Chapter 30 — Further Reading

Textbooks

• Clayden, Greeves, and Warren. Organic Chemistry, 2nd ed. (Oxford University Press, 2012). Chapter 22 ("Amines") and various places throughout. Particularly good on amine basicity and the contrast with phenols/amides.

• McMurry, John. Organic Chemistry, 9th or later ed. (Cengage). Chapter 24 ("Amines"). Functional-group treatment.

• Carey and Sundberg. Advanced Organic Chemistry, Part B: Reactions and Synthesis, 5th ed. (Springer, 2007). Chapter 5 ("Reactions of Amines") and Chapter 8 ("Heterocyclic Chemistry"). Detailed advanced treatment.

• Smith, Michael B. March's Advanced Organic Chemistry, 7th ed. (Wiley, 2013). Chapter 16 covers amine reactions in detail.

• Acheson, R. M. (1976). An Introduction to the Chemistry of Heterocyclic Compounds, 3rd ed. (Wiley). The standard reference for heterocyclic amine chemistry.

• Joule, J. A., and Mills, K. (2010). Heterocyclic Chemistry, 5th ed. (Wiley-Blackwell). Modern treatment of heterocyclic amine chemistry; covers all major heterocyclic ring systems.

Primary literature

• Sertürner, F. W. A. (1817). "Über das Morphium." Annalen der Physik 25, 56–89. The original isolation of morphine — the first alkaloid ever isolated.

• Gabriel, S. (1887). "Synthese primärer Amine." Berichte der Deutschen Chemischen Gesellschaft 20, 2224. The Gabriel synthesis of primary amines.

• Hofmann, A. W. (1851). "Beiträge zur Kenntnis der flüchtigen organischen Basen." Hofmann's foundational papers on amine elimination, alkylation, and rearrangement.

• Sandmeyer, T. (1884). "Über das Verhalten der Diazoverbindungen zu den Cuprosalzen." Berichte der Deutschen Chemischen Gesellschaft 17, 1633–1635. The Sandmeyer reaction.

• Schiemann, G., and Roselius, J. (1929). On the Schiemann reaction (ArN₂⁺ + HBF₄ → ArF). Berichte der Deutschen Chemischen Gesellschaft.

• Robinson, R., and Schöpf, C. (1917). The tropinone synthesis using a Mannich reaction; the first total synthesis of an alkaloid. Berichte der Deutschen Chemischen Gesellschaft.

• Woodward, R. B., and Doering, W. v. E. (1944). "The total synthesis of quinine." Journal of the American Chemical Society 66, 849. The first total synthesis of quinine, completed during WWII.

• Woodward, R. B., et al. (1954). "The total synthesis of strychnine." Journal of the American Chemical Society 76, 4749. A landmark synthesis showing that even the most complex alkaloids could be built from simple precursors.

• Magnus, P., et al. (2007). The Magnus synthesis of vinblastine. Journal of the American Chemical Society. A modern alkaloid total synthesis.

Pharmaceutical and medicinal chemistry

• Wermuth, C. G. (ed.) (2008). The Practice of Medicinal Chemistry, 3rd ed. (Academic Press). Comprehensive reference for drug design, including extensive coverage of amine pKa modulation.

• Patrick, G. L. (2017). An Introduction to Medicinal Chemistry, 6th ed. (Oxford University Press). Excellent intro to drug design; particularly good chapter on drug-target interactions.

• Lipinski, C. A., et al. (2001). "Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings." Advanced Drug Delivery Reviews 46(1-3), 3–26. The Lipinski's rule of 5 paper — including pKa as a key parameter.

• Hartung, J., and Pulst, M. (2018). Various reviews on covalent inhibitor design, including amine warheads. Useful for understanding modern targeted drugs.

Alkaloid chemistry references

• Manske, R. H. F., and Holmes, H. L. (eds.) (1953–present). The Alkaloids: Chemistry and Pharmacology. Academic Press. Multi-volume series on alkaloid chemistry; the standard reference.

• Aniszewski, T. (2015). Alkaloids: Chemical, Biological, Ecological and Medical Aspects, 2nd ed. (Elsevier). Modern overview.

• Cordell, G. A. (1981). Introduction to Alkaloids: A Biogenetic Approach. (Wiley). Biosynthetic perspective.

Computational tools

• Avogadro (https://avogadro.cc/). Build amines and visualize their N pyramidalization, pKaH (using built-in tools), and protonation behavior at various pH.

• MarvinSketch / MarvinView (ChemAxon, free for academic use): predict pKaH from structure for any amine; very useful for drug design exploration.

• PubChem — look up: morphine (CID 5288826), caffeine (CID 2519), nicotine (CID 89594), quinine (CID 8549), atropine (CID 174174), strychnine (CID 441071).

Online resources

• Master Organic Chemistry, "Amines" series (https://www.masterorganicchemistry.com/). Free, undergraduate-level explanations of amine basicity, nucleophilicity, and reactions.

• Organic Chemistry Portal (https://www.organic-chemistry.org/). Searchable reaction database including all major amine syntheses.

For practice problems

• Klein, David. Organic Chemistry as a Second Language, 4th ed. (Wiley). Chapter on amine chemistry.

• Karty, Joel. Organic Chemistry: Principles and Mechanisms, 2nd ed. (W. W. Norton, 2018). Chapter on amines is well-organized.

• Sorrell, Thomas N. Organic Chemistry, 2nd ed. (University Science Books, 2006). Chapter on amine chemistry.

Mathematically inclined readers

• Tehan, B. G., et al. (2002). "Estimation of pKa using semi-empirical molecular orbital methods." Quantitative Structure-Activity Relationships 21(3), 283–289. Computational pKa prediction.

• Eckert, F., and Klamt, A. (2002). COSMO-RS: a method for predicting amine pKa from quantum chemistry. AIChE Journal 48(2), 369–385.

Notes on this chapter's pedagogy

Chapter 30 caps the carbonyl-related chemistry of Part VI with the most prevalent functional group in drugs: the amine. The chapter unifies several different reaction types (SN2 alkylation, imine/enamine formation, amide formation, aza-Michael, diazonium chemistry) under the umbrella of "what nitrogen does." The reactions of amines as Brønsted bases and as Lewis nucleophiles are presented as two faces of the same chemistry.

The biological connections (neurotransmitters, alkaloids, drug design) are at the heart of pharmacology, making this chapter the bridge from "pure organic chemistry" to "applied chemistry of biology."

After Chapter 30, students should have a complete understanding of: - All three carbonyl reactivity families (Chs 24–29). - Amine chemistry (Ch 30). - The synthesis tools to make complex amine-containing molecules.

Chapter 31 (Synthesis Workshop 2) brings these together for retrosynthetic analysis of complex drug-like targets.