Organic Chemistry Second Edition Chapter 23 David Klein Amines Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.1 Introduction to Amines Amines are derivatives of ammonia Amines are designated as primary, secondary, or tertiary The terms, 1°, 2°,and 3° are used differently for amines than for alcohols. HOW? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.1 Introduction to Amines There are hundreds of examples of amines found in natural products Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.1 Introduction to Amines Some naturally occurring amines take part in neurochemistry Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.1 Introduction to Amines The trigonal pyramidal nitrogen atom of an amine carries a partial negative charge on its lone pair HOW do you think the amine is likely to react? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.1 Introduction to Amines Amines often react as a base or as a nucleophile What feature(s) of the amine do you think might determine whether it is more likely to act as a base or as a nucleophile? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.3 Properties of Amines The N atom in typical amines is sp3 hybridized The angles are 108 degrees. WHY? The C-N bond lengths are 147 pm, which is slightly shorter than C-C bonds. WHY? Under what circumstances would the nitrogen be sp2 hybridized? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.3 Properties of Amines N atoms with three different alkyl groups are chiral Chiral compounds are generally optically active. WHAT does that mean? Amine are generally not optically active. WHY? See next slide Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.3 Properties of Amines Klein, Organic Chemistry 2e Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.3 Properties of Amines Many small molar mass amines have unpleasant odors Practice with conceptual checkpoint 23.4 and 23.5 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.4 Preparation of Amines: A Review Let’s review all of the methods we’ve learned in previous chapters to synthesize amines Carbon skeleton expanded by 1 carbon Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.4 Preparation of Amines: A Review Let’s review all of the methods we’ve learned in previous chapters to synthesize amines Carbon skeleton is not changed Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.4 Preparation of Amines: A Review Let’s review all of the methods we’ve learned in previous chapters to synthesize amines Reduction with a metal is a bit more mild than reduction with H2. WHY might mild conditions be preferred? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.4 Preparation of Amines: A Review Let’s review all of the methods we’ve learned in previous chapters to synthesize amines Why is NaOH used in a final step? Practice with conceptual checkpoints 23.10 and 23.11 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Klein, Organic Chemistry 2e Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.5 Preparation of Amines via Substitution Reactions Let’s learn some new amine syntheses Explain WHY the reaction will not stop at the primary amine but will continue to form a quaternary ammonium salt Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.5 Preparation of Amines via Substitution Reactions Let’s learn some new amine syntheses See mechanism on next few slides Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.5 Preparation of Amines via Substitution Reactions Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.5 Preparation of Amines via Substitution Reactions N2 is a great leaving group. WHY? Does the N2 technically act as a leaving group in the mechanism? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.5 Preparation of Amines via Substitution Reactions The Gabriel synthesis produces primary amines as well First, potassium phthalimide is formed Although the N1- is stabilized by resonance, it is still nucleophilic Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.5 Preparation of Amines via Substitution Reactions The attack works best on 1° amines and does not work for 3° amines. WHY? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.5 Preparation of Amines via Substitution Reactions The last step generally employs aqueous acid or hydrazine Practice with SkillBuilder 23.2 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Klein, Organic Chemistry 2e Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.6 Preparation of Amines via Reductive Amination Recall the method for forming imines If a reducing agent is present, the imine can be reduced in situ to form an amine Reductive amination can be accomplished with a variety of reducing agents Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.6 Preparation of Amines via Reductive Amination Sodium cyanoborohydride, which is similar to NaBH4, is commonly used The inductive effects of the –CN group make the cyanoborohydride reagent more selective HOW? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.6 Preparation of Amines via Reductive Amination Why can’t NaBH4 be used for reductive aminations? Practice with SkillBuilder 23.3 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Klein, Organic Chemistry 2e Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Klein, Organic Chemistry 2e Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Klein, Organic Chemistry 2e Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.7 Synthetic Strategies Let’s review reactions that form amines Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.7 Synthetic Strategies Let’s review reactions that form amines Practice with SkillBuilder 23.4 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Klein, Organic Chemistry 2e Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Klein, Organic Chemistry 2e Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Klein, Organic Chemistry 2e Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.8 Acylation of Amines Recall that amines can attack acyl chlorides Two moles of the amine are used. WHY? Polysubstitution is not observed. WHY? An acyl group can act as a protecting group. HOW? An acyl group can help to limit the reactivity of amines in EAS reactions – see next slide Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.8 Acylation of Amines How might you perform the following synthesis? Adding bromine won’t work, because polysubstitution can not be avoided Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.8 Acylation of Amines How might you perform the following synthesis? The disadvantage of this synthesis is that amide hydrolysis requires harsh conditions Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.8 Acylation of Amines Aromatic amines also can not undergo Friedel Crafts directly How does the addition of the AlCl3 group deactivate the ring? Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.8 Acylation of Amines To achieve ring alkylation, first the amine must be acylated Practice with conceptual checkpoints 23.22 through 23.24 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Klein, Organic Chemistry 2e Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.9 The Hofmann Elimination Like alcohols, amines can be converted into leaving groups for elimination reactions Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.9 The Hofmann Elimination Like alcohols, amines can be converted into leaving groups for elimination reactions Unexpectedly, the less substituted (less stable) product is observed – see next slide Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.9 The Hofmann Elimination Sterics in the anticoplanar conformation hinders attack at the more substituted site. Draw an energy diagram Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Klein, Organic Chemistry 2e Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Klein, Organic Chemistry 2e Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Klein, Organic Chemistry 2e Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.11 Reactions of Aryldiazonium Ions Alkyl diazonium salts are extremely reactive (potentially explosive) because of the excellent N2 leaving group Aryl diazonium salts are a bit more stable and synthetically versatile Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.11 Reactions of Aryldiazonium Ions Treatment with a copper salt yields an aryl halide or nitrile Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.11 Reactions of Aryldiazonium Ions Explain each step in the synthesis below A fluorine can also be installed Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.11 Reactions of Aryldiazonium Ions There are many other diazonium salt substitutions Using this synthesis, amines can be used as a directing group and subsequently replaced with a –H atom Practice with conceptual checkpoint 23.30 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Klein, Organic Chemistry 2e Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Klein, Organic Chemistry 2e Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.11 Reactions of Aryldiazonium Ions Diazonium salts can also be attacked by aromatic rings with an activating group – EAS mechanism Draw each resonance contributor of the sigma complex Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

23.11 Reactions of Aryldiazonium Ions Azo coupling produces azo dyes WHY are azo compounds colored? Varying the substitution on the rings affects the specific dye color Practice with SkillBuilder 23.6 Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Klein, Organic Chemistry 2e Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Klein, Organic Chemistry 2e Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Klein, Organic Chemistry 2e Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Klein, Organic Chemistry 2e Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Klein, Organic Chemistry 2e Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Additional Practice Problems Give an appropriate name for the following molecule Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Additional Practice Problems Predict the major product for the following reaction Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Additional Practice Problems Give necessary reagents to make the secondary amine below Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e

Additional Practice Problems Give necessary reagents for the synthesis below Copyright © 2015 John Wiley & Sons, Inc. All rights reserved. Klein, Organic Chemistry 2e