Chapter 10 — Further Reading

Annotated bibliography for the $S_N2$ reaction, organized by topic.

Textbook treatments

• Clayden, Greeves, Warren (2012). Organic Chemistry, 2nd edition. Oxford. Chapter 17 covers $S_N2$ in depth with Clayden's trademark elegance. Read alongside this book for deeper detail on stereoelectronic effects and TS analysis.

• Carey, F. A., and Sundberg, R. J. (2007). Advanced Organic Chemistry, Part A: Structure and Mechanisms, 5th edition. Springer. Chapter 5 on nucleophilic substitution. Goes into solvent effects, neighboring-group participation, and detailed energetics. Beyond first-year level but the canonical reference.

• Anslyn, E. V., and Dougherty, D. A. (2006). Modern Physical Organic Chemistry. University Science Books. Chapter 10 covers substitution mechanisms with a strong physical-organic perspective. Excellent treatment of kinetics and TS structure.

• Smith, M. B., and March, J. (2007). March's Advanced Organic Chemistry, 6th edition. Wiley. The standard reference for any specific $S_N2$ transformation; tabulated examples and conditions for thousands of reactions.

Historical and foundational

• Hughes, E. D., Ingold, C. K., and others (1933–1935). Series of papers in J. Chem. Soc. establishing the kinetic distinction between $S_N1$ and $S_N2$. The foundation.

• Walden, P. (1896). Papers describing the discovery of stereochemical inversion in nucleophilic substitution. The original "Walden inversion" report. (German.)

• Gleave, J. L., Hughes, E. D., and Ingold, C. K. (1935). The systematic study of the rate of nucleophilic substitution as a function of substrate, nucleophile, and solvent. J. Chem. Soc. 236.

• Brown, H. C. (1956). Hydroboration. The introduction of the steric/electronic separation in mechanism analysis. Brown won the 1979 Nobel for related work.

On stereoelectronic effects and TS structure

• Kirby, A. J. (1980). The Anomeric Effect and Related Stereoelectronic Effects at Oxygen. Springer. Although focused on a different topic, the book's treatment of orbital alignment is essential for understanding why $S_N2$ requires backside attack.

• Deslongchamps, P. (1983). Stereoelectronic Effects in Organic Chemistry. Pergamon. The classic monograph on how orbital geometry constrains reaction outcomes. The chapter on $S_N2$ remains relevant.

• Houk, K. N., et al. Various computational papers on $S_N2$ TS structure and substituent effects. Modern DFT calculations confirm the Hughes-Ingold qualitative picture and add quantitative detail.

On solvent effects

• Reichardt, C., and Welton, T. (2010). Solvents and Solvent Effects in Organic Chemistry, 4th edition. Wiley-VCH. The monograph on solvent effects. Chapters on nucleophilic substitution document the dramatic acceleration in polar aprotic media.

• Buncel, E., and Wilson, H. (2007). Carbon Acid Solvent Effects. The treatment of how protic and aprotic solvents differ in solvation of small anions.

On enzyme catalysis and biological SN2

• Cheng, X., and Blumenthal, R. M. (eds.) (2010). S-Adenosylmethionine-Dependent Methyltransferases: Structures and Functions. World Scientific. Comprehensive treatment of the biological methylation reactions.

• Schramm, V. L. (2007). Enzymatic transition states. Curr. Opin. Struct. Biol. 17, 666. On how enzymes use TS-stabilization to catalyze $S_N2$ and related reactions.

• Wolfenden, R., and Snider, M. J. (2001). The depth of chemical time and the power of enzymes as catalysts. Acc. Chem. Res. 34, 938. On the magnitude of enzymatic acceleration of $S_N2$ reactions (and others).

On nitrogen mustards and chemotherapy

• DeVita, V. T., and Chu, E. (2008). A history of cancer chemotherapy. Cancer Res. 68, 8643. The standard history of how nitrogen mustards became the first chemotherapy drugs.

• Goodman, L. S., et al. (1946). Nitrogen mustard therapy. JAMA 132, 126. The first published clinical trial of mechlorethamine for non-Hodgkin lymphoma.

• Lawley, P. D., and Phillips, D. H. (1996). DNA adducts from chemotherapeutic agents. Mutat. Res. 355, 13. Modern review of the DNA damage caused by alkylating agents, including the cross-links from mustards.

On synthesis applications of SN2

• Mitsunobu, O. (1981). The use of diethyl azodicarboxylate and triphenylphosphine in synthesis and transformation of natural products. Synthesis 1, 1. The foundational Mitsunobu paper.

• Larrow, J. F., and Jacobsen, E. N. (1996). Synthetic applications of asymmetric epoxide opening via $S_N2$. J. Am. Chem. Soc. 118, 7420. Asymmetric variants.

On the alpha effect and unusual nucleophiles

• Edwards, J. O., and Pearson, R. G. (1962). The factors determining nucleophilic reactivities. J. Am. Chem. Soc. 84, 16. Classic paper on the α effect.

• Hoz, S., and Buncel, E. (1985). The alpha effect: a critical reexamination. Isr. J. Chem. 26, 313. Modern treatment.

Online resources

• The Organic Chemistry Portal (organic-chemistry.org): aggregator with discussions of $S_N2$ and named reactions.
• NPTEL India (free online course): video lectures on physical-organic chemistry including $S_N2$.

Practice

• Warren, S., and Wyatt, P. (2008). Organic Synthesis: The Disconnection Approach, 2nd edition. Wiley. Workbook-style. Chapters using $S_N2$ in synthesis.

• Klein, D. (2017). Organic Chemistry I as a Second Language, 4th edition. Wiley. A very useful problem-by-problem walkthrough of substitution and elimination reasoning. Inexpensive and worth owning if these topics give you trouble.

Most students find that doing 50+ practice problems on $S_N2$ in a focused two-week period is enough to internalize the mechanism. Then it returns over and over throughout the rest of organic chemistry, refreshing the skill.