ARTICLE pubs.acs.org/IECR
Versatile and Scalable Method for Producing N-Functionalized Imidazoles Jason E. Bara* Department of Chemical & Biological Engineering, University of Alabama, Tuscaloosa, Alabama, United States 35487-0203
bS Supporting Information ABSTRACT: Imidazolate salts are powerful and versatile starting materials that can be used to generate many useful compounds. To this end, a method for producing sodium imidazolate (NaIm) from only commodity starting materials has been developed. NaIm was directly produced at a scale of ∼400 g via the neutralization of molten imidazole by NaOH, followed by dehydration. The NaIm product was then utilized as a starting material to produce 20 different N-functionalized imidazole and bis(imidazole) compounds, with the application of a common procedure involving minimal solvent volumes and straightforward purification via flash chromatography and solvent evaporation. Generating N-functionalized imidazoles “on demand” from NaIm and alkyl halides (or similar compounds) can eliminate the need for hazardous starting materials such as NaH and anhydrous solvents that have typically been employed in their synthesis. This method may ultimately enhance the availability of N-functionalized imidazoles for a variety of research and commercial applications.
1. INTRODUCTION N-Functionalized imidazoles (Figure 1) are a class of nitrogencontaining heterocycles that are potentially useful as tailored solvents with controlled physical and chemical properties1 or as building blocks for a variety of materials.2 N-Functionalized imidazoles feature a reactive nitrogen center which can be exploited as a base or nucleophile. Despite these attractive features and potential utility as solvents in engineering applications, even the most simple physical property data such as density, viscosity, and vapor pressure have only recently been reported for relatively simple alkyl-functionalized derivatives (commonly referred to as alkylimidazoles or N-alkylimidazoles).1,3,4 The general lack of systematic studies or structureproperty relationships devoted to a series of N-functionalized imidazoles might be correlated to their lack of availability. With the exception of 1-methylimidazole (Figure 1, R1 = CH3), virtually every other N-functionalized imidazole must either be purchased in small quantities or synthesized for the desired application. N-Functionalized imidazoles are vital to the pharmaceutical industry.5 Imidazoles with large and complex ‘R’ groups are antifungal agents such as miconazole, clotrimazole, and other commercial products. Simple alkylimidazoles such as 1-hexylimidazole have also been shown to exhibit antibacterial properties.6 Other applications for N-functionalized imidazoles have included ligands7 and catalysts.8,9 Of course, N-functionalized imidazoles also serve as the primary starting materials for imidazolium salts, the most common class of ionic liquids (ILs).10,11 Also of interest have been bis(imidazole) compounds (Figure 2), wherein two imidazole rings are tethered across their respective nitrogen atoms with a variety of linkers (R in Figure 2). Of these, 1,1 0 -(1,4-butanediyl)bis(imidazole) (Figure 2, R = C4H8) has been most used for its rigidity and ability to interact with metal cations to create coordination polymers.12,13 Bis(imidazoles) with this and other linkers have also been used to generate imidazolium-based ionenes (main-chain polycations),14,15 r 2011 American Chemical Society
cross-linkable IL monomers,16,17 and gemini liquid crystals18 and surfactants.19 The Radziszewski reaction was first reported in the 19th century and is the primary industrial method to synthesize imidazole (Figure 1) from glyoxal, formaldehyde, and ammonia.2027 Addition of a primary amine (e.g., methylamine) to the reaction mixture allows for the generation of N-functionalized imidazoles (e.g., 1-methylimidazole).27 Other modifications to the reaction mixture are possible to produce imidazoles with functional groups attached to one or more of the three carbon atoms within the 5-membered ring.27 However, the Radziszewski reaction is noted for poor yields and side reactions,27 limiting its efficacy to a narrow range of N-functionalized imidazole products. For many purposes, it is often more convenient to create the desired N-functionalized imidazoles using the parent imidazole (Figure 1) as a starting material. In laboratory settings, various methods have been utilized for the synthesis of N-functionalized imidazoles. The most commonly employed approach is the deprotonation of imidazole with a strong base to generate a metal imidazolate, such as sodium imidazolate (NaIm), in situ (Figure 1).6,16,18,28 An alkyl halide, or other compound with a suitable leaving group, is then added to produce the desired N-functionalized imidazole derivative (Scheme 1).6,1618,28,29 While the in situ method has been applied to the synthesis of many N-functionalized imidazoles, it is less than optimal and would be difficult to scale for both logistic and economic reasons. Typically, anhydrous solvents (e.g., N,N-dimethylformamide (DMF) or tetrahydrofuran (THF)) and air/H2O-sensitive reagents (e.g., Na metal, sodium methoxide (NaOMe) or sodium Received: December 20, 2010 Accepted: November 6, 2011 Revised: November 4, 2011 Published: November 17, 2011 13614
dx.doi.org/10.1021/ie102535c | Ind. Eng. Chem. Res. 2011, 50, 13614–13619
Industrial & Engineering Chemistry Research
ARTICLE
Figure 1. Structures of imidazolate anions, imidazole, N-functionalized imidazoles, and imidazolium cations and their relationships in synthetic chemistry.
Scheme 2. Direct Production of NaIm from Imidazole and NaOH Figure 2. Generic structure of bis(imidazole) compounds.
Scheme 1. Synthesis of N-Functionalized Imidazoles via in Situ Generation of Metal Imidazolate
hydride (NaH)) are required to generate the key metal imidazolate intermediate. These alkali metal-based reagents pose safety hazards and must be properly handled and stored. The use of Na or NaH to deprotonate imidazole will liberate one equivalent of H2 gas, the presence of which must be considered from the standpoints of safety and reactor design. The need for anhydrous solvents to maintain the reagent potency adds additional handling/storage considerations and costs. N-Functionalized imidazoles have also been produced by a multitude of other procedures using various bases in solvents such as water, DMSO, toluene, or acetonitrile13,15,3033 and often relying on the use of phase transfer catalysts. While these methods are capable of generating the desired product with acceptable yields, the N-functionalized imidazole must be separated from these high boiling solvents through some combination of distillation, extraction, or precipitation. Because N-functionalized imidazoles and bis(imidazoles) have very low vapor pressures and high boiling points themselves, distillation of the final product can be very difficult or virtually impossible in many cases. Unconventional approaches to the synthesis of N-functionalized imidazoles have made use of ultrasound3438 or microwaves3942 with catalysts with varying degrees of success at small scales. With the exception of the Radziszewski reaction16 and unconventional approaches, virtually every methodology for producing N-functionalized imidazoles makes use of imidazole and a base to generate the metal imidazolate intermediate in situ for immediate reaction. However, much less effort has been focused on methods that isolate these important and versatile intermediates. Thus, a strategy that produced metal imidazolate salts in bulk, without the use of anhydrous solvents or hazardous reagents, could enable a much more convenient procedure for generating
N-functionalized imidazoles “on demand” at both large and small scales and open new opportunities for imidazole-based compounds. Toward this end, a procedure for generating NaIm using only commodity starting materials, imidazole and NaOH, is herein reported. As the melting point of imidazole is ∼91 °C,43 it can transition from a crystalline solid to a neat liquid under relatively mild conditions. Direct addition of solid NaOH to the molten imidazole resulted in the formation of NaIm and H2O via an acid base neutralization. H2O produced from the reaction was sufficient to keep the mixture fluid, though addition of small amounts of H2O (
