Richard F. Daley and Sally J. Daley www.ochem4free.com Organic Chemistry Chapter 12 Aliphatic Nucleophilic Substitution 12.1 Naming Single Bonded Heteroatom Functional Groups 579 12.2 Comparing Nucleophilic Substitution Reaction Mechanisms 586 12.3 The SN1 and SN2 Reaction Mechanisms 588 12.4 Stereochemistry of Nucleophilic Substitutions 592 12.5 The Substrate 595 12.6 Nucleophiles and Leaving Groups 601 12.7 Common Nucleophiles 606 12.8 The Reaction Medium 607 12.9 SN1 versus SN2 613 12.10 Halide Nucleophiles 613 Synthesis of 1-Bromobutane 616 12.11 Oxygen Nucleophiles 620 12.12 Nitrogen Nucleophiles 625 Synthesis of 2,5-Diaminoadipic Acid 628 12.13 Carbon Nucleophiles 631 12.14 Neighboring Group Participation 634 Special Topic - SN1 vs. SN2 637 Key Ideas from Chapter 12 641 Organic Chemistry - Ch 12 578 Daley & Daley Copyright 1996-2005 by Richard F. Daley & Sally J. Daley All Rights Reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the copyright holder. www.ochem4free.com 5 July 2005 Organic Chemistry - Ch 12 579 Daley & Daley Chapter 12 Aliphatic Nucleophilic Substitution Chapter outline 12.1 Naming Single Bonded Heteroatom Functional Groups Naming alcohols, ethers, phenols, thiols, thioethers, sulfides, and amines 12.2 Comparing Nucleophilic Substitution Reaction Mechanisms A comparison of the mechanism for SN1 and SN2 reactions with the mechanism of nucleophilic substitution at carbonyl groups 12.3 The SN1 and SN2 Mechanisms More details for the SN1 and SN2 reaction mechanisms 12.4 Stereochemistry of Nucleophilic Substitutions The stereochemistry of the SN1 and SN2 reaction mechanisms 12.5 The Substrate Effect of substrate structure on the outcome of nucleophilic substitution reactions 12.6 Nucleophiles and Leaving Groups The factors that make good nucleophiles or leaving groups 12.7 Common Nucleophiles A listing of some of the common nucleophiles used in organic chemistry 12.8 The Reaction Medium Effect of the solvent on the outcome of nucleophilic substitution reactions 12.9 SN1 versus SN2 Factors that influence whether an E1 or an E2 mechanism will prevail 12.10 Halide Nucleophiles Substitution reactions with halide nucleophiles 12.11 Oxygen Nucleophiles Reactions using oxygen nucleophiles 12.12 Nitrogen Nucleophiles Using nitrogen nucleophiles in substitution reactions 12.13 Carbon Nucleophiles Substitution reactions with carbon nucleophiles derived from Grignard reagents and alkyllithium reagents 12.14 Neighboring Group Participation How a group adjacent to a functional group affects the outcome of reactions www.ochem4free.com 5 July 2005 Organic Chemistry - Ch 12 580 Daley & Daley Objectives ✔ Apply the IUPAC rules of nomenclature to naming alcohols, thiols, ethers, sulfides, and amines ✔ Be able to write the mechanisms for both the SN1 and SN2 reaction types ✔ Know the effect of the SN1 and SN2 reaction mechanisms on the stereochemistry of reactions ✔ Recognize how the structure of the substrate affects the outcome of nucleophilic reactions ✔ Understand the factors that affect the stability of carbocations ✔ Recognize the factors that make good nucleophiles and good leaving groups ✔ Know how the solvent affects the outcome of nucleophilic substitution reactions ✔ Understand how halide, oxygen, nitrogen, and carbon nucleophiles react with various substrates ✔ Know how a functional group adjacent to the site of a nucleophilic substitution affects the course of reactions If there was two birds sitting on a fence, he would bet you which one would fly first. - Mark Twain liphatic nucleophilic substitution is the third A installment in the study of nucleophilic reactions in organic chemistry. The previous two installments, nucleophilic addition and nucleophilic substitution at the carbonyl group, describe the formation of new bonds to the carbonyl carbon of aldehydes, ketones, and the carboxylic acid family. Chapters 7 and 8 discuss the nature of the substituents bonded to the carbonyl carbon and how they determine whether a substitution or an addition reaction takes place. This chapter presents the study of aliphatic nucleophilic substitution reactions at sp3 hybridized carbon atoms. The outcome of www.ochem4free.com 5 July 2005 Organic Chemistry - Ch 12 581 Daley & Daley aliphatic nucleophilic substitution reactions depends on such variables as nucleophilicity, stereochemistry, the reaction medium, and the intermediate's stability. Aliphatic nucleophilic substitution reactions have two, often competing, reaction mechanisms. These two mechanisms account for a large variety of reactions in organic chemistry. Although the two mechanisms are different, they both have a nucleophile, a leaving group, and a substrate; and all three play an important part in the outcome of each reaction. An understanding of the characteristics of these two mechanisms gives you a broader understanding of organic chemistry. What you learn about these two mechanisms will help you later with further organic syntheses and mechanisms. Through their work with aliphatic nucleophilic substitutions, chemists have perhaps learned more about organic reaction mechanisms than through their study of any other reaction type. However, these gains did not come easily. From the early years of the twentieth century until the 1970s, the debate raged over the issues surrounding aliphatic nucleophilic substitution. This debate included such things as experimental results that various investigators interpreted in opposite ways and experimental results that all agreed seemed mutually incompatible. Fortunately, most of these questions are now resolved. 12.1 Naming Single Bonded Heteroatom Functional Groups This section covers the nomenclature of compounds that contain a singly bonded oxygen, sulfur, or nitrogen; that is, alcohols, ethers, phenols, thiols, thioethers (or sulfides), disulfides, and amines. Each of these functional groups replaces a hydrogen on the carbon skeleton of the organic compound. Each functional group also changes the suffix of the parent name in a way characteristic of that group. The parent compound, in most cases, includes the carbon in the main chain that bears the functional group. Alcohols replace a hydrogen on the parent carbon chain with an —OH group. The suffix for an alcohol is –ol in the IUPAC nomenclature. When naming an alcohol, follow these steps. Step 1 Determine the parent chain. Step 2 Drop the final –e of the parent hydrocarbon name and add the –ol ending. Step 3 To number substituents, number the carbon chain to give the carbon bearing the —OH group the lowest possible number. www.ochem4free.com 5 July 2005 Organic Chemistry - Ch 12 582 Daley & Daley OH CH3OH CH3CH2OH CH3CH2CHCH3 Methanol Ethanol 2-Butanol OH OH CH3 2-Methylcyclohexanol 3-Methyl-2-butanol Frequently, chemists call the —OH group a hydroxy group and compounds that contain two or more hydroxy groups polyols. To A polyol is a molecule name polyols, use the IUPAC suffixes of –diol, –triol, and so forth. 1,2- that contains two or Ethanediol (HOCH CH OH) is an example of the proper naming of a more —OH groups. 2 2 polyol. Alcohols can be classified according to the number of carbon atoms bonded to the carbon that bears the alcohol group. For example, Primary, secondary, ethanol is a primary alcohol because the carbon bearing the hydroxy and tertiary alcohols have one, two, or three group is attached to only one other carbon. 2-Propanol is a secondary alkyl groups attached alcohol because the carbon bearing the —OH group is bonded to two to the carbon bearing other carbons, and 2-methyl-2-propanol is a tertiary alcohol because the —OH group. the —OH bearing carbon is bonded to three other carbons. OH OH OH Ethanol 2-Propanol 2-Methyl-2-propanol A primary alcohol A secondary alcohol A tertiary alcohol Benzyl alcohol is alcohol attached to a carbon that also bears Benzyl alcohol is a a phenyl group. carbon attached to a benzene ring and an —OH group. OH OH I 4-Iodobenzyl alcohol Benzyl alcohol www.ochem4free.com 5 July 2005 Organic Chemistry - Ch 12 583 Daley & Daley Chemists call a hydroxy group connected to a carbon atom of a A phenol is a benzene benzene ring a phenol after the simplest member of this group, ring substituted with hydroxybenzene or, more commonly, phenol. To name substituted an —OH group. phenols, number the ring so that the carbon bearing the —OH group is C—1. Because the common name for an alcohol is alkyl alcohol (i.e., ethanol is often called ethyl alcohol) many organic chemistry students are tempted to confuse benzyl alcohols with phenols. Be careful! Phenol nomenclature is complicated by the fact that many phenols have common names that are more widely used than the IUPAC names. For example, 2-methylphenol is known as o-cresol, 3- methylphenol is known as m-cresol and 4-methylphenol is known as p- cresol. OH OH Cl OH CH3 Phenol 3-Methylphenol 3-Chlorophenol (m-Cresol) (m-Chlorophenol) A thiol, also called a Chemists call the sulfur analogs of the alcohols thiols, or mercaptan, contains an mercaptans. To name thiols, add the suffix –thiol to the parent —SH group. name. However, unlike most suffixes, the –thiol suffix does not replace the final –e of the hydrocarbon name. CH3SH CH3CH2SH Methanethiol Ethanethiol Thiols have a characteristic intensely unpleasant odor. Some common examples are the defensive odor of the skunk and the characteristic odors of garlic and onion. Replacing the oxygen in a phenol with a A thiophenol is the sulfur creates a class of compounds called thiophenols. Name sulfur analog of a thiophenols following the same rules for naming phenols. phenol. Exercise 12.1 Name the following compounds. www.ochem4free.com 5 July 2005 Organic Chemistry - Ch 12 584 Daley & Daley a) b) OH OH c) d) Cl OH SH e) f) OH SH Sample solution b) The common name for this compound is menthol. Menthol is extracted from the oil of peppermint.