Communication pubs.acs.org/jchemeduc
Nucleophilic Aromatic SubstitutionAddition and Identification of an Amine Steven W. Goldstein,*,† Ashley Bill,† Jyothi Dhuguru,‡,§ and Ola Ghoneim‡ †
Department of Chemistry, University of Saint Joseph, 1678 Asylum Avenue, West Hartford, Connecticut 06117-2791, United States Department of Pharmaceutical Sciences, University of Saint Joseph-School of Pharmacy, 229 Trumbull Street, Hartford, Connecticut 06103, United States
‡
S Supporting Information *
ABSTRACT: The addition of a nucleophilic functional group to an electrondeficient aromatic ring is a versatile reaction in the modern organic chemistry arsenal. The proper positioning of a leaving group on this ring effectively allows for a substitution reaction to occur. A 3 h laboratory experiment is described in which students utilize a common electrophilic aromatic ring and affect a substitution with an unknown amine, the identity of which is later characterized by the melting point and 1H NMR spectrum of the product. KEYWORDS: Second-Year Undergraduate, Organic Chemistry, Problem Solving/Decision Making, Addition Reactions, Amines/Ammonium Compounds, Aromatic Compounds, Nucleophilic Substitution
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INTRODUCTION The addition of a nucleophilic functional group to an electrondeficient aromatic ring, often called the SNAr reaction, is a versatile reaction in the modern organic chemistry arsenal. The reaction involves the addition of a nucleophilic functional group to an aromatic ring (containing a leaving group), with the concomitant formation of a stabilized Meisenheimer or Jackson−Meisenheimer complex.1 The stability of this anionstabilized intermediate increases with the number, position, and strength of the electron-withdrawing substituents on the ring.2 The positioning of a leaving group at the proper position then allows for a substitution reaction to take place, effectively replacing the leaving group with the nucleophile (Scheme 1).3
electron density at the site of attack, resulting in a faster attack by the nucleophile. The fastest reaction rates are observed when the leaving group is fluoro, which is in agreement that the mechanism by which SNAr proceeds is very different than that of SN1 or SN2 reactions.7 The range of nucleophiles includes amines, alkoxides, sulfides, and stabilized carbanions.3,8 Having an invariant order of nucleophilicity is not possible because different substrates and different reaction conditions affect the order of nucleophilicity. It is generally accepted that nitrogen nucleophiles such as NH2−, R2NH, and ArNH2 have good reaction rates. However, one must consider the multiple factors controlling the reactivity in SNAr reactions, such as the polarizabilities of both nucleophile and leaving group, the size of the leaving group, the basicity and size of the nucleophile, and the solvent used.9,10 Often times, the reaction conditions employed to effect this reaction require anhydrous conditions, strong bases, or highly reactive aromatic coupling partners, especially when relatively bulky amines are used as nucleophiles. Although the starting materials and products may be similar, this reaction is mechanistically quite different from the analogous Buchwald11,12 or Ullmann reaction.13,14 Given the importance and versatility of this reaction, other than Sanger-type reactions,15 we could find few examples of nucleophilic aromatic substitution in this Journal.16−21 Herein we report this communication as an experiment that exemplifies this versatile reaction as a teaching tool by engaging students in a novel exercise that allows them to determine the identity of an unknown amine reagent.
Scheme 1. Mechanism of the SNAr Reaction
The aromatic ring may be a heterocycle4 or a carbocyclic aromatic ring containing one or more substituents capable of stabilizing an anion and activating the aromatic ring. Commonly used substrates are substituted at ortho and/or para positions on the ring with strong electron-withdrawing groups (EWGs).5 A nitro group is by far the most common activating group.6 Other reported activating groups are cyano, acyl, and even metal substituted in which vacant metal orbitals are available, e.g., para tricarbonyl chromium phenyl halides.5 The leaving group that undergoes the exchange process is frequently a halogen, although sulfides and their oxidized congers are commonplace as well.3 An increase in the electronegativity of the leaving group causes a decrease in the © XXXX American Chemical Society and Division of Chemical Education, Inc.
Received: September 5, 2016 Revised: June 13, 2017
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DOI: 10.1021/acs.jchemed.6b00680 J. Chem. Educ. XXXX, XXX, XXX−XXX
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EXPERIMENT Students completed this experiment in a single 3 to 4 h laboratory session either alone or with a partner. The studentselected amino nucleophile (as a 1 M solution in 2-propanol) is reacted with methyl 4-fluoro-3-nitrobenzoate in the same solvent (Scheme 2). Immediately upon addition, the solution
amino component of their reaction. Generally, the observed melting point was within 7 °C of the accepted values. Although several final products have similar melting points (within 5 °C) or similar 90 MHz 1H NMR spectra due to CHCl3 impurities (e.g., CH2Ph and CH2C6H4(4-Cl)), students relied on utilizing both analyses in tandem to differentiate and identify their products. Both melting points and student run 1H NMR spectra are located in the Supporting Information. Based on pre- and postlaboratory questions, 91% of students could correctly predict the products of an amine of their choosing with another aromatic coupling partner (5-acetyl-2fluorobenzonitrile). All students could correctly identify the correct orientation of electron-withdrawing substituents required for the reaction to occur. The commercially available 4-fluoro-3-nitrobenzoate was selected as a starting material. The fluorine atom will act as a good leaving group and is able to form a strong hydrogen bond with the protic solvent, and this is in agreement with the predicted hydrogen bond acceptor properties of aromatically bound halogens.23 The presence of the methyl carboxylate group at the para-position, and the nitro group at the ortho position, helps activate the C−F bond and facilitates the Narylation. The efficiency of the N-arylation/substitution reaction was also enhanced as the amines employed were highly soluble in 2-propanol. Additionally, there was no byproduct formation due to N-acylation of unhindered primary amines or ester hydrolysis. While this reaction works with a broad range of primary and secondary amines, primary amines give the highest yield and are generally the most crystalline (Table 1 for student results)
Scheme 2. SNAr Reaction of 4-Fluoro-3-nitrobenzoate
turned a bright yellow, indicating that the reaction has begun, a key observation for many students. Heating for 30 min ensured that sufficient product would be isolated from the solution via filtration. The addition of 2 equiv of the amine, relative to the methyl 4-fluoro-3-nitrobenzoate, ensured that the hydrofluoric acid liberated in the course of the reaction was neutralized. The use of the amines at a fixed concentration allowed for rapid reaction setup and discouraged students from utilizing calculations to determine the identity of the unknown material. The details of this experiment may be found in the Supporting Information. The amines for this experiment were chosen such that the methyl 4-amino-3-nitrobenzoate products were sufficiently crystalline that they could be isolated directly out of the reaction via filtration. The observable physical characteristics (melting point and 1H NMR spectrum) of the product must be instrumental in the identification of the unknown amino starting material. We have found that products from this experiment with very similar low-field 1H NMR spectra (e.g., products derived from benzylamine and 4-chlorobenzylamine) have dramatically different melting points.22 After the yellow to orange crystalline material was dried overnight, the students obtained melting points and 1H NMR spectra (no trace of 2propanol was seen in the 1H NMR spectra).
Table 1. Range of Student Yieldsa
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HAZARDS Chemical splash goggles and other forms of PPE (e.g., gloves, aprons) should be worn at all times. 2-Propanol is flammable and an inhalation and contact hazard. The amines, methyl 4fluoro-3-nitrobenzoate and the methyl 4-amino-3-nitrobenzoate products are flammable and should be disposed of following guidelines for organic waste disposal. CDCl3 is a contact hazard and should be disposed of following guidelines for organic waste disposal.
R
Student Yelds (%)
CH2Ph CH2C6H4(4-CH3) CH2C6H4(4-Cl) CH2CH2C6H5 cyclo-C5H9
72−100 89−100 77−93 34−85 87−91
a
Results from 65 individual student experiments, approximately 13 trials per amine monomer.
because the isolation of these products requires a balance of reactivity and solubility. The products arising from a variety of different anilines were isolated without difficulty; however, the potential toxicity of the starting amines led us to avoid them in this student-based experiment. We have also found that methyl 4-morpholino-3-nitrobenzoate, prepared from morpholine and methyl 4-fluoro-3-nitrobenzoate was comparatively more soluble in 2-propanol than the other products described. Isolation of the solid required performing the reaction in 50% less solvent and cooling in ice to isolate this product.
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RESULTS AND DISCUSSION The goal of this experiment was to enable students to predict both the electronic requirements of a nucleophilic aromatic substitution reaction (e.g., substitution pattern on the aromatic ring) as well as the correct product of the reaction. A total of 45 students in four laboratory sections over two years in a secondsemester introductory organic chemistry course have completed this experiment as individuals. Additionally, many students repeated the laboratory experimental portion of the exercise (without prelab and postlab write-ups) with a different set of amines for a total of 65 individual experiments. Yields of the amino substitution products were typically greater than 70%, and 96% of the students correctly identified the starting
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SUMMARY This student experiment exemplified a nucleophilic aromatic substitution reaction whereby an amine reacted with an electron-deficient aromatic ring, resulting in a highly colored B
DOI: 10.1021/acs.jchemed.6b00680 J. Chem. Educ. XXXX, XXX, XXX−XXX
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(12) Wolfe, J. P.; Buchwald, S. L. Highly Active Catalyst for the Room-Temperature Amination and Suzuki Coupling of Aryl Chlorides. Angew. Chem., Int. Ed. 1999, 38 (16), 2413−2416. (13) Bringmann, G.; Walter, R.; Weirich, R. The Directed Synthesis of Biaryl Compounds: Modern Concepts and Strategies. Angew. Chem., Int. Ed. Engl. 1990, 29 (9), 977−991. (14) Nelson, T. D.; Crouch, R. D. Cu, Ni, and Pd Mediated Homocoupling Reactions in Biaryl Syntheses: The Ullmann Reaction. Org. React. 2004, 63 (3), 265−555. (15) Mottishaw, J. D.; Erck, A. R.; Kramer, J. H.; Sun, H.; Koppang, M. Electrostatic Potential Maps and Natural Bond Orbital Analysis: Visualization and Conceptualization of Reactivity in Sanger’s Reagent. J. Chem. Educ. 2015, 92 (11), 1846−1852. (16) Santos, E. S.; Garcia, I. C. G.; Gomez, E. F. L.; Vilchis-Reyes, M. A. Synthesis of Aryl-Substituted 2,4-Dinitrophenylamines: Nucleophilic Aromatic Substitution as a Problem-Solving and CollaborativeLearning Approach. J. Chem. Educ. 2010, 87 (11), 1230−1232. (17) Taber, D. F.; Brannick, S. J. One Step Preparation of a Crystalline Product by Nucleophilic Aromatic Substitution. J. Chem. Educ. 2015, 92 (7), 1261−1262. (18) During preparation of this manuscript, the following article was accepted for publication: Lu, G.-P.; Chen, F.; Cai, C. Thiourea in the Construction of C−S Bonds as Part of an Undergraduate Organic Chemistry Laboratory Course. J. Chem. Educ. 2017, 94 (2), 244−247. (19) Goodrich, S.; Patel, M.; Woydziak, Z. R. Synthesis of a Fluorescent Acridone Using a Grignard Addition, Oxidation, and Nucleophilic Aromatic Substitution Reaction Sequence. J. Chem. Educ. 2015, 92 (7), 1221−1225. (20) Key, J. A.; Li, M. D.; Cairo, C. W. A Fluorogenic Aromatic Nucleophilic Substitution Reaction for Demonstrating Normal-Phase Chromatography and Isolation of Nitrobenzoxadiazole Chromophores. J. Chem. Educ. 2011, 88 (1), 98−100. (21) Avila, W. B.; Crow, J. L.; Utermoehlen, C. M. Nucleophilic Aromatic Substitution. J. Chem. Educ. 1990, 67 (4), 350−351. (22) Melting point of the 4-chlorobenzylamine adduct, 142 °C and the benzylamine adduct, 101 °C. Oezden, S.; Atabey, D.; Yildiz, S.; Goeker, H. Synthesis and potent antimicrobial activity of some novel methyl or ethyl 1H-benzimidazole-5-carboxylates derivatives carrying amide or amidine groups. Bioorg. Med. Chem. 2005, 13 (5), 1587− 1597. (23) Persson, J.; Axelsson, S.; Matsson, O. Solvent Dependent Leaving Group Fluorine Kinetic Isotope Effect in a Nucleophilic Aromatic Substitution Reaction. J. Am. Chem. Soc. 1996, 118 (1), 20− 23.
product. Students could then correctly identify the starting amine by utilizing melting point and 1H NMR spectroscopy.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available on the ACS Publications website at DOI: 10.1021/acs.jchemed.6b00680. A detailed student handout of the experiment and instructor notes (PDF, DOCX) NMR spectra of Amines A, X, B, D, and Y (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Steven W. Goldstein: 0000-0002-7314-0114 Present Address §
Jyothi Dhuguru’s current address is Department of Pharmacology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors are grateful to the Spring 2016 and Spring 2017 Chem 210 laboratory classes for data and feedback. We would also like to thank Dr. Ralph Robinson of Pfizer, Inc. for Mass Spectral data.
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REFERENCES
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DOI: 10.1021/acs.jchemed.6b00680 J. Chem. Educ. XXXX, XXX, XXX−XXX
