Reactions of Alcohols, Amines, Ethers, and Epoxides Essential Organic Chemistry Paula Yurkanis Bruice Chapter 10 Reactions of Alcohols, Amines, Ethers, and Epoxides

10.1 Nomenclature of Alcohols Compounds in which a hydrogen is replaced by an OH group. We distinguish three types:

Naming Alcohols Common names are the name of alkyl group followed by the word “alcohol”

Naming 1. Longest carbon chain containing the alcohol. 2. OH suffix gets the lowest possible number.

Naming 3. Find also lowest possible number for other substituent. 4. For more than one substituent they are listed in alphabetical order.

10.2 Substitution Reactions of Alcohols Alcohols are not reactive in nucleophilic substitution or elimination reactions since hydroxide is a strong base, poor leaving group. SN1 SN2 no reaction in either case strong base poor leaving group

Substitution Reactions of Alcohols The situation improves under acid conditions. We change the leaving group to water, a neutral group. neutral neutral

Figure: 11-00-18UN Title: Substitution Reactions of Various Alcohols Caption: Primary, secondary, and tertiary alcohols all undergo nucleophilic substitution in the presence of such acids as HCl, HBr, and HI to form alkyl halides. Notes: Secondary and tertiary alcohols undergo substitution by an SN1 mechanism with these hydrogen halides.

Figure: 11-00-19UN Title: Mechanism of an SN1 Reaction of an Alcohol Caption: The carbocation formed in this mechanism has two fates: either reaction with a nucleophile to produce a substitution product or to form an elimination product. Notes: Even if the elimination product forms it reacts with the excess acid to form the alkyl halide.

Figure: 11-00-21UN Title: Mechanism of an SN2 Reaction of an Alcohol Caption: The protonation of the alcohol by the acid is the rate-determining step and it is bimolecular. Notes: Primary alcohols undergo SN2 reactions with hydrogen halides.

10.3 Elimination Reactions of Alcohols Elimination of water, dehydration, is commonly obtained using sulfuric acid (H2SO4) as a catalyst. The acid is mandatory to convert the poor leaving group OH– into a good leaving group H2O.

Elimination First step is protonation of the hydroxyl group. Loss of water leads to a carbocation.

Figure: 11-00-26UN Title: Dehydration of an Alcohol Caption: Dehydration of an alcohol requires an acid catalyst and heat. The most common catalyst is sulfuric acid. This reaction proceeds by an E1 mechanism. Notes: An acid protonates the most basic atom (electron-rich) in a molecule. Secondary and tertiary alcohols undergo dehydration by an E1 mechanism.

Elimination Second, a base removes a proton b to the carbocation center. Notice that this reaction is an E1 reaction. Rate-determining step is the formation of the carbocation.

Elimination In case we have a choice between several b-hydrogens, the most stable alkene is formed preferentially. 84 % 16 %

Figure: 11-01 Title: Reaction Coordinate Diagram for Dehydration of an Alcohol Caption: The reaction coordinate diagram for the dehydration of a protonated alcohol. The major product is the more substituted alkene because the transition state leading to its formation is more stable, allowing it to be formed more rapidly. Notes: The formation of the carbocation is the rate-determining step since it has the highest activation energy.

Elimination As a result of the E1 mechanism, the ease of dehydration follows the order: That directly reflects the stability of the intermediate carbocations.

Figure: 11-01-01UN Title: Relative Ease of Dehydration Caption: A tertiary alcohol is more easily dehydrated than a secondary than is a primary. This is because of the stability of the carbocation intermediate that forms during the reaction. Notes: Remember that tertiary carbocations are easier to form than are secondary carbocations.

Elimination Primary alcohols undergo dehydration by an E2 pathway. First, however, we generate the good leaving group. The subsequent steps, removal of water and deprotonation, take place simultaneously.

Figure: 11-01-04UN Title: Dehydration of a Secondary Alcohol Caption: The products obtained in this acid-catalyzed dehydration are the same as those obtained from the elimination of an alkyl halide. There is formation of the two stereoisomers E and Z, with the E isomer being the favored product. Notes: There is also some production of 1-butene.

10.4 Oxidation of Alcohols Dehydrogenation (oxidation) is possible for 1o and 2o leading to aldehydes and ketones, respectively. aldehyde ketone

Oxidation of Alcohols Aldehydes can be further oxidized to acids.

Oxidation of Alcohols Typical oxidizing agents are chromic acid (H2CrO4) or pyridinium chlorochromate (PCC). chromic acid PCC

Examples cyclopentanol cyclopentanone butanol butanal butanoic acid

Examples PCC is a more selective oxidizing agent. butanol butanal PCC is a more selective oxidizing agent. Oxidation can be stopped at the aldehyde level.

10.5 Reaction of Amines Amines are less reactive than alcohols. This can be evaluated by inspection of the pKa values of the leaving group. Protonation of the amine improves the situation only slightly.

Amines Amines are the most common organic bases.

10.6 Nomenclature of Ethers Common Name: Name of alkyl substituents followed by “ether”

Nomenclature of Ethers IUPAC Parent alkyl compound with RO substituent. “-yl” is then replaced by “oxy”

10.7 Substitution Reactions of Ethers The behavior of ethers is comparable to alcohols. pKa of the leaving group is comparable. Activation by acid allows substitution.

Figure: 11-01-32UN Title: General Substitution Reaction of Ether Caption: Ethers can be activated by protonation. They can undergo substitution with HBr or HI but the reaction must be heated. Notes: This is the same as with alcohols. The OR group is not a good leaving group until it is protonated.

Substitution of Ethers The mechanism involves first a protonation step. The subsequent steps are determined by the stability of the intermediates. Stable carbocation  SN1 Unstable carbocation  SN2

Substitution of Ethers Examples attack of nucleophile stable carbocation

Figure: 11-01-33UN Title: Mechanism of Substitution Reaction of Ether Caption: The first step is the protonation of the ether by the acid. This makes a better leaving group and a carbocation can be formed. Notes: This mechanism is an SN1 mechanism since a stable carbocation is formed.

Substitution of Ethers Primary carbocations are unstable; thus, reaction proceeds via SN2. Reaction takes place on the less hindered of the two alkyl groups.

Figure: 11-01-34UN Title: Mechanism of a SN2 Reaction of an Ether Caption: If the departing group does not form a stable carbocation the leaving group cannot leave. The mechanism becomes SN2. Notes: Ethers are frequently used as solvents since the only thing they react with are acids.

Ethers Only hydrogen halides react with ethers Ethers commonly used as solvents Often used solvents are:

Figure: 11-01-35UN.T1 Title: Table 11.1 - Ethers Used as Solvents Caption: Ethers are frequently used as solvents since the only thing they react with are acids. Notes: Listed are common ethers such as diethyl ether, THF, DME, and MTBE.