen atom transfer intramolecularly from carbon to nitrogen, involving a six-membered transition state; 1,6 hydrogen transfer was observed in some cases, while 1,4 hydrogen transfer was demonstrated in both the N-alkyl and Nacyl chains of N-halamides containing fewer than three methylene units.295 Similar to acyclic N-chlorimide or acyclic N-chloramide, cyclic N-halamines are prone to intramolecular photolytic rearrangement. Kocer et al.272 investigated the UV stability of the N−Cl bond and the structures of decomposition products for N-halamine siloxanes (see Figure 40). The

Figure 40. (A) Photolytic rearrangements for 3-butyl-1-chlorohydantoins. (B) Proposed decomposition of an N-chlorohydantoinylsiloxane. Reproduced from ref 272. Copyright 2010 American Chemical Society.

decomposition mechanism of the chlorinated siloxane coatings was found to depend on the Hoffmann-Loeffler rearrangement, along with the cleavage of the alkyl group from the Si atom. This cleavage resulted in the loss of hydantoin units from the surface of the coated materials. Phenyl substitution at the 5 position of the hydantoin ring did not protect the siloxane coatings from UVA photodegradation. Kocer et al.272 reported the effect of UV light on halogen atoms that were bound to carbon atoms in alpha or beta positions with respect to a silicon atom. They found that with exposure to UVA light, the cleavage of the Si−C bond initiated the loss of the hydantoin units from the surface of the coated materials and consequently reduced the antimicrobial efficacy, as demonstrated in other literatures.296−300

4.4. pH

Usually, pH is considered an important factor in the synthesis of N-halamines. In addition, the stability of N-halamines strongly depends on the pH value of the surrounding medium.161,175,210,282,301−303 Worley and coauthors282,301 investigated the stabilities of several N-halamines in water at varying pH levels: 3-chloro-4,4-dimethyl-2-oxazolidinone (I), 3bromo-4,4-dimethyl-2-oxazolidinone (IB), 1,3-dichloro-4,4,5,5tetramethyl-2-imidazolidinone (A), 1,3-dibromo-4,4,5,5-tretramethyl-2-imidazolidinone (AB), 1-bromo-3-chloro-4,4,5,5-tetramethyl-2-imidazolidinone (ABC), and tetrachlorodimethylglycoluril (G) (see Figure 41). When sodium acetate, sodium AA


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Figure 41. Stabilities of different N-halamines in demand-free water at 22 °C as a function of pH: (A) pH 4.5, (B) pH 7.0, and (C) pH 9.5. Reproduced with permission from ref 282. Copyright 1987 Elsevier.

4.5. Water

phosphate, and borate-sodium hydroxide were used to make solutions with pH levels of 4.5, 7.0, and 9.5, respectively, the stabilities of these N-halamines were found to gradually decrease with increasing pH. Worley et al. believed that the N−Cl bond reacted with water to produce the N−H bond and a weak acid of HOCl under neutral or acidic conditions, while the reaction equilibrium could be driven toward the side of products such as N−H and HOCl under highly basic conditions. Elder et al.303 examined the effect of pH on the in situ synthesis and stability of N-halamines such as 3-chloro4,4-dimethyl-2-oxazolidinone. They confirmed that the rate of synthesis was the slowest at pH 4.5 and 5.0, intermediate at pH 5.5, and most rapid at pH 6.0, 6.5, and 7.0. Moreover, the stability of the N-halamines could be enhanced if acidic or neutral conditions were used during their synthesis. To further study the stability of N-halamines in different pH conditions, Scully and Bempong210 monitored the decomposition of two aqueous solutions of the organic N-halamines N-chloropiperidine (NCP) and N-chlorodiethtlamine (NCDEA). The NCP and NCDEA lived for 3.3 days and 2.2 days at pH 7.0, respectively, and their half-lives did not change from pH 3.5 to pH 9.0; but below 3.0, the stabilities of both dramatically increased. Their photodecomposition, however, followed a much different pH profile. The photodecomposition rate of NCDEA increased with decreasing pH value, suggesting that its stability fell. The main products of its photodecomposition reaction were ethylidene ethylamine and acetaldehyde. Antelo et al.302 investigated the effect of pH in the range of 6.55−12.01 on the stability of N-chlorodiethanolamine in water. In the presence of suitable boric acid/NaOH or boric acid/HCl buffers, the decomposition rate of Nchlorodiethanolamine increased with the pH value. In their analysis of the mechanism, they suggested that the decomposition of N-chlorodiethanolamine resulted primarily from its deprotonation rather than from its bimolecular reaction with OH−. Bastarrachea et al.161 confirmed the stability of Nhalamines to be pH-dependent. They used a layer-by-layer assembly route to prepare N-halamine-modified polyethylene and exposed it to a controlled pH value of 3, 5, or 7. Their results showed that the stability increased with decreasing pH.

The literature indicates that water is an important influence upon the stability of N-halamines.304−307 Via the hydrolysis process, N-halamines react with water to produce their precursor compound (i.e., amine, amide, or imide) and hypochlorous acid. The stability of N-halamines in water depends on their structures, which are often related to their dissociation constants in aqueous solution. The dissociation constants for various typical N-halamines are summarized in Table 5.237 This table indicates that the stabilities of various NTable 5. Dissociation Constant of Various N-Halamines in Aqueous Solutiona

a

Reproduced with permission from ref 237. Copyright 2014 Royal Society of Chemistry.

halamines in water follows this order according to the functional group: amine > amide > imide; conversely, their antibacterial capability was in the reverse order: amine < amide < imide. Clearly, amine N-halamines are more stable and have a slower kill rate than amide and imide N-halamines. Among these three types, the imide N-halamines offer the fastest kill rate and present the least stable structure, resulting in the most rapid loss of active chlorine. As is well-known, stability in water is quite important for N-halamines because this stability can effectively prevent the re-establishment of microbes. Hence, amide N-halamines containing amide N−X bonds should be the most practical candidates for antibacterial applications, since they seem to offer a reasonable compromise between stability and biocidal efficacy. Amide N-halamines can exhibit a AB


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3-Chloro-4,4-dimethyl-2-oxazolidinone was selected as a model N-halamine because it can have good stability in water due to two methyl substituents at the 4 position in the oxazolidinone ring. These electron-donating alkyl groups can destabilize the development of negative charges in nitrogen as Cl+ leaves the molecules, thereby improving the stability of the N−Cl bond. The “chlorine demand-free” water was buffered, sterilized, distilled, and deionized, while the WCW contained 375 mg/L of each of the following inorganic salts: calcium chloride, magnesium chloride, potassium chloride, and sodium chloride; it also contained 50 mg/L of bentonite clay, 30 mg/L of humic acid, 0.01% final concentration of heat-treated horse serum, and 5 × 105 cells/mL of heat-killed yeast cells. In contrast to the result in “chlorine demand-free” water, the total chlorine content of 3-chloro-4,4-dimethyl-2-oxazolidinone in the WCW had seriously decayed after 3 weeks. This suggests that the stability of N-halamines cannot be maintained for long in water with a heavy organic load. The stability of N-halamine-based antibacterial materials in water depends on two factors: the stability of N−X bonds in water and the stability of the covalent bonds between the Nhalamine moieties and the support materials.305−307 Typically, the washing stability of N-halamine-grafted cotton fabrics is related not only to the N−X bond stability but also to the covalent bond of the N-halamines moiety with cotton. According to the American Association of Textile Chemists and Colorists’ test method 61−1996,285,287 the washing stability of N-halamine-grafted cotton fabrics was investigated by measuring the active chlorine on the fabrics after repeated standard washing cycles. After each washing cycle, a small piece of fabric was used to determine its chlorine content, while other small pieces were used to measure its chlorine content after rechlorination. Interestingly, the active chlorine lost due to the departure of a whole N-halamine moiety from the cotton fabric could not be fully regained after a rechlorination treatment, although the decrease in active chlorine during the hydrolysis of the N−X bonds was easily reversed. In general, N-halamines grafted onto cotton (or other supports such as silica, synthetic polymers, cellulose, etc.) show excellent stability in water during wash cycling.

moderate rate of active chlorine transfer to the cells of microorganisms and provide sufficient biocidal activity. Certain important factors, such as functional group, substituent type, and solution concentration, may influence the dissociation rate of N-halamines in aqueous solution. For instance, a halogen atom bound to a secondary amide group of an N-halamine (e.g., N-tert-butylacrylamide) is more resistant to hydrolysis than one bound to the primary amide group (e.g., in acrylamide).304 Conversely, the halogenation of secondary amide groups results in a more difficult hydrolysis for Nhalamines than that of primary amide groups due to the former’s steric hindrance. When cyclic N-halamines and acyclic N-halamines were compared in terms of their ability to withstand hydrolysis of the N−X bond,304 the former seemed more stable due to their structural characteristics. In cyclic N-halamines, the electrondonating alkyl group is always substituted on the heterocyclic ring adjacent to the oxidative N-halamine moieties, hindering the hydrolysis reaction. Further, the N−X bonds in cyclic Nhalamines exist in a “crowded space” that can to some extent inhibit the release of active chlorine into water. In comparison, acyclic N-halamines seem more sensitive to hydrolysis because of their open structure, which makes it easy for water to attack the N−X bond. Sun et al.78,91 found that after continuous machine washings, the active chlorine of hydantoin- and imidazolidinone-containing N-halamines decreased slightly, whereas their antibacterial efficacies were almost unchanged. Even after 50 cycles of washing, their bactericidal ability remained unchanged (see Table 6), indicating that the Table 6. Relationship between Washing Times and Log Reduction for Halogenated Polymers Against E. coli after a Contact Time of 30 min (E. coli concentration = 106 to 107 CFU/mL)a log reduction of E. coli after repeated washing chlorinated polymer

0 wash

5 washes

15 washes

50 washes

PAN-co-ACTMIO PMMA-co-ACTMIO PVAC-co-ACTMIO grafted cottonc grafted PET grafted PP grafted nylon-66

1 2 3 6 6 6 6

NDb ND ND 6 6 6 6

ND ND ND 3 2 2 3

ND ND ND 3 1 2 3

4.6. Chemicals

Due to their significant oxidizing capacity, N-halamines are susceptible to certain reducing agents, including gaseous SO2, SO32−, and HSO3−.267,308−319 These chemicals can be used as dechlorination agents to remove residual N-halamines in water.267,318 Jensen and Helz267 systematically studied the reaction kinetics between N-chloropiperidine and sulfite (SO32−), in which chlorine was transferred from the Nhalamine to nucleophiles via an acid-catalyzed pathway related to the use of sulfite as a reducing agent. Subsequently, Crugeiras’s group310,311,313,317 confirmed the acid-catalyzed reaction of N-halamines in water, using a range of nucleophiles (SO 32− , HSO 3 − , Br −, I− , N 3− , SCN −, HOCH 2 CH 2 S − , HOCH2CH2SH, and HOCH2CH2SCH3). To systematically investigate the effect of reducing agents on the dechlorination of N-halamines, MacCrehan’s group318 compared the sulfite with other agents, such as ascorbic acid, iron metal, thiosulfate, and sulfite/iodide, by using three model N-halamines: N-Clpiperidine, N-Cl-AlaAla, and N-Cl-LeuAla. The dechlorination effectiveness was in the following order: iron metal ≫ sulfite/ iodide ≈ thiosulfate > sulfite ≫ ascorbic acid.

a

Reproduced with permission from ref 91. Copyright 2001 John Wiley and Sons. bND = no determination. cFor grafted cotton samples, the contact time was 10 min, a one-log reduction equals a 90% kill, and a six-log reduction is a 99.9999% kill.

significant stability of these two cyclic N-halamines should result from their stable structure. The same group115 also revealed that the chlorine content of 4-piperidinol-containing N-halamines, as well as the antibacterial efficacy, did not change after their storage at 25 °C and 30−90% relative humidity (RH) for more than 10 months. However, chitosan-bearing Nhalamines as examples of acyclic N-halamines have a slightly lower stability at 65% RH194 because their hydrophilic nature induces chitosan to absorb more moisture from the air and thus promotes the dissociation of N−X bonds. Interestingly, water quality was found to have an impact on the stability of N-halamines in water. For example, Worley et al.282,301 monitored the stability of N-halamines in “chlorine demand-free” water and synthetic “worst case water” (WCW). AC


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N-Halamines are susceptible to acids as well. Evans et al.314 found that under acidic conditions, an aqueous solution of Nhalamines formed nitrogen-centered radicals. In this process, the loss of a halogen atom resulted from the homolytic cleavage of N−X in a manner analogous to Hufman-Löffler radical formation in N-halamines, which can be catalyzed by Fe2+. The N-centered free radicals played an important role in the oxidizing property of N-halamines. This oxidizing property has been further validated by the oxidation of spin trap 5,5dimethyl-1-pyrroline-1-oxide (DMPO) into its paramagnetic derivative, which, via electron spin resonance (ESR) spectroscopy using the spin trapping method, can be used to investigate the radicals obtained from N-halamines. It has also been reported that in the presence of hydriodic acid, N-halamines tend to produce iodine, that is, N-halamines liberate iodine from an acidified solution of potassium iodide.237−240 With the assistance of starch, the iodine might induce a chromogenic reaction, resulting in a blue color. The oxidative chlorine content of N-halamines could then be quantified by exhausting the as-formed iodine in a thiosulfate solution. Many research groups have used a plasma system to investigate thiol oxidation with N-halamines.315,316 Hawkins’s group315,316 found that the addition of N-halamines to a plasma testing system led to a rapid loss of thiols, and that N-halamines reacted more readily with protein thiols than with other targets in the plasma. When they studied the ability of different Nhalamines to selectively oxidize thiol-containing plasma proteins, they found the plasma proteins were susceptible to thiol oxidation resulting from the N-halamines. Recently, the same group312 proved that N-halamines are more sensitive to selenium compounds than analogous sulfur compounds. Conversely, Peskin and Winterbourn243 demonstrated that compared to HOCl, N-halamines are less reactive oxidants. However, N-halamines can retain a preference for thiol groups, and this preference is selectively used for different cellular thiols. Recently, N-halamines have been used as antibacterial finishes for textile materials. Their stability against chemicals should be very important in determining their practical applications. Ren et al.122 grafted N-halamines onto cotton fabrics and tested their ability to oxidize chloroethyl ethyl sulfide. Their NMR spectroscopy results proved that after the oxidation test, the major product was chloroethyl ethyl sulfoxide, suggesting that N-halamines are effective in oxidizing sulfides to the sulfoxides. Also using N-halamine fabrics, Fei and Sun308 studied the oxidative degradation of organophosphorus pesticides such as methyl parathion, malathion, and chlorpyrifos. The reaction occurred at the thione group, and the final products were oxon compounds. At room temperature, the fabrics containing imide and amide N-halamines oxidized 90% of the methyl parathion in fewer than 2 h of contact time, while the amine N-halamines took longer to reach the same level of oxidation. On the basis of their findings, they suggested that Nhalamines could be employed in clothing materials that protect against certain organophosphorus pesticides. In a different direction, Liu’s group309 focused on different antibacterial dressings containing amide N-halamines to investigate their stability when subjected to ethylene oxide (EtO) sterilization. They demonstrated that N-halamines converted from polymethacrylamide (PMAA) had the highest stability against EtO sterilization, hydantoin-containing N-halamines followed, and poly(N-chloroacrylamide) had the lowest stability.

4.7. Bacteria

As the foregoing discussion has indicated, antibacterial action is an important property of N-halamines. Essentially, it is dependent on oxidative halogen transfer from N-halamines to bacterial cells.254 Similar to the halogen transfer described earlier, active halogen(s) can be transferred into water via the hydrolysis of N-halamines. Interestingly, Margel et al.304 demonstrated that in the presence of bacteria, oxidative halogen transfer takes place from N-halamines to bacteria rather than to water. Gao’s report320 made it clear that Nhalamines can revert to their precursor compound (i.e., amine, amide, or imide) after contact with bacteria. Typically, this is the case for hydantoin-containing N-halamines. The transformation of N−X to N−H can be detected in FTIR measurements because the N−H stretching vibrations of hydantoin rings reappear when those of the N−X bond disappear. Conversely, the transformation of N−H to N−Cl is thought to depend closely on the breakage of the hydrogen bonding in N−H···OC, resulting in few shifts in the wavenumber for the CO stretching vibration when the Nhalamine is formed. The characteristic absorption bands for CO relate to when the N-halamines encountered the bacteria. Interestingly, the lost chlorine can be recharged by rebleaching, a unique feature of N-halamines after they react with bacteria. After the “bleaching-quenching-bleaching” treatment, both the chlorine contents and the antibacterial efficiencies of the N-halamines are essentially unchanged, indicating that they are fully regenerable. Among all the factors above related to structural stability of N-halamines, heat and light can commonly destroy the structure of N-halamines in two main ways. One way is to induce a transformation of N−X to N−H, while the other is to detach the N−X from N-halamines. Different from heat and light, the other three factors, such as pH, water, and bacteria, result in the failure of structure stability of N-halamines, primary by inducing the transformation of N−X to N−H. Interestingly, chemicals as an important factor can collapse the structure of N-halamines either by dissociating N−X into the radicals related to N and X, respectively, or by following the transformation of N−X to N−H. Generally, it is evidenced that with high stability under some conditions such as heat, light, pH, water, and/or chemicals, N-halamines can perform an effective antibacterial procedure in which N-halamines should be very sensitive toward bacteria. Therefore, it is very necessary to pre-evaluate the stability at some conditions (i.e., heat, light, pH, water, bacteria, etc.) before the design and synthesis of new N-halamines. In particular, the effect of bacteria on the designed N-halamines should be considered as well. Up to now, considerable research has underlined the stability of Nhalamines in their experimental studies, whereas theoretical investigations on stability are quite rare and should be needed in the furture work.

5. ANTIBACTERIAL ACTION OF N-HALAMINES 5.1. Antibacterial Activity

5.1.1. Inherent Properties. It is well-known that antibacterial effectiveness of materials toward different bacteria species has become a significant factor related to their practical use.43 Recently, N-halamines have become popular antibacterial agents because of their effective antibacterial action toward a broad spectrum of bacteria, including Escherichia coli, Staphylococcus aureus, Mycobacterium tuberculosis, Pseudomonas AD


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Table 7. Antibacterial Activities of Different Antibacterial Materialsa types of antibacterial materials N-halamine-based materials

Ag NPs-based materials

ZnO-based materials

TiO2-based materials

typical examples PSA-N-Cl MNPs Cl-DMH/SiO2 hybrid NPs AgNPs@WMSsSO3− Am-PGMA/Ag PSA/Ag-NPs GSH-capped Ag NPs 5% Ta-doped ZnO Na-doped ZnO nanowires ZnO NPs

Ag/TiO2 (AT10) Pd-TiO2 quaternary ammonium/phosphonium salt- quaternized based materials dendrons poly(QPM-r-AM-rATC) chitosan-based materials CS-Lys-NPs sulfonated chitosan chitosan-blended PLA Cu-chitosan/nanoAl2O3

MBC (bacteria species) (μg/mL)

ref

0.20 (E)/0.20 (SA) 25 (E)/15 (SA)

MIC (bacteria species) (μg/mL)

5.0 (E)/7.0 (SA) 30 (E)/20 (SA)

117 285

36.55 (E)/73.10 (SA)

48.55 (E)/97.10 (SA)

328

20 (E)/20 (SA) 50 (E)/25 (SA) 15 (E)/180 (SA)

20 (E)/160 (SA) 200 (E)/100 (SA) no data

329 330 331

180 (E)/200 (SA)/160 (B) 1−10 (E)

no data no data

332 333

25 (E)/6.25 (SA)/6.25 (B)/12.5 (PA)/25 (PM)/ 25 (CA)/25 (CT) 15 (E)/10 (SA) 99.4−313.7 (E) 4−256 (E)/0.5−64 (B)

50 (E)/12.5 (SA)/12.5 (B)/25 (PA)/50 (PM) 20 (E)/80 (SA) no data 16−1024 (E)/0.5−64 (B)

334 335 336 337

3.1−60 (E)/1.3−20 (SA)

no data

338

156.25 (E)/312.5 (B) 130 (E)/2000 (SA) 15000 (E)

156.25 (E)/312.5 (B) 1000 (E)/16000 (SA) no data

339 340 341

15.6 (E)/125 (SA) 62.5 (SF)/62.5 (B)

no data

342

a

MIC = minimum inhibitory concentration; MBC = minimum bactericidal concentration; B = Bacillus subtilis; CA = Candida albicans; CT = Canadida tropicalis; E = Escherichia coli; PA = Pseudomonas aeruginosa; PM = Proteus mirabilis; SA = Staphylococcus aureus; and SF = Streptococcus faecalis.

2.60 × 1018 atoms/cm2 of active chlorine delivered a good efficacy against Staphylococcus aureus and Escherichia coli with log reductions of 7.4 and 7.5 within 10 and 5 min of contact time, respectively.198 On the basis of the research of antibacterial efficacy, Nhalamines have been found to have comparable antibacterial activities to other praised biocides, such as those antibacterial materials related to silver, zinc oxide, titania, quaternary ammonium/phosphonium salts, or chitosan.328−342 Table 7 summarizes and shows the antibacterial efficacies of several typical N-halamines versus other antibacterial materials. In terms of MIC/MBC values ranging from 1 to 200 μg/mL, Nhalamines seem to have similar or even lower values in comparison with other materials listed in Table 7. For Nhalamines, the lower MIC and MBC values often indicate the excellent antibacterial activities. According to Liang and coworkers,327 the hydantoin-containing N-halamine/silica hybrid nanoparticles (Cl-DMH/SiO2 hybrid NPs) gave the minimum inhibitory concentration and minimum bactericidal concentration values: 15 and 20 μg/mL for Staphylococcus aureus; 25 and 30 μg/mL for Escherichia coli. Moreover, their assessment on the antibacterial efficacy of acyclic amide N-halamines demonstrated that the as-tested poly(styrene-co-N-(t-Bu)-Nchlorine-acrylamide) micro/nano particles (PSA-N-Cl MNPs) followed a concentration-dependent manner.159 Surprisingly, the corresponding bacteriostatic and bactericidal concentrations reached as low as 0.2 and 5.0 μg/mL for E. coli, respectively; 0.2 μg/mL and 7.0 μg/mL for S. aureus, respectively. Also, N-halamines have been shown to rapidly and thoroughly eliminate other microorganisms, including fungi, yeasts, and viruses. Sun’s group147,178 examined the acyclic Nhalamines, emphasizing their powerful activity against E. coli and S. aureus, C. tropicalis, the MS2 virus, and Bacillus subtilis

aeruginosa, Klebsiella pneumonia, Shigella dysenteriae, Proteus vulgaris, Staphylococcus epidermidis, Clostridium difficile, Streptococcus pyogenes, Shigella boydii, Candida albicans, Salmonella typhimurium, Salmonella chlolerasuis, Serratia marcescens, Enterobacter cloacae, Sphaerotilus natans, and Bacillus subtilis.87,96,99,114,117,321−327 After imidazolidinone- and oxazolidinone-containing N-halamines had been discovered in Worley’s group84,88,90 to exhibit the antibacterial effectiveness toward Salmonella enteritidis, Salmonella gallinarum, Salmonella typhimurium, Pseudomonas aeruginosa, and Pseudomonas fluorescens, new paints were modified with 4-piperdinol-containing Nhalamines in Sun’s group117 to offer potent antimicrobial activities against many different species (e.g., Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, vancomycinresistant enterococcus, Escherichia coli, and Candida tropicalis, etc.), as well as a good capability to prevent biofilm formation. N-Halamines have been widely accepted as biocides because they can exhibit not only a broad antibacterial spectrum toward bacteria but also their powerful antibacterial activities within a brief contact time even at a low concentration. Williams et al.87 found that at 50 mg/L, 3-chloro-4,4-dimethyl-2-oxazolidinone, or 1,3-dichloro-4,4,5,5-tetramethyl-2-imidazolidinone caused a 99.9999% decline in viable bacterial flora within 1 min. In the meantime, with a concentration of 0.5 mmol/L, polymeric 4piperdinol-containing N-halamines114 was discovered to present a broad antibacterial activity against Candida albicans, Staphylococcus aureus, and Escherichia coli. In contrast to these cyclic N-halamines above, some of acyclic N-halamines showed a stronger antibacterial effect. For instance, the poly(styrene-coN-(t-Bu)-N-chloro-acrylamide) (PSA-N-Cl) resin322 was capable of about 7.95-log and 7.81-log reductions of Escherichia coli and Staphylococcus aureus within 1 and 3 min of contact time, respectively, while the N-halamine-based chitosan films with AE


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films were then treated with a series of procedures: rinsing with sodium cacodylate buffer, fixing with glutaraldehyde at 4 °C for 24 h, dehydration through an alcohol gradient, and drying in a critical point drier. Finally, the film samples were mounted onto a sample holder and then sputter-coated with gold−palladium, enabling the use of SEM to check the anticolonization/ antibiofilm functions of the N-halamines. Compared to the qualitative tests described above, some quantitative tests can consistently provide detailed data for the analysis of antibacterial N-halamines. Typically, in a plate counting test for antibacterial assay,155,324 several concentrations of bacterial suspensions in a fixed media are mixed with N-halamines dispersed in sterilized distilled water, followed by an incubating procedure under constant shaking. After a certain period of contact time, an excessive amount of sodium thiosulfate aqueous solution is added to the suspension to neutralize the active chlorine and stop the antibacterial action. Then, the mixture is serially diluted and dispersed onto an agar plate, which is incubated at 37 °C for about 24 h to count the survival colonies. Bacteria diluted by deionized water in the same way as the test samples works as a negative control. The bacterial survival is calculated using eq 18:

spores. Significantly, the same group189 demonstrated the effectiveness of melamine-containing N-halamines on bacteria, especially multidrug resistant species, yeasts, viruses, and spores. They also demonstrated the potent activity of antimicrobial paints against E. coli, S. aureus, methicillin-resistant S. aureus (MRSA, a drug-resistant Gram-positive bacteria), vancomycin-resistant enterococcus (VRE, another drug-resistant Gram-positive bacteria), C. tropicalis, MS2, and S. chartarum spore (a mold);117 the paints had 4-piperidinol-containing Nhalamines, which prevented the formation and development of biofilms. After dissociation, active chlorine can be recharged through rechlorination treatment; this has become an outstanding feature of N-halamines.115,117,194,322,323 Although N-halamines degrade into their N−H-containing precursors at the dissociation of halogen from N−X bonds, a simple bleach treatment can restore the N−X bonds. Given halogens’ rechargeable property, Sun’s group115,117 examined the recoverability of N-halamines. First, they treated 4-piperidinol-containing N-halamines with sodium thiosulfate to quench the active chlorine, and then they recovered the chlorine with a sodium hypochlorite (or dichlorisocyanurate sodium) solution in bleach. After 10 cycles of “quenching-rebleaching” treatments, the chlorine content and antibacterial efficacy remained. Chitosan-based N-halamines also demonstrate the same regenerative capacities. Cao and Sun194 confirmed that after a 5-cycle procedure of “quenching-rebleaching,” the recovered chitosan-containing N-halamines possessed the same chlorine content and biocidal activity as the originals. 5.1.2. Antibacterial Assay. Several methods have been used to evaluate the antimicrobial activity of N-halamines; they can be divided into two categories: qualitative tests and quantitative tests.72,102,129,168,194,324−327,343,344 The evaluation of agar diffusion is representative of the former.129,168,194,344 Nutrient agar plates covered with N-halamine samples were inoculated with bacterial cells. After the plates were incubated at 37 °C for about 24 h, the bacterial growth around the edges of the N-halamines was examined. The aseptic area around the N-halamines, which showed antibacterial properties resulting from the diffusion of active chlorine into the agar, was designated an inhibition zone. The agar diffusion test was thought to strongly depend on the release action of active chlorine as well as the bacterial concentration on the agar plates. The evaluation of agar diffusion has sometimes been reported as an inhibition zone test. To effectively investigate, using a qualitative method, the antibacterial function of surfaces modified by N-halamines, Worley’s group103 developed a helpful surface bacterial test in which the bacterial suspension was placed on the surface and then, after certain contact times, aliquots were removed. After the aliquots were incubated on the agar plate at 37 °C for 48 h, the bacterial survival was measured to examine the surface bacterial function. Conventionally, qualitative examinations have used a biofilmcontrolling test associated with an SEM technique to monitor the ability of N-halamine films to prevent biofilm formation.118,147,178,194,258 In a typical test, Sun’s group118 immersed N-halamine films in a bacterial suspension. After being shaken gently at 37 °C for a certain period, the N-halamine films were taken out of the bacterial suspension and then washed with buffers to remove loosely attached bacterial cells. Some of the N-halamine films were subjected to SEM to examine the level of the initial absorption, while the residual films were immersed in a broth solution to incubate at 37 °C for 72 h. The immersed

survival (%) = (A /B) × 100%

(18)

where A is the number of surviving bacterial colonies and B is the number of colonies in the control. The antibacterial kinetics of N-halamines can also be examined using the plate counting method and tuning contact time. Compared to the time-consuming and complicated plate counting test, the blended agar test is a simple and effective way to measure antibacterial activity. Typically, molten nutrient agar cooled to 40 °C is blended with certain amounts of Nhalamines and then poured into plates while the bacterial suspensions are prepared and incubated at 37 °C for 17 h.125,344 The final viability of the bacteria on the blended plate is compared with the viability of those on the nonblended agar plate. As a modified plate counting test, a sandwich method has been also developed to quantitatively measure antibacterial activity.194,325,326 A bacterial suspension is placed in the center of a N-halamine swatch, while a second swatch is laid upon it to ensure good contact between bacteria and swatch. After a certain period, the swatches are placed in sterile conical centrifuge tubes. Sodium thiosulfate is added to quench the free chlorine, followed by full vortex mixing to remove bacteria. After the swatches are removed, serial dilutions of the quenched solutions are incubated on agar plates at 37 °C for 24 h to count the visible bacterial colonies. For insoluble polymeric N-halamines, a column filter test72,93,102,343,344 was deemed suitable to analyze them against bacteria in flowing water. First, the glass columns were packed with the N-halamines. Then, sterilization was carried out in an autoclave, along with extensive washing using autoclaved, distilled, and deionized water. Finally, the bacterial suspensions were pumped through the columns using a peristaltic pump. The dilutions of the effluents were incubated on agar plates at 37 °C for 24 and 48 h to examine the N-halamines’ antibacterial performance. For those N-halamines developed to combat airborne bacteria, a spray test325,326 has been developed to examine their activity. In most cases, the bacterial aerosol imitates the airborne bacteria. For example, a bacterial suspension with a known population is prepared and aerosolized with a jet nebulizer (sprayer). The aerosolized bacteria are collected by a N-halamine-treated fabric. Similar to AF


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Figure 42. FE-SEM images and size distribution histograms of core−shell nanoparticles as a function of diameter: (a) 11, (b) 16, and (c) 26 nm. In the histograms, the dotted line indicates the diameter of the silica core used. Reproduced with permission from ref 39. Copyright 2008 Royal Society of Chemistry.

Comparisons of three halogenated N-halamines, chlorinated, brominated, and iodinated, have shown that the iodinated possess the highest sterilization power.127,128 Ahmed’s group127 demonstrated that iodinated N-halamines have the most powerful biocidal effect. Their investigation was based on several synthesized barbituric acid-bearing N-halamines, and they used halogenating barbituric acid−based polyurethane with halogen-containing sodium hydroxide aqueous solution. They found that the N−I bond had lower stability than the N− Cl and N−Br bonds, so there was easy exchange between the N−I support and the bacteria. Worley et al.84 did not examine N−I bonds but instead compared the antibacterial action of brominated and chlorinated imidazolidinones, using oxazolidinones as a blank antibacterial agent. They demonstrated an inverse relationship between antimicrobial efficacy and stability for both brominated and chlorinated N-halamines, based on the stability of N−Br and N−Cl bonds. Because the N−Br bond is much more labile than the N−Cl bond, chlorinated Nhalamines are more stable than brominated ones, but the latter have better antimicrobial activity. In fact, the antibacterial activity of N-halamines can be enhanced by the addition of a second N−X bond. Gerson and Worley346 found that N,N-dihalamines became more effective than N-monohalamine analogues when N−Cl bonds were added to both. The addition of the N−Cl bond produced an intramolecular hydrogen bond, N−H···O, increasing the electron density at the nitrogen and thus improving the polarity of the N−Cl bond. N-Halamines bearing more highly polarized N−C1 bonds would be denatured more rapidly by the donation of positive chlorine to the denaturant, rendering them less effective as antimicrobial agents. For the same reason, N-bromo-N-chloro-dimethylhydantoin345 also exhibits superior antibacterial activity to N,N-dibromo and N,N-dichlorodimethylhydantoin. 5.2.2. Effect of Size. For N-halamines, size has an important effect on antibacterial activity:321,324,327,347,348,353 the smaller the particle size, the stronger the activity. To enhance this activity, many researchers have sought to reduce the size of N-halamines. Jang and Kim39 investigated the antibacterial activity of core−shell structured silica-N-halamine nanoparticles, whose sizes they manipulated by encapsulating colloidal silica nanoparticles (7, 12, and 22 nm) with hydantoin-containing N-halamine polymers (see Figure 42). They found that the surface area increased as the size decreased, resulting in smaller products and more N-halamine functional sites on the surface. The antibacterial efficiency was thereby enhanced, confirming that it was strongly dependent on the size of the N-halamines.

the previous test process, the collectors are transferred into a sodium thiosulfate solution to neutralize any residual chlorine. This step is followed by a vortex mixing. Finally, the serial diluted solutions in buffers are incubated on agar plates at 37 °C for 24 h to test the bacteria. Two other tests, the liquid medium turbidity test155 and the minimum inhibitory concentration (MIC)/minimum bactericidal concentration (MBC) test,85,324,327 have also become popular ways to evaluate the quantitative antibacterial activity of N-halamines. In the former, the bacterial suspension is added into the culture solution under constant shaking. Then, the Nhalamines are added into the glass tubes containing the above suspension and diluted to an appropriate concentration. While the glass tubes are incubated in a shaking incubator at 37 °C, the liquid is withdrawn from the glass tubes at different incubation times. Finally, the turbidity is measured by the optical density at 600 nm (OD600) to determine bacterial survival. In comparison with the former method, the latter seems more quantitative in terms of the incubation of the bacteria in solutions containing different concentrations of Nhalamines. The MIC is defined as the sample concentration at which the colonies are reduced in the CFU/mL numbers of ≥3 log, while the MBC is defined as the sample concentration at which no colony is visible. The measured MIC/MBC values should indicate the bacteriostatic/bactericidal activity of the given N-halamines. 5.2. Factors Affecting Antibacterial Activity

This section will examine the numerous factors that influence the antibacterial activity of N-halamines: N-halamine type, size, and substitution; hydrophilic−hydrophobic balance; solution pH; and bacteria species.127,128,253,261,345−357 5.2.1. Effect of Type. N-Halamine type plays an important role in determining the material’s antimicrobial properties. Many investigations have shown that the antibacterial activity of N-halamines decreases in the following order: imide > amide > amine.253,261,353 Obendorf et al.253 compared the antibacterial activity of chlorinated 5,5-dimethylhydantoin (CDMH) with the activities of chlorinated 2,25,5-tetramethyl-imidozalidin-4one (CTMIO) and chlorinated 3-dodecyl-5,5-dimethylhydantoin (CDDMH). Structurally, the CDMH contained imide and amide N−Cl bonds, the CTMIO had amide and amine N−Cl bonds, and the CDDMH contained only one amide N−Cl bond. The antimicrobial rate of the CDMH was much higher than the rates of CTMIO and CDDMH. Dong’s group261,353 also showed that the antibacterial activity of imide N-halamines was superior to that of amide types by comparing barbituric acid containing N-halamines with hydantoin-bearing ones. AG


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To further study the effect of size, Liang’s group327 used a modified Stöber method to obtain hydantoin-containing silica hybrid particles in various size ranges: 25−30, 90−100, 110− 125, 225−250, and 475−500 nm (see Figure 43). MIC and

such as 1-chloro-3-alkyl-5,5-dimethylhydantoin (CADMH), with alkyl chain lengths from C-2 to C-22 to investigate how chain length at position 3 of hydantoin affected antibacterial activity. They found that shorter alkyl chain length led to faster antimicrobial action because the good solubility of the Nhalamines ensured full contact with the bacteria. As the alkyl chain length increased, the solubility decreased and the antibacterial activity lessened. Worley’s group studied what happened to the antibacterial activity of N-halamines when alkyl/phenyl substitution was change from position 3 to position 5 on the hydantoin ring.271,286 On the one hand, the alkyl group with a long chain length at position 5 influenced the antibacterial rate in three ways.286 First, the alkyl groups strengthened the N−X bond by increasing its polarity, thereby reducing the rate. Second, the alkyl group with the longer chain length induced steric hindrance and thereby decreased the rate. Third, the elongation of the alkyl group increased the lyophilicity of the N-halamines and thus promoted contact between them and the bacteria, which increased the rate. However, elongation of the alkyl group also caused less wetting of the entire surface, hindering contact between the N-halamines and the bacteria, thus decreasing the rate. Yet, better antibacterial activity was found after phenyl derivatization was carried out at position 5 of the hydantoin-containing N-halamines, as oxidative chlorine was donated to the bacteria more easily for the phenyl derivatives.271 The phenyl group weakens the N−X bond more readily than the methyl group and thereby enhances the material’s antibacterial activity. The fluorination of N-halamines has also played an important role in enhancing antibacterial activity. Lin et al.258 compared a fluorinated N-halamine (1-chloro-3-1H,1H,2H,2H-perfluorooctyl-5,5-dimethylhydantoin, Cl-FODMH) and its unfluorinated counterpart (1-chloro-3-octyl-5,5-dimethylhydantoin, ClODMH) in terms of their antibacterial activity. Antimicrobial tests showed that when they were used as additives in polyurethane (PU) film, the PU containing Cl-ODMH had higher antibacterial potency than the PU with Cl-FODMH. This was attributed to the Cl-FODMH having lower compatibility with PU film, causing it to aggregate on the film surface and prevent complete contact with bacteria. The researchers also suggested the high hydrophobicity of ClFODMH as an alternative factor because it precluded complete contact between Cl-FODMH and bacteria, leading to lower antibacterial potency. 5.2.4. Effect of Hydrophilic−Hydrophobic Properties. Hydrophilic-hydrophobic properties have become key factors affecting the antibacterial activity of N-halamines. Usually, the N−X (N = Cl, Br, or I) bonds in N-halamines display hydrophobicity, which can detract from their antibacterial action. In accordance with the literature,122,260,348,349,353 increasing the content of N-halamines on a substrate material can render the material’s surface hydrophobic, resulting in decreased contact with the bacteria and thus less efficacy, although it enhanced the bactericidal efficacy. In addition to the effect of hydrophobicity in the N−X moiety, the hydrophilic−hydrophobic properties of the other moiety are also important for tuning their antibacterial activities. To differentiate the effects of hydrophilicity and hydrophobicity, Sun’s group349 synthesized and studied Nhalamine-modified cotton and synthetic fabrics used in antibacterial applications. Thanks to their better hydrophilicity, the cotton fabrics’ antibacterial action was faster than that of the

Figure 43. FE-SEM images of DMH/SiO2 hybrid NPs prepared with different TS-DMH/TEOS mass ratios: (A) 1:3, (B) 1:6, (C) 1:9, and (D) 1:12. The volume ratio of 28% NH4OH/H2O was 10:23. Reproduced with permission from ref 327. Copyright 2014 Springer.

MBC tests showed that these particles had higher antibacterial activity than their bulk counterparts. In addition, examination of the inhibition zone confirmed the size effect, showing that the smallest N-halamines had the strongest activity. The size effect of N-halamines on antibacterial activity is essentially attributed to the surface area-activity relationship. Using N-halamine-decorated polystyrene nanoparticles as a research target, Dong et al.321 studied the correlation of antibacterial activity with surface area. It was evidenced that in a plate counting test for antibacterial assay, the antibacterial activity is proportional to the surface area while the nanoparticle size directly determine the surface area. With increasing surface area, N-halamine-decorated polystyrene nanoparticles in antibacterial evaluation provided an increasing antibacterial capability both against Pseudomonas aeruginosa and Staphylococcus aureus, which suggests that the larger the surface area is, the more active the antibacterial function of Nhalamines will be (see Figure 44). 5.2.3. Effect of Substitution. With successful substitution on the hydantoin ring in N-halamines, the relationship between substitution and antibacterial activity was established. Chen and Sun59 synthesized a series of hydantoin-bearing N-halamines,

Figure 44. Reduction of bacterial colonies upon the 60 min exposure to the N-halamine-based PS nanoparticles with different surface area. Reproduced with permission from ref 321. Copyright 2014 Elsevier. AH


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halamines, and imide N-halamines) has played an important influence on their antibacterial activity. Along with a rapid development of nanotechnology, the size of N-halamines has been controlled easily in an effective range and is being regarded as a significant factor to affect antibacterial activity. In contrast to the influence of the N-halamines’ type on antibacterial activity, the effect of bacteria species on antibacterial activity was only found in a compared research of N-halamines’ antibacterial function on E. coli and on S. aureus. Furthermore, the media like the solution’s pH value was rarely discussed in some research related to its effect on antibacterial properties. Therefore, more extensive studies should be encouraged to clarify the detailed antibacterial effect of bacteria species, solution media, and bacterial species.

synthetic fabrics, and because the bacterial suspension easily diffused into the inner N-halamines of the hydrophilic cotton, more bacteria were killed from the combined effect of the outer and inner N-halamines. In contrast, the hydrophobicity of the synthetic fabrics hindered good contact between the bacteria and the N-halamines, so only the surface N-halamines had antibacterial activity. Once the outer N-halamines were consumed, the inner ones would migrate to the surface, but this took a long time. To minimize hydrophobicity and obtain high antibacterial functionality, hydrophilic groups have been introduced into Nhalamines, providing better contact between them and the bacteria. Ren et al.122 designed antibacterial cotton fabrics modified with 1,3,8-triazaspiro[4.5]-decane-2,4-dione-containing N-halamines. The use of the N-halamine precursor 3-(2,3dihydroxypropyl)-7,7,9,9-tetramethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione (TTDD diol) rendered the resulting Nhalamine-modified cotton fabrics less hydrophobic due to the N-halamine’s hydroxyl groups. Consequently, hydrophobicity did not significantly decrease the antibacterial activity of the TTDD diol-based N-halamines in comparison with TTDD siloxane-based N-halamines. 5.2.5. Effect of Solution pH. A unique feature of Nhalamines is their pH-dependent antibacterial activity.171,175 Amiri et al.175 investigated the disinfection effectiveness of amino acid containing N-halamines. At a pH of 6.0 or 6.9, Nchloro-glycine was found to exhibit obvious antibacterial action against E. coli, while it was almost inert at a pH of 8.1. They inferred that the better antibacterial behavior of these Nhalamines under more acidic conditions probably resulted from several factors, including increased free chlorine, the species of N-halamine, and/or the synergistic effect of pH stress and the presence of N-halamines. Jacangelo et al.358 also found such pH-dependent antibacterial kinetics when they studied the E. coli inactivation action of inorganic N-halamines. To date, the mechanism for pH-dependent antibacterial kinetics is unclear and requires further study. 5.2.6. Effect of Bacteria Species. It has been reported that N-halamines present much stronger antibacterial activity against Gram-positive species than Gram-negative ones, suggesting that the antibacterial activity of N-halamines varies depending on the species.39,250,357 In Jang’s experiment,39 silica-N-halamine core−shell nanoparticles were proven to have higher biocidal efficacy against S. aureus than E. coli. Gao’s study250 also showed the higher susceptibility of Gram-positive bacteria, after two species were treated with silica-polystyrene-N-halamines using a MIC test. The results from both groups are thought to be attributable to the bacteria’s different structures. In accordance with Sun’s report,357 the lipid bilayer cell membranes of Grampositive bacteria are covered by a porous peptidoglycan layer, which does not exclude most antimicrobial agents. In contrast, Gram-negative bacteria are surrounded by two membranes, with the outer membrane, containing lipopolysaccharides and protein, serving as an efficient permeability barrier. Hence, the latter are better protected against N-halamines than the former. Generally, the antibacterial activity is closely dependent on many factors such as structure and composition of N-halamines, solution media, and bacteria species. So far most researches have devoted themselves to the influence of N-halamines’ type, size, composition, and hydrophilicity/hydrophobicity on antibacterial activity due to the easy controllability and tenability of these factors in antibacterial function. Particularly, the type of N-halamines (e.g., amine N-halamines, amide N-

5.3. Mechanism of Antibacterial Action

To date, numerous studies have investigated the mechanisms for the antibacterial action of N-halamines.359−368 Basically, the biocidal mechanisms of N-halamines can be classified into three types: (1) contact killing: direct transfer of a positive halogen from N-halamines to bacterial receptors; (2) release killing: dissociation of a positive halogen from N-halamines to solutions, with subsequent inactivation; and (3) transfer killing: transfer of a halogen from N-halamines to medium constituents, inhibiting bacterial growth and viability. Figure 45 shows the schematic diagram of these three mechanisms.

Figure 45. A schematic illustration for three antibacterial mechanisms of N-halamines, such as contact killing, release killing, and transfer killing.

Some research groups promote a contact killing method that does not involve freely released halogen, while others promote release killing from free halogen. Few endorse transfer killing. 5.3.1. Contact Killing. The contact killing mechanism involves the direct transfer of an active halogen from Nhalamines to bacterial cells. The halogen has a strong tendency to participate in ionic reactions or to combine with another element, destroying or inhibiting the metabolic process in bacteria cells. In this way, antibacterial action occurs without the dissociation of free halogen from N−X bonds. The first nonleachable N-halamines were reported about two decades ago, and new ones are still emerging.359 N-Halamines with stable N−X bonds are more suitable for contact killing. For example, Luo et al.112 found that the high stability of aminebased N-halamines inclined them to the contact killing mechanism. They prepared poly[(6-morpholino-s-triazine-2,4AI


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5.3.2. Release Killing. The inhibition zone test238 has become an effective route to verify the release-killing mechanism of N-halamines (see Figure 47), as confirmed by

diyl)-N-chloro-[2,2,6,6-tet-ramethyl-4-piperidyl)imino]hexamethylene[(2,2,6,6−4-piperidyl) imino]] (APA-1) and incorporated it as an additive into PU via a solvent casting method. They then used a sandwich test to determine the contact killing mechanism of the APA-1 modified PU, while the release killing mechanism was studied using an inhibition zone study. Interestingly, the product was discovered to exhibit excellent antibacterial activity in the sandwich test, while no inhibition region was found around the sample in the inhibition zone method, suggesting that APA-1 inactivates bacteria by direct contact rather than by releasing halogen. This nonleaching characteristic of APA-1 was strongly dependent on the good stability of its N−Cl bonds because the four-electron donating methyl groups, which were attached to the neighboring carbons of the N−Cl bonds, tended to destabilize any developing negative charge on N, rendering the N−Cl stable. However, at contact with bacteria, APA-1 donated its Cl+ to the adherent bacteria and then killed them, while the noncontacting bacteria were not killed. This suggests the antibacterial action of APA-1 proceeds via the contact killing mechanism. Similarly, Sun’s group260 studied and confirmed the contact killing mechanism in the antibacterial action of amide Nhalamines, using chlorinated poly(3-(4′-vinylbenzyl)-5,5-dimethylhydantoin-co-vinyl acetate) to synthesize a hydantoin-based N-halamine representative of amide N-halamines. In the experimental investigation of fabrics modified with this hydantoin-based N-halamine, they believed there was sufficient contact between the fabrics and bacteria to benefit the antibacterial function, and that therefore the N-halamines killed the bacteria by direct contact killing rather than release killing. To further study the contact killing mechanism, Liu’s group360 designed a series of new biocides with both hydantoin-containing N-halamines and quaternary ammonium moieties. They demonstrated that E. coli has a lipopolysaccharide layer with a negative charge (see Figure 46). This acted as a

Figure 47. Optical images of the inhibition zone against E. coli: (A) Untreated E. coli; (B) E. coli treated with 4-piperidinol-containing Nhalamines. Reproduced with permission from ref 238. Copyright 2015 Elsevier.

Worley and coauthors.101−103 In their inhibition zone test, they synthesized a series of oxazolidinone-containing N-halamines to study the materials’ antibacterial activity; the appearance of inhibition zones around the N-halamines proved the release killing mechanism. Hu et al.105 confirmed the release killing capacity of oxazolidinone-containing N-halamines. With an oxazolidinone-containing N-halamine and quaternary ammonium salt, they prepared bifunctional antibacterial materials and oxidative chlorine. Ahmed et al.129 studied barbituric acid containing N-halamine-modified silica gels with different N−X bonds (X = Cl, Br, and I). Their inhibition zone study results illustrated that all three kinds of N-halamines have obvious inhibitory zones, confirming the release killing mechanism. Interestingly, most polysaccharide-containing N-halamines appear to act via the release-killing mechanism in their antibacterial action. Using chitosan-bearing N-halamines, Cao and Sun194 found that chlorinated chitosan had an obvious inhibition zone, indicating that at least some of the oxidative chlorine diffused away from the chlorinated chitosan to attack bacteria via a release-killing mechanism. Kan’s group195 and Park’s group 196 also confirmed release killing in the antibacterial activity of cotton modified with chitosancontaining N-halamines and chlorinated chitosan salt/cotton knit composites, respectively, in inhibition zone studies. In Moustafa’s study,200 starch-containing N-halamines exhibited release-killing action. Although the functional groups of hydantoin-bearing Nhalamines mean they have different chemical structures than oxazolidinone-containing and polysaccharide-containing Nhalamines, they also use the release-killing mechanism. Liang’s group327 used a zone inhibition study to quantify the antibacterial activity of hydantoin-containing, N-halaminemodified silica nanoparticles of different sizes. The appearance of an inhibition ring was determined to be effective evidence for the release-killing action of hydantoin-based N-halamines. Sun et al.361 confirmed this mechanism in the hydantoin-type Nhalamines by utilizing DMH attached to PU with 1,6hexamethylene diisocyanate (HDI) as the coupling agent. The chlorinated PU-HDI-DMH presented a palpable inhibition zone, suggesting the disassociation of active chlorine from Nhalamines to kill bacteria. On the basis of inhibition zone testing, a release-killing mechanism was also found for Nbromoamines364,367 and amide type acyclic N-halamines.168 Farah et al.363,367 studied the release mechanism of N-

Figure 46. Schematic illustration of boosting microbiocidal function between cation and N-chloramine. Reproduced with permission from ref 360. Copyright 2012 Wiley Periodicals.

negatively charged shell that, through electrostatic interaction, made it more susceptible to the quaternary ammonium moieties, resulting in the transfer of N-halamines when they came in full contact with bacteria. The contact killing mechanism was also confirmed in Ahmed’s group128 to explain the antibacterial function of imide N-halamines. By freezedrying a bacterial suspension and placing it between two disks of barbituric acid containing N-halamines, without the presence of any liquid media necessary to mediate free halogen release, they found that E. coli and S. aureus numbers significantly decreased, indicating they had been killed from direct contact. AJ


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polymers can kill bacteria via a combination of contact killing and release killing, by studying a serious antibacterial method. In general, N-halamines following the mechanism of contact killing tend to directly contact and kill bacteria without the dissociation of active halogen from the N−X bond, while for two other mechanisms, such as release killing and transfer killing, the positive halogen(s) can migrate from N-halamines into either water solution or nitrogen-containing media and then attack bacteria. In this way, the stability of the N−X bond is an important key to influence and determine the antibacterial process in the three mechanisms above. Also, the actual surrounding at which N-halamines can encounter with bacteria can act as the other important factor because it is closely related to the effectiveness of antibacterial action of N-halamines. For amine N-halamines, amide N-halamines, and imide N-halamines, their contact killing is the only antibacterial pathway in the absence of liquid media, while the cyclic N-halamines, acyclic N-halamines, chlorinated N-halamines, and brominated N-halamines perform a combination of two or three mechanisms in antibacterial action at the presence of the water solution, in which the release killing is a leading mechanism. When the media contains the N−H bond, Nhalamines can often follow the mechanism of transfer killing to kill bacteria.

bromoamines such as N-bromohydantoin derivatives and Nbromo uracil derivatives. They demonstrated that compared to the latter, the former showed more bromine release; the electron-withdrawing groups being substituted onto uracil increased the bromine release to a sufficient level for antibacterial action. Using chlorinated N-(3-triethoxysilylpropyl)-N′-(N‴-heptylcarbamido-N″-ethyl)-butanediamide (TSHCEB) as a typical amide type acyclic N-halamine, Wu et al.168 studied the controlled release of chlorine from (TSHCEB)-coated cotton swatches. The appearance of an inhibition ring indicated that the oxidative chlorines diffused away from the chlorinated TSHCEB to attack bacteria, and the inhibition ring sizes suggested good release behavior for the active chlorines. In addition to inhibition zone tests, a permeable membrane method has been used as an effective route to investigate the release action of N-halamines. For instance, Ahmed et al.128 encapsulated barbituric acid bearing N-halamines into a semiporous membrane (dialysis tubing) and immersed this into a bacterial culture. Interestingly, after this permeable membrane test, the bacterial viability was obviously decreased. Since the N-halamines were unable to permeate the membrane, the released chlorine acted as the main factor to kill the bacteria without direct contact. In an effort to enlarge the research methods for uncovering antibacterial mechanisms, Natan et al.366 compared acyclic amide N-halamine nanoparticles (NPs) with sodium hypochlorite. The mechanisms of these Nhalamine NPs involved generating reactive oxygen species (ROS) upon exposure to organic media rather than in water, suggesting that the mode of killing action should be targetspecific. They found that with the release of oxidative chlorine, the ROS could generally target the use of N-halamines rather than the use of sodium hypochlorite. 5.3.3. Transfer Killing. In addition to the release-killing mechanism, the transfer-killing mechanism is also used by barbituric acid containing N-halamines.127,128 One possible explanation, confirmed by Ahmed’s group,127 is that halogen exchange occurs between the N−X bonds of the N-halamines and the amide N−H of the medium, giving the medium biocidal properties. Via evidence, they attested the presence of chlorine species releasing from the barbituric acid bearing Nhalamines via the iodometric titration of N-halamines isolated after their full contact with water and broth medium, respectively. They found that the amount of chlorine in the broth medium was much higher than in the water because of chlorine exchange between the N-halamines and protein in the broth; this changed the nature of the nutrients and led to bacterial death. To further confirm the transfer mechanism of barbituric acid based N-halamines, the same group128 designed a new method of culturing bacteria using barbituric acid based N-halamines pretreated in a broth medium. The bacteria failed to grow in this medium, proving the halogen transfer. According to Sun and co-workers,189 it was claimed that a single antibactrial mechanism of contact killing or release killing may not be potent enough for the efficient antibacterial action of N-halamines. It has been suggested that a combination of two or three mechanisms should be more responsible for biocidal efficacy at the same time. For example, Ahmed’s group128 believed that a combination of three mechanisms (i.e., contact killing, release killing, and transfer killing) would be suitable to reveal antibacterial function of N-halamines. Most recently, Bai et al.41 confirmed that N-halamine-containing

5.4. Biological Effect on Bacteria

N-Halamines can damage the cell structure of bacteria,237,238,369,370 and SEM and TEM are the best ways to record the morphological changes in bacterial cells after treatment with N-halamines. Figure 48 shows the biological

Figure 48. SEM images of E. coli and S. aureus before and after treatment with 4-piperidinol-containing N-halamines. Reproduced with permission from ref 238. Copyright 2015 Elsevier.

effects of N-halamines on cell structure for rod-shaped bacteria,238 using E. coli as the model. Intact E. coli is a typical Corynebacterium, with two obtuse ends and a smooth surface. After contact with N-halamines, the bacterial surface was rugged, with small holes and major crevasses. Sometimes, Nhalamines can cut bacterial cells into cellular debris. Figure 48 shows similar damage to the spherical bacterium S. aureus.238,369 When exposed to N-halamines, S. aureus exhibited a grapelike appearance, with roughening and blebbing on the surface, and it leaked cell contents. Margel’s group366 used TEM to examine the interactions between amide N-halamine NPs and S. aureus (Figure 49). They found no significant change in the bacterial morphology after a treatment using N-halamine NPs. However, N-halamines AK


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various N-halamines by separately reacting N-α-acetyl-histidine (His-C), N-α-acetyl-lysine (Lys-C), glycine (Gly-C), taurine (Tau-C), and ammonia (Mono-C) with HOCl, and then examined the effect of the synthesized N-halamines on DNA and its constituents. They also demonstrated that His-C was capable of chlorinating DNA and related materials, both in isolation and in a cellular environment. In contrast to the biological effect on bacteria, toxicology is also of utmost significance to judge the antibacterial property of N-halamines in biomedical applications. With their focuses on three tests, such as cytotoxicity, genotoxicity, and protein toxicity, several groups have devoted their efforts to the research of the toxicity effect of N-halamines. On the basis of in vitro cytotoxicity tests, Agarwal’s group 356 and Ren’s group134,135,201,265 demonstrated that as shown in Figures 50

Figure 49. TEM micrographs of S. aureus bacteria treated with amide N-halamine NPs. Reproduced from ref 366. Copyright 2015 American Chemical Society.

were organized like “necklaces” around the S. aureus, forming a kind of cell wall. This occurred after only a short contact period, suggesting a specific interaction between the Nhalamines and the bacterial cells. This phenomenon was not observed with S. aureus treated using water, nonchlorinated NPs, or sodium hypochlorite, indicating that the N-halamines had a unique tendency to strongly adhere to and encircle the bacterial cell wall. Notably, the same was not detected when Nhalamine NPs interacted with E. coli, probably due to the different cell wall composition of Gram-negative versus Grampositive bacteria. N-halamines are reported to kill bacteria in a protein-targeted manner because they select a protein-related point to start their attack. De Silva et al.371 found that the initial attack focused on the chlorination of the bacteria’s external protein matrix. The chlorine cover surrounded the bacteria so that active chlorine could penetrate the bacterial cells, attacking many thiol-containing constituents by oxidation and denaturing the protein by transchlorination. As a result, the bacteria became dysfunctional and died. This clearly suggested that Nhalamines are very unlikely to induce bacterial resistance, because they easily and nonspecifically interact with vital bacterial proteins. In addition to proteins, DNA, RNA, and enzymes are also targeted when N-halamines attack bacteria. Investigating cellular mechanisms in the action of N-halamines, Bodor’s group372 used two model compounds: 3-chloro-4,4-dimethyl-2oxazolidinone and N-chlorosuccinimide. They found that at a concentration of ∼10−5 M, N-halamines could inhibit bacterial growth, particularly bacterial DNA, RNA, and protein synthesis. They could also inhibit enzymes, including sulfhydryl groups, at a concentration of ∼10−4 M. However, without sulfhydryl groups, dihydrofolate reductase could be inhibited only at chloramine concentrations up to 10−2 M, while ribonuclease without sulfhydryl groups was unaffected. This indicated that the inhibitory effect of N-halamines could be prevented if the sulfhydryl-containing reagents were added in advance or were used along with N-halamines. Once inhibition was produced, it was not reversible by subsequent addition of the sulfhydryl reagents. The inhibitory effect of N-halamines on bacterial DNA was further confirmed by Pero et al.373 In their experiments, the model, chloramine T, which was similar in cellular systems to reactive oxygen species such as H2O2, O2•−, •OH, and HOCl, was used to induce cellular DNA damage in a dose-dependent manner. They demonstrated that the N-halamines could naturally inhibit DNA repair, confirming the attack of Nhalamines on bacterial DNA. Hawkins et al.374 synthesized

Figure 50. Cell viability of 3T3 fibroblasts on cyanuric acid-containing N-halamines and control (tissue culture plate) at 4 and 24 h. Reproduced from ref 135. Copyright 2013 American Chemical Society.

Figure 51. Cell viability of 3T3 fibroblasts on hydantoin-containing Nhalamines and control (tissue culture plate) at 4 and 24 h. Reproduced with permission from ref 201. Copyright 2014 Elsevier.

and 51, two cyclic N-halamines (i.e., hydantoin- and cyanuric acid-containing N-halamines) are measured to be low toxic or even nontoxic, which is suitable for biomedical applications. Similar to these two cyclic N-halamines above, amide Nhalamines as one of acyclic N-halamines were proven to be noncytotoxic after the evulation of cytotoxicity in Ding’s group155 and Ren’s group.251 However, unlike amide Nhalamines, amino acid-containing N-halamines can show AL


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polystyrene with halogenated hydantoin and imidazolidinone derivatives. These N-halamine-based beads were packed into glass columns as cartridge filters and thus effectively inactivated viruses and bacteria in water. The same group36 also directly synthesized many N-halamine-containing insoluble polymers, among which hydantoinylated polystyrene was successfully used in commercial products produced by HaloSource Inc. In particular, their HaloPure Br had bromine covalently bonded to the hydantoin ring structures on a substrate of polystyrene porous beads. This product demonstrated a reliable capacity to control heterotrophic microbial contamination and inhibit biofilm formation by making contact with microbes in water as it percolated through a bed of HaloPure medium. Later, Coulliette and Rose379−381 further explored the applications of HaloPure products, using point-of-use (POU) techniques (Figure 52). Two types of N-halamine beads, poly[1,3-

different toxicological effects under some cytotoxicity assessments,51 although they belong to acyclic N-halamines also. According to Humpage and co-workers,368 it is demonstrated that their MTS assay evidenced the cytotoxic effect of amino acid-containing N-halamines, resulting in the harm of mammalian cells. Interestingly, Bull et al.51 thought that amino acid-containing N-halamines facilely generate nitrogen and halogen radicals, each of which could contribute to the toxicity. Parallel to the cytotoxicity, the genotoxicity has also started as an effective factor to determine biomedical applications of N-halamines. In accordance with the literature,35,368 amino acid-containing N-halamines have become important research examples in some research activities of toxicity. With an assist of a flow cytometry-based micronucleus assay, Laingam et al.368 revealed that four amino acidcontaining N-halamines, such as Cl-glycine, Cl-ethanolamine, Cl-histamine, and Cl-lysine, are genotoxic in mammalian cells, indicating that these amino acid-containing N-halamine molecules could be of toxicological significance during the chlorination of drinking water. In this way, these genotoxic amino acid-containing N-halamines are not suitable to be utilized in biomedical applications. Apart from cytotoxicity and genotoxicity related to the toxicology of N-halamines, the protein toxicity, especially the toxicity toward thiol-containing proteins, was used in the evaluation of the toxicological property of N-halamines as well.312,315,316,375,376 Carrying out an in vitro assay, Carr’s group315 and Hawkins’s group316 found that as one of thiolcontaining proteins, the plasma proteins are apt to react with N-chloramines due to the thiol oxidation, resulting in a selective loss of thiol groups. Similar to the research in these two groups above, Peskin’s group375,376 demonstrated that the presence of thiols can result in the preferential attack of Nchloramines on thiol-containing proteins. Also, using amino acid-containing N-halamines as research examples, Bull and coworkers et al.51 evidenced that the formation of nitrogencentered free radicals, resulting from the metabolic processing in vivo, played an important role in the inactivation of proteins when the proteins met with amino acid-containing Nhalamines.

6. APPLICATIONS OF N-HALAMINES The past few decades have seen a number of different Nhalamines developed and some of those commercialized. Scientists and engineers have studied various N-halamines in different applications, including: water treatment, air purification, textile products, medical and healthcare products, dyes and paints, silica materials, and other applications.

Figure 52. A schematic of the AquaSure system used for the water disinfection. The arrows represent the flow of water in the system, and the sections are designated as a (A) upper reservoir, (B) HaloPure canister within a (C) lower reservoir and (D) halogenated beads. Reproduced with permission from ref 381. Copyright 2013 Elsevier.

dichloro-5-methyl-5-(4′-vinylphenyl)hydantoin] and poly[1,3dibromo-5-methyl-5-(4′-vinylphenyl)hydantoin], were placed in canisters to be disinfection POU devices for drinking water, and they effectively reduced bacteria and viruses. Taking a different approach, Ahmed and co-workers127,131,132 utilized several imide N-halamines in single and multistage filtration systems (Figure 53). After trying several approaches, agar plate, agar blend, stirred flash, and column, to verify the antimicrobial efficacy of these imide N-halamines, they demonstrated that the presence of N-halamines prevented internal bacterial growth and killed filtered cells, especially in the deep and lower parts of the filters. Duan et al.382 fabricated novel poly(ether sulfone) ultrafiltration hybrid membranes containing N-halamine-grafted halloysite nanotubes using a phase inversion method. The

6.1. Water Treatment

For water treatment, halogen disinfectants, such as free halogen and its other analogues, have been the most popular antibacterial agents owing to their cost-effectiveness and rapid killing rate for most microorganisms.377 However, the main drawback of halogen disinfectants is the potential for carcinogenic byproducts because the organic substances in water can easily react with them. To avoid this problem, it is advisible to use insoluble contact disinfectants that can kill bacteria without releasing any active species in water; Nhalamine type polymers have been used widely for this purpose.378−388 Worley’s group36 developed several insoluble porous beads bearing N-halamines (N-bromo and N-chloro derivatives) for water treatment, by functionalizing commercial AM


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Figure 53. A design for a large-scale water purification system based on multifiltration technology. Reproduced from ref 42. Copyright 2013 American Chemical Society.

addition of N-halamines not only provided good antimicrobial performance but also enhanced the membranes’ hydrophilicity, resulting in a high water flux. They suggested that these hybrid membranes have the potential to reduce bacterial fouling in wastewater treatment. To explore novel techniques in water treatment, Wang et al.383−386 prepared N-halamine-modified membranes in which commercial aromatic polyamide reverse osmosis (RO) membranes were modified with chlorinated hydantoin derivatives via free-radical graft polymerization. Their final modified membranes had an obvious sterilization effect on bacteria. In particular, the membranes substantially reduced microbial fouling and showed chlorine-resistant properties. Lee’s group179 prepared antibacterial m-aramidbased N-halamine membranes for nonpressure-driven filtration. They found that this filtration membrane provided sufficient antimicrobial efficacy against E. coli and S. aureus. Moreover, the chlorine lost during filtration could be regained upon rechlorination treatment. Their results indicated a new approach to water disinfection as well as innovative applications in the water industry using m-aramids.

fabrics via a pad-dry technique to impart antimicrobial properties. The effectiveness was evaluated against bioaerosols of S. aureus and E. coli using bioaerosol testing, as presented in Figure 54. The air filters exhibited not only superior biocidal

Figure 54. A schematic diagram of the experimental setup for bioaerosol testing of filters. Reproduced from ref 326. Copyright 2014 American Chemical Society.

6.2. Air Purification

efficacy against both types of bacteria but also good air permeability, suggesting that these fabrics have excellent potential for use in protective face masks and air filters to combat airborne bacteria. Elsewhere, using a cross-linked polyacrylamide on polypropylene, Zhao and Liu389 fabricated a surface thermoplastic semi-interpenetrating network, coupled with chlorination. Their products offered excellent antibacterial

To safeguard humans against host-to-host transmission of airborne pathogens, many of them lethal, air filters are among the most effective protection devices.207,208,325,326,389 N-Halamines have been proven to reduce the risk of infection from airborne pathogens when used in air filter devices. Demir et al.326 coated N-halamines (e.g., 1-chloro-2,2−5,5-tetramthyl-4imidazolidinone) onto polypropylene, melt-blown, nonwoven AN


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Figure 55. SEM images of (A) cotton, (B) cotton treated with poly[5,5-dimethyl-3-(3′-triethoxysilylpropyl)hydantoin] (PSPH), and (C) cotton treated with PSPH/TiO2. Reproduced from ref 74. Copyright 2014 American Chemical Society.

activity, along with good air permeability. Cerkez et al.208 developed antimicrobial surface coatings for polypropylene nonwoven filters using anionic and cationic N-halamine polyelectrolytes. The N-halamine coatings somewhat reduced the filters’ air permeability, but it remained comparable to that of most protective applications.

products employed in healthcare. For example, Sun’s group349 incorporated N-halamine structures into various synthetic fabrics to produce antibacterial properties. They grafted ADMH monomers onto textile materials (including nylon-66 no. 306A, polyester no. 755H, polypropylene no. 983, acrylic Orlon no. 864, polyester/cotton blend, and polyester/ polyamide blend) in a continuous finishing process with different initiators. After chlorination, the grafted hydantoin structures could be transformed into N-halamines to provide powerful, durable, and regenerable antibacterial activity. The same group78 also found that without an initiator, the ADMH could not be satisfactorily grafted onto synthetic fabrics (the grafting yield was less than 0.5 wt %), but that the effective initiator triallyl-1,3,5-triazine-2,4,6(1H,3H,5H)-trione (TATAT) could greatly enhance the grafting yield (raising it to 3.4−17.2 wt %) and thus give good antibacterial activity. The same group91 also used TATAT to graft imidazolidinonecontaining N-halamines onto several synthetic fabrics. The modified fabrics exhibited durable antibacterial properties against E. coli that could be refreshed with chlorine bleaching.

6.3. Textile Products

Textile products can carry pathogenic microorganisms.390,391 Consequently, antibacterial functionalization is becoming a standard finishing step for natural textiles and artificially synthesized textile products. Natural fibers such as cotton can be particularly good media for bacterial growth, due to their hydrophilic properties.391 The development of antimicrobial cottons has therefore offered a promising method for preventing infections in clinical settings, since microbial shedding from our bodies can help microorganisms spread into textiles, either directly in clothing or via surrounding textiles. Three main methods have been developed to modify cotton fabrics using antibacterial N-halamines. The first approach is to graft N-halamines onto cotton using polymerization to produce antimicrobial functionality.82,102,113,116,147,149,152,305 Using a radical polymerization process, Sun’s group152,305 synthesized two N-halamine products: cyclic N-halamine-grafted cotton and acyclic Nhalamine-modified cotton. Investigation of the fabrics’ antimicrobial functions showed that the products were very effective, suggesting that both of these N-halamines can give the cotton the ability to inactivate bacteria. The second approach is to react silanol groups with cellulose to form antibacterial coatings (Figure 55); the synthesis of siloxane Nhalamines, especially cyclic forms, can directly confer antimicrobial properties onto cotton.70,73,74,124 Worley’s group70 achieved antimicrobial coating surfaces on cotton by attaching 3-triethoxysilylpropyl-5,5-dimethylhydantoin in a polymeric form that was transformed to hydantoin-containing N-halamines after a chlorinating treatment. The final cotton was biocidal against both S. aureus and E. coli. A third approach is to react cotton directly with N-halamines containing diol groups (or epoxide rings).60,62,134,135 For example, by the attachment of diol/epoxide, Ren’s group134 tethered 1-glycidyls-triazine-2,4,6-trione and 1-(2,3-dihydroxypropyl)-s-triazine2,4,6-trione onto cotton fabrics with 1,2,3,4-butanetetracarboxylic acid as a cross-linking agent. The as-grafted cotton was then chlorinated by hypochlorite solutions to give it antibacterial properties. Although many synthesized textile materials and polymers have been widely used in practical applications, they have been regarded as potential vectors in the cross-transmission of infectious diseases. An effective way to avoid this is to chemically endow most synthetic polymers with biocidal properties. This approach is very useful for the polymer

6.4. Medical and Healthcare Products

Infectious diseases, in particular some of those induced by pathogenic bacteria, are of great concern in the medical and healthcare fields, including for the providers and users of medical devices, hospital furniture, surgery equipment, healthcare products, and hygienic applications.3 To reduce threats to human health, antimicrobial agents can often be used to combat and eradicate pathogens in these contexts.6 Unlike other antibacterial agents, N-halamine-based materials have garnered a great deal of interest for use in medical and healthcare products owing to the unique antimicrobial functions related to halogens and/or halogen analogues.392−394 Luo et al.392 used a surface grafting approach to introduce acyclic Nhalamines onto the inner surfaces of continuous, small-bore, polyurethane (PU) dental unit waterline (DUWL) tubing (Figure 56). Experimentally, methacrylamide (MMA) was grafted onto the tubing’s inner walls by a polymerization approach in which dicumyl peroxide (DCP) was used as a freeradical initiator. Upon chlorine bleach treatment, the amide groups transformed into N-halamines and made the DUWL tubing antibacterial. Although the mechanical properties of the tubing were not significantly affected by the N-halamine grafting, evaluation with P. aeruginosa in a continuous bacterial flow model showed that the inner surfaces of the grafted PU tubing completely prevented the formation of bacterial biofilm for at least 3 to 4 weeks. Porteous et al.393 subsequently examined bacterial growth and type on biofilm-controlling Nhalamine-grafted DUWL tubing and on controlled manufacturer’s tubing in a laboratory DUWL model to check the modified tubing’s efficacy. After 3 weeks, biofilm was still absent from that tubing, whereas it was present on the inner surfaces AO


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adequate biocidal efficacy when tested using a Petri dish method.70 The second method was to use N-halamine precursors with a commercial polyurethane coating formulation to prepare N-halamine-based paints. The formulation was coated onto a Petri dish and then chlorinated to obtain smoother paints with good antibacterial function. Notably, the N-halamines in the paints showed excellent stability even after long-term storage. To extend the use of N-halamines in pigments and paints, the same group mixed 3-triethoxysilylpropyl-5,5-dimethylhydantoin and its polymer with commercial floor enamel to produce liquid paint and then brush it onto wood.395 After treatment with a bleach solution, these precursors transformed into N-halamine-modified surfaces, showing good antibacterial activity against both E. coli and S. aureus. Cao et al.117 studied 4-piperidinol-containing N-halaminebased antibacterial paints (Figure 57). They mixed a small Figure 56. (A) Experimental setup for dicumyl peroxide (DCP) absorption into the inner walls of PU tubing. (B) Experimental setup for treatment of the tubing’s inner surfaces. Reproduced from ref 392. Copyright 2011 American Chemical Society.

of the controlled tubing, suggesting that the former had prevented biofilm formation. However, some scattered bacteria, variants in the genera Proteobacteria, were detected on the Nhalamine-grafted DUWL tubing after long-term usage. The researchers speculated that over time, this bacterial growth had probably resulted from the biofilm-controlling properties being exhausted and/or the appearance of bacteria resistant to Nhalamines. This study not only offered a clue to the ecological adaptation of bacteria but also provided a potential way to prevent DUWL contamination. Using a layer-by-layer assembly technique, Umair et al.394 prepared bactericidal surgical sutures based on N-halamines. They deposited polymeric 4-piperidinol-containing N-halamines onto polyglycolide sutures to produce the antibacterial activity. Evaluation showed that the synthesized N-halaminebased sutures with a chlorine loading of 0.22% effectively inactivated bacterial strains in a short contact period. Straightpull and knot-pull strength tests of the sutures showed a slight decline in tensile properties, while in vitro hemolysis and cytocompatibility tests indicated good biocompatibility. Such antibacterial, biocompatible N-halamine coatings should be ideal candidates for developing biocidal sutures.

Figure 57. Paint films of (A) Color Place exterior latex semigloss house paint, white paint, (B) Color Place exterior latex semigloss house paint, white paint containing 20 wt % of N-chloro-2,2,6,6tetramethyl-4-piperidinyl methacrylate (poly(Cl-TMPM)), (C) Auditions satin paint, blue paint, and (D) Auditions satin paint, blue paint containing 20 wt % of poly(Cl-TMPM). Reproduced from ref 117. Copyright 2009 American Chemical Society.

amount of homemade water-based polymeric N-halamine latex emulsion into commercial water-based latex paints as an antibacterial additive. The resulting paints provided long-lasting antibacterial activity against S. aureus, methicillin-resistant S. aureus (MRSA), vancomycin-resistant enterococcus (VRE), E. coli, C. tropicalis, MS2 virus, and S. chartarum spores, suggesting that these N-halamine-based paints should be able to effectively prevent biofilm formation.

6.5. Dyes and Paints

Because of the fast-growing need to control surface microbial contamination in residential, commercial, institutional, industrial, and hygienic settings, antibacterial dyes and/or paints that inactivate pathogenic bacteria are experiencing tremendous growth.117 In this context, N-halamine-based antibacterial dyes and/or paints have greatly advanced in the past several decades.70,117,395 Worley’s group70 used two methods to obtain biocidal paints by combining them with N-halamines. One approach was to use as-prepared N-halamine-based pigment to modify paint. A commercial TiO2 pigment was suspended in an ethanol/water solution of 3-triethoxysilylpropyl-5,5-dimethylhydantoin, followed by post-treatment filtering and drying. After chlorination with 5% bleach, the hydantoin groups resulted in the formation of an N-halamine-based pigment for preparing the biocidal paint. The N-halamine-coated paint formed in this manner appeared grainy. The pigment displayed

6.6. Silica Materials

Silica materials such as glass, sand, and silica gel have been widely used in many fields because they are almost nontoxic, are chemically inert, and are amenable to surface modification. Endowing them with antibacterial properties will make silica materials even more popular.396−398 Worley et al.103 coated polymeric N-halamines on commercial glass to prepare antibacterial glass in which N-halamine siloxane and its polymers constituted the main precursors of biocidal coatings on silica materials. Experimentally, the polymeric solution containing the N-halamine precursors was added to coat the surface of the glass without running over the sides. Then, the coated glass was heated in an oven at 80−100 °C until the AP


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water was removed. After the surface was chlorinated by soaking it in a dilute solution of sodium hypochlorite, they obtained the N-halamine-surface functionalized glass. This glass efficiently inactivated bacterial organisms after a relatively brief contact period of several minutes. It would be very useful to endow sand with antibacterial properties, so some researchers have explored this possibility. For example, Worley’s group72 polymerized an N-halamine monomer (3-triethoxysilylpropyl-5,5-dimethylhydantoin) on the surface of sand particles to produce an adhered N-halamine film after treatment with dilute sodium hypochlorite bleach. The final hydantoin-containing, N-halamine-functionalized sand particles became very biocidal. Later, the same group used N-halamine acrylamidesiloxane copolymers to prepare biocidal sand.399 Some N-halamines have been utilized to fabricate antibacterial silica gels.129,400−402 Using an N-halamine monomer (5,5-dimethyl-3-(3′-triethoxysilylpropyl)hydantoin) and its hydrolysis-generated polymer (poly[3-(5,5-dimethylhydantoinylpropyl)hydroxysiloxane] to anchor onto the surfaces of silica gels, Worley’s group400 synthesized hydantoin-containing compounds for the functionalization of silica gel. After chlorination treatment with sodium hypochlorite bleach, the modified silica gel particles showed biocidal efficacy in a cartridge filter experiment against E. coli and S. aureus. Notably, when the bound chlorine was depleted, the loss of biocidal activity for the silica gel particles could be renewed by further exposure to dilute bleach. To find various effective N-halamines for the functionalization of silica gels, Jie et al.401 explored using quaternarized N-halamine groups. In their experiments, (5,5dimethylhydantoinyl)-3-ethyl dimethylamine was grafted onto silane-modified silica gels, which were then subjected to a chlorination procedure. The as-prepared silica gels possessed powerful and fast biocidal capacity, suggesting potential for use in the disinfection of flowing water. Two other materials, 4piperidinol-containing N-halamines402 and barbituric acid containing N-halamines,129 were used in the functionalization of silica gels. Barnes et al.402 covalently bonded 4-[3triethoxysilylpropoxyl]-2,2,6,6-tetramethylpiperidine to the surfaces of silica gels and then treated them with sodium hypochlorite to form stable N−Cl bonds at the hindered amine nitrogen sites. These silica gels, which were functionalized with 4-piperidinol-containing N-halamines, provided a greater than 6 log inactivation of S. aureus and E. coli in a column filter application in the 30−60 s contact time range. Interestingly, Ahmed et al.129 used barbituric aid rings to prepare N-halamine-functionalized silica gels. After chlorination, the modified silica gels exhibited powerful antibacterial activity against Gram-positive (S. aureus) and Gram-negative (E. coli) bacteria (Figure 58).

Figure 58. SEM of modified silica gel particles (A) before and (B) after halogenation. Reproduced with permission from ref 129. Copyright 2010 Wiley Periodicals.

CaCO3 fillers with an N-halamine-based fatty acid (Cl-DMHUA) to confirm the simultaneous achievement of antibacterial activity (see Figure 59). Chylińska et al.403 modified the regular

Figure 59. SEM images of (A) unmodified CaCO3 and (B) Cl-DMHUA-CaCO3. Reproduced from ref 71. Copyright 2009 American Chemical Society.

coating method using dry-blend extrusion and injection molding. They successfully processed a mixture of N-halamines and poly(vinyl chloride) to obtain biocidal plastics that demonstrated clear antibacterial activity. To obtain the antibacterial qualities of stainless steel in the fabrication of food processing facilities and biomedical devices, Bastarrachea and Goddard163 used N-halamines to modify the surface of stainless steel and render it bactericidal, as seen in Figure 60. Using hydantoin-containing N-halamines and a grafting method, Worley and coauthors396 developed a kind of antibacterial stainless steel in which 3-triethoxysilylpropyl-5,5dimethylhydantoin and its polymers were coated onto the surface of stainless steel and then charged with free halogen by

6.7. Other Applications

On the basis of their unique chemical structure and antibacterial functions, N-halamines are being explored for other important applications.61,89,90,191,308,396,403−405 For instance, Williams et al.396 developed melamine-containing Nhalamines for kitchen work surfaces by imparting antimicrobial properties to the materials in furniture surfaces, such as plastics, ceramic tiles, cardboard, wood, marble, aluminum, formica, grout cement, and glazed porcelain. They found that antibacterial coatings on a wide variety of hard and soft substrates could be obtained by exposing surfaces treated with N-halamines. Padmanabhuni et al.61 coated the surfaces of

Figure 60. Schematic illustration for N-halamine-modified stainless steel prepared using a layer-by-layer deposition technique. Reproduced with permission from ref 163. Copyright 2013 Wiley Periodicals. AQ


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effective methodologies for synthesizing N-halamine-based antibacterial materials. Most of the early procedures focused on the facile halogenation of ammonia or low-molecular amine/amide/imide compounds, such as hydantoins, imidazolidinones, oxazolidinones, and amino acids. As synthesis techniques and skills have improved, certain advanced chemical approaches have been used to produce N-halamine polymers and coatings on materials’ surfaces; presently, homo- or heteropolymerization and grafting/coating approaches are the most common techniques for giving such materials biocidal functions. Some nonclassical pathways, transforming cation amines to N-halamines, combining amination and halogenation, and transforming N-halamines with nitrogenous compounds to form alternative N-halamines, have also been used to synthesize novel N-halamine-based materials. Although numerous and diverse N-halamines have been created using various synthesis approaches, we can observe the following: (1) all N-halamines are obtained by halogenating the corresponding nitrogenous precursor compounds; (2) Nchloramines prepared by chlorinating amine/amide/imidecontaining compounds constitute the majority of N-halamines; (3) among the various halogenating agents favorable for synthesizing N-halamines, sodium hypochlorite is the most popular due to its physicochemical advantages; and (4) Nhalamine polymers/coatings have become the main focus for developing N-halamine-based antibacterial materials. It is essential to use chemical and/or physical techniques to identify the structures of the diverse N-halamines. Because Nhalamines are susceptible to certain reducing agents (e.g., methionine and 5-thio-2-nitrobenzoic acid), oxidation−reduction reactions are often conducted to chemically identify an Nhalamine’s structure. These investigations can be qualitative or quantitative. Certainly, physical methods can assist with further examination, because they direct much more attention to the specific characterization of N−X bond(s), coupled with advanced techniques (e.g., X-ray photoelectron spectroscopy). In addition, semispecific and nonspecific physical approaches have been introduced as auxiliary tools in the characterization and confirmation of N-halamines. Most of the chemical and physical methods are simple, easy to carry out, and effective for identifying both inorganic and organic N-halamines. However, some are not sufficiently sensitive to detect synthesized Nhalamines present in trace levels. This problem can, though, be addressed by combining N-halamine sample preprocessing techniques and time-dependent physical/chemical methods. It can be very difficult to distinguish two or more N-halamines using the various chemical and/or physical methods, especially when the materials have similar structures and physicochemical properties. New or updated techniques, such as isotopelabeling, molecular imprinting, and scanning transmission electron microscopy (STEM), can be combined with off-theshelf techniques to structurally characterize N-halamines and thereby make their identification more accurate. In addition to improving the synthesis and characterization of N-halamines, it has been important to improve their stability under a wider range of harsh chemical/biological conditions and thereby increase their practical applications. In terms of physicochemical properties, the stability of N-halamines strongly depends on external conditions, such as heat, light, pH value, water, chemicals, and bacteria. The most common strategy to enhance stability is to design stable structures for the N-halamines. The structural stability of N-halamines toward the release of free halogen decreases in this order: amine N-

soaking them with sodium hypochlorite bleach solutions. The resulting N-halamine-grafted stainless steel can offer an excellent antibacterial activity. N-Halamines have proven useful in the field of paper products. Worley’s group70 fabricated biocidal papers by immobilizing hydantoin-containing N-halamines on two kinds of commercial paper: white and brown commercial office envelopes. After spraying an alkaline solution of 3-triethoxysilylpropyl-5,5-dimethylhydantoin from an atomizer bottle onto both sides of the two samples, they also sprayed a bleach solution on both sides to obtain N-halamine-based antibacterial paper. The two treated samples stabilized the oxidative chlorine very well over a 36-day period. An antibacterial kinetic assay proved that the samples were effective in killing S. aureus due to the presence of the oxidative chlorine. Interestingly, N-halamines are also used as potent disinfectants in daily life. Russo et al.404 developed a new intact skin antisepsis formulation: a solution containing 0.5% chloramine-T diluted in 50% isopropyl alcohol. Worley’s group89,90 demonstrated that instead of free chlorine, Nhalamines acted as effective disinfectants in the egg-processing and poultry-processing industries. N-Halamines have played a significant role in reducing the human toxicity of pesticides and warfare agents. Sun’s group308,405 used chemical approaches to demonstrate treated fabrics’ ability to detoxify oxime carbamate pesticides due to the formation of thio bonds upon contact. Kocer et al.191 treated fabrics with melamine-containing N-halamines to detoxify paraoxon, a warfare agent stimulant. Generally, N-halamines have become most important antibacterial agents in our daily life and work. Compared with other applications (e.g., air purification, medical and healthcare products, dyes and paints, and silica materials), water disinfection and textile products are two most frequent applications for antibacterial N-halamines probably because they are directly related to the essential requirements of the people: food, clothing, housing, and transportation. It is a fact that the used antibactial N-halamines can directly or indirectly prevent infections induced by pathogens. Although antibacterial N-halamines were involved into dental unit, waterline tubing, and surgical sutures, it is important and necessary for researchers and developers to further explore N-halamines in the medical and healthcare applications. Also, antibacterial Nhalamines should be developed widely in some applications, such as medical apparatus, public facilities, and hospitals, to prevent and control microbial contamination.

7. CONCLUSIONS AND PERSPECTIVES In the past several decades, there has been increasing interest in the chemistry of antibacterial N-halamines, prompting a rise in the research and development of N-halamine-based materials. They have several advantages, including structural characteristics, physicochemical stability, antibacterial properties, and real-world applicability, offering new avenues for exploring and creating advanced antibacterial materials. This review has provided comprehensive chemical insights into antibacterial N-halamines, including their synthesis, characterization, stability, and activity, as well as their correlation. It has also presented a variety of methods for preparing advanced N-halamines to use in antibacterial applications, exploring a wide range of these materials for potential use as efficient bactericidal agents. As N-halamines are very useful for preventing pathogenic infections, many groups covered in this review have developed AR


Chemical Reviews

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AUTHOR INFORMATION

halamines > amide N-halamines > imide N-halamines. Conversely, their antibacterial capability toward most bacteria species is in the reverse order: amine N-halamines < amide Nhalamines < imide N-halamines. Hence, developing N-halamines that can be widely applied requires coordinating these materials’ stability and antibacterial activity. Many other factors also affect the antibacterial activity of Nhalamines, including type, size, substitution, hydrophilic− hydrophobic balance, solution pH, and bacteria species. In the search for the best biocidal action, numerous studies have explored advanced chemical and/or biological methods to optimize the biological effect of N-halamines on bacteria. Good stability and powerful biocidal activity are key for developing advanced N-halamines in the future. The fundamental studies done to date on the synthesis, characterization, stability, and antibacterial action of N-halamines are useful guides for designing and fabricating novel N-halamines and/or their analogs, and exploring their potential applications. Although much exciting progress has been achieved with Nhalamines, they still have significant disadvantages, including expensive synthesis, complicated preparation methods, instability under certain conditions (e.g., water, light, or heat), unclear mechanisms for killing bacteria, and insufficient antibacterial efficiency. To overcome these challenges and generate advanced N-halamines with optimal structure and properties, several important future research strategies can be pursued: (1) constructing a fundamental understanding of antibacterial N-halamines via a combination of experiments and theoretical studies that establish the correlation between antibacterial activity and their molecular structures. In particular, theoretical studies can guide the structural design as well as predict the antibacterial activities of N-halamines before experimental research is started. (2) Introducing “green chemistry” (e.g., innovative biotechnology alternatives to chemical approaches, greener and safer chemicals for generating N-halamines, and sustainable procedures) into the synthesis of N-halamines, and fabricating “environmentally friendly” routes for the healthy and sustainable development of N-halamines. (3) Pursuing systematic, in-depth studies to determine the antibacterial mechanisms when N-halamines are used to kill bacteria (e.g., destroying the integrity of subcellular structures, disrupting cell membranes, inhibiting protein synthesis, and interacting with DNA). An understanding of these mechanisms can then be used to guide the design and synthesis of targetspecific N-halamines. (4) Optimizing and tuning macroscopic/ microscopic factors, such as chemical group, structure, morphology, and/or size to obtain N-halamines with the best antimicrobial efficacy to fight against multidrug-resistant superbugs. Previous research conditions and results have shown how necessary it is to build a database of such information and tailor the experimental factors to optimize the design and synthesis of N-halamines for the best antimicrobial function. (5) Transforming the bench research on N-halamines in academic laboratories into practical applications by developing close collaboration between scientists/engineers and front-line workers. It is very important, necessary, and timely to drive more N-halamines forward from the laboratory to practical applications. These research strategies define the essential trends for the future development and exploration of advanced antibacterial N-halamines.

Corresponding Authors

*E-mail: [email protected]. Tel: 86-471-4992982. *E-mail: [email protected]. Tel: 1-604-827-3232. *E-mail: [email protected]. Tel: 86-0431-81954036. ORCID

Alideertu Dong: 0000-0002-2812-3649 Notes

The authors declare no competing financial interest. Biographies Dr. Alideertu Dong received his B.S. in Chemistry from Inner Mongolia University for Nationalities in 2007 and his Ph.D. in Polymer Chemistry and Physics at Jilin University in 2012. He then joined the College of Chemistry and Chemical Engineering, Inner Mongolia University, as a lecturer and was promoted to associate professor in 2015. His research focuses on the development of biomedical materials, particularly their synthesis and application. To date, he has published two books and over 30 peer-reviewed papers. Dr. Yan-Jie Wang obtained his M.S. from North University of China in 2002 and his Ph.D. in Materials from Zhejiang University, China, in 2005. Subsequently, he conducted two and a half years of postdoctoral research at Sungkyunkwan University, Korea, followed by two years as a research scholar at Pennsylvania State University, studying advanced functional materials. In April of 2009, he was cohired by the University of British Columbia, Canada, and the National Research Council of Canada to research advanced materials. Since November of 2012, he has worked as a senior research scientist for the University of British Columbia and Vancouver International Clean-Tech Research Institute Inc. (VICTRII), researching core−shell structured materials. Dr. Wang is also an adjunct professor of Fuzhou University in China. He is particularly interested in materials synthesis, modification, characterization, and application in clean energy technology, biomass engineering, and medical areas. Yangyang Gao is currently pursuing her M.S. degree in Chemistry under the supervision of Professor Alideertu Dong at Inner Mongolia University. Her work focuses on the synergistic antibacterial action of N-halamines and graphene oxides on pathogenic bacteria. Tianyi Gao is currently pursuing her M.S. degree in Chemistry under the supervision of Professor Alideertu Dong at Inner Mongolia University. She is working on the design and fabrication of halogencontaining polymers for biomedical applications. Dr. Ge Gao is currently a full professor at the Department of Polymer Science, College of Chemistry, Jilin University. He obtained B.S. and Ph.D. degrees with highest honors in Polymer Chemistry (1982) and Polymer Chemistry and Physics (1998) from Jilin University and a M.S. in Polymer Chemistry from the Changchun Institute of Applied Chemistry in 1985. He is a polymer scientist with particular expertise in polymer composite materials and polymeric antimicrobial agents.

ACKNOWLEDGMENTS We are grateful for the financial support of the National Natural Science Foundation of China (21304044 and 51663019), the Natural Science Foundation of the Inner Mongolia Autonomous Region (2015MS0520), and the State Key Laboratory of Medicinal Chemical Biology (201603006). ABBREVIATIONS 2-MBTZ 2-mercapto-benzothiazole AS


Chemical Reviews AAM AATCC ACHT ACTMIO ADCT ADMH AFM AMP AN APA-1

ASF BDE BMA BPO BTCA BUA CA CADMH CDDMH CDMH CFA Cl-BTMP Cl-DCSDMH Cl-DDMH Cl-DMH-UA Cl-FODMH Cl-ODMH Cl-TMPM Cl-TMPL CTMIO DA DANASO2H DCA DCP DCSDMH DDMH DFT DMH DMH-N3 DMH-UA DMPO DMTPTD DPD DSC DTBHY DTNB DTT DUWL

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EDX EtO ESR FIA FTIR Gly-C GM GPC GTT HA-1

acrylamide American Association of Textile Chemists and Colorists 2-amino-4-chloro-6-hydroxy-s-triazine 1-acryloyl-2,2,5,5-tetramethyl-4-imidazolidinone 2-amino-4,6-dichloro-s-triazine 3-allyl-5,5-dimethylhydantoin atomic force microscopy 2-amino-2-methyl-1-propanol acrylonitrile poly[(6-morpholino-s-triazine-2,4-diyl)-Nchloro-[2,2,6,6-tetramethyl-4-piperidyl)imino]-hexamethylene-[(2,2,6,6−4-piperidyl) imino]] ammonium sulfate with ferrous iron bond dissociation enthalpies n-butyl methacrylate benzoyl peroxide 1,2,3,4-butanetetracarboxylic acid 11-bromoundecanoic acid cellulose acetate 1-chloro-3-alkyl-5,5-dimethylhydantoin chlorinated 3-dodecyl-5,5-dimethylhydantoin chlorinated 5,5-dimethylhydantoin continuous-flow analysis bis(N-chloro-2,2,6,6-tetramethyl-4-piperidinyl) sebacate 1-chloro-3-docosyl-5,5-dimethylhydantoin 1-chloro-3-dodecyl-5,5-dimethylhydantoin 3-chloro-4,4-dimethylhydantoin undecanoic acid 1-chloro-3−1H,1H,2H,2H-perfluorooctyl5,5-dimethylhydantoin 1-chloro-3-octyl-5,5-dimethylhydantoin N-chloro-2,2,6,6-tetramethyl-4-piperidinyl methacrylate N-chloro-2,2,6,6-tetramethyl-4-piperidinol laurate chlorinated 2,25,5-tetramethyl-imidozalidin-4-one N-(1,1-dimethyl-3-oxobutyl)acrylamide 5-(dimethylamino) naphthalene-1-sulfinic acid dichloramine dicumyl peroxide 3-docosyl-5,5-dimethylhydantoin 3-dodecyl-5,5-dimethylhydantoin density functional theory 5,5-dimethylhydantoin 3-(2′-azido-ethyl)-5,5-dimethylhydantoin dimethylhydantoin undecanoic acid 5,5-dimethyl-1-pyrroline-1-oxide 6,6-dimethyl-3-(3′-triethoxysilylpropyl)1,3,5-triazinane-2,4-dione N,N-diethyl-p-phenylenediamine differential scanning calorimeter 2,5-dimethyl-2,5-(tert-butylperoxy)hexyne 5,5′-dithiobis(2-nitrobenzoic acid) 1-(2,3-dihydroxypropyl)-s-triazine-2,4,6trione dental unit waterline

HDI His-C HPLC HS-GC GC LBL LC LOQs Lys-C MAA m-APH MBA MBC MCA MF MMA m-PDA MIC MIMS MRSA MS MTPTD MVBBA NCDEA NCNMPT NCP NCS NDAM NMA NMR NPs NTAAM NTMAM OD600 PAA PAN PBI PE PEG-NH2 PEI PET PMAA poly-AN-Barb-Cl poly-CTD POU PP AT

energy-dispersive X-ray spectroscopy ethylene oxide electron spin resonance flow-injection analysis infrared spectroscopy glycine glycidyl methacrylate gel permeation chromatography 1-glycidyl-s-triazine-2,4,6-trione poly[(6-morpholino-s-triazine-2,4-diyl)[2,2,6,6-tetramethyl-4-piperidyl]-imino]hexamethylene[(2,2,6,6-tetramethyl-4-piperidyl)-imino]] 1,6-hexamethylene diisocyanate Nα-acetyl-histidine high-performance liquid chromatography headspace GC gas chromatography layer-by-layer liquid chromatography limits of quantitation Nα-acetyl-lysine methacrylamide m-amino-phenyl hydantoin N,N′-methylenebis(acrylamide) minimum bactericidal concentration monochloramine melamine formaldehyde methyl methacrylate m-phenylenediamine minimum inhibitory concentration membrane introduction mass spectrometry methicillin-resistant S. aureus mass spectrometry 6-phenyl-3-(3′-triethoxysilylpropyl)-1,3,5triazinane-2,4-dione 5-methyl-5-(4′-vinylbenzyl)barbituric acid N-chlorodiethtlamine N-chloro-N-methyl-p-toluenesulfonamide N-chloropiperidine N-chlorosuccinimide 2,4-diamino-6-diallylamino-1,3,5-triazine N-(hydroxymethyl) acrylamide nuclear magnetic resonance spectroscopy nanoparticles N-tert-butylacrylamide N-tert-butylmethacrylamide optical density at 600 nm poly(acrylic acid) polyacrylonitrile polybenzimidazole polyethylene poly(ethylene glycol) terminated amine polyethylenimine polyester polymethacrylamides poly[acrylonitrile-co-(1,3-dichloro-5-methyl-5-(4′-vinylbenzyl)-barbituric acid)] poly(1,3,5-trichloro-6-methyl-6-(4′-vinylphenyl)-1,3,5-triazine-2,4-dione) point-of-use polypropylene DOI: 10.1021/acs.chemrev.6b00687 Chem. Rev. XXXX, XXX, XXX−XXX

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PP-g-DAM poly(propylene-g-diallylmelamine) PU polyurethane PVA-co-PE-g-DAM poly(vinyl alcohol-co-ethylene-g-diallylmelamine) QM trimethyl-2-methacryloxyethylammonium chloride RO reverse osmosis ROS reactive oxygen species SA 2-acrylamido-2-methyl-1-propanesulfonic acid sodium SEM scanning electron microscope SL 3-(trimethoxysilyl)propyl methacrylate TATAT triallyl-1,3,5-triazine-2,4,6(1H,3H,5H)-trione Tau-C taurine t BuOCl tert-butyl-hypochlorite TCA trichloramine TGA thermogravimetric analysis TMB 3,3′,5,5′-tetramethylbenzidine TMIO 2,2,5,5-tetramethylimidazolidinone TMP 2,2,6,6-tetramethyl piperidinol TMPA 2,2,6,6-tetramethylpiperidinyl acrylate TMP·HCl 2,2,6,6-tetramethyl-4-piperidinol hydrochloride TNB 5-thio-2-nitrobenzoic acid TSCHB N-(3-triethoxysilylpropyl)-N′-cyclohexylbutanediamide TSHB N-(3-triethoxysilylpropyl)-N′-hexylbutanediamide TSHCEB N-(3-triethoxysilylpropyl)-N′-(N‴-heptylcarbamido-N″-ethyl)-butanediamide TSPB N-(3-triethoxysilylpropyl)-N′-phenylbutanediamide TTDD 7,7,9,9-tetramethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione TTDD diol 3-(2,3-dihydroxypropyl)-7,7,9,9-tetramethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione TTDD siloxane 3-(3′-triethoxysilylpropyl)-7,7,9,9-tetramethyl-1,3,8-triazaspiro[4.5]decane-2,4dione UV UV−vis spectroscopy VAC vinyl acetate VBDMH 3-(4′-vinylbenzyl)-5,5-dimethylhydantoin VRE vancomycin-resistant enterococcus WCW worst case water XPS X-ray photoelectron spectroscopy XRD X-ray diffraction β-CD β-cyclodextrin

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