Alcohols and Ethers-2 Dr AKM Shafiqul Islam School of Bioprocess Engineering University Malaysia Perlis (UniMAP)

Alcohols are not reactive in nucleophilic substitution or elimination reactions since hydroxide is a strong base, poor leaving group. strong base no reaction in either case poor leaving group SN1SN1 SN2SN2 Substitution Reactions of Alcohols

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

Electrophiles Molecules that contain atoms with empty orbital, which can accommodate electrons. Typically, these are positively charged. Boron has only 6 valence electrons. BF 3 is a Lewis acid.  Examples:

Nucleophiles Molecules that contain atoms with lone pairs, which can donate electrons. Often these are negatively charged. Almost all the time they contain elements from groups 15–17 of the periodic table, since those have lone pairs.  Examples:

S N 1 reaction ► The S N 1 reaction is a substitution reaction in organic chemistry. "S N " stands for nucleophilic substitution and the "1" represents the fact that the rate-determining step is unimolecular. ► It involves a carbocation intermediate and is commonly seen in reactions of secondary or tertiary alkyl halides or, under strongly acidic conditions, with secondary or tertiary alcohols.

S N 2 reaction ► The S N 2 reaction (known as bimolecular substitution nucleophilic) is a type of nucleophilic substitution, where a lone pair from a nucleophilic attacks an electron deficient electrophilic center and bonds to it, expelling another group called a leaving group. Thus the incoming group replaces the leaving group in one step. ► Since two reacting species are involved in the slow, rate- determining step of the reaction, this leads to the name bimolecular nucleophilic substitution, or S N 2. ► The somewhat more transparently named analog to S N 2 among inorganic chemists is the interchange mechanism.

Nucleophilic Substitution

Examples

Mechanism of Substitution ► Secondary and tertiary alcohols undergo S N 1 reaction.

Mechanism of Substitution ► Primary alcohols undergo S N 2 reaction. Primary carbocations are too unstable to be formed. Attack from back-side

Elimination ► Elimination of water, dehydration, is commonly obtained using sulfuric acid (H 2 SO 4 ) as a catalyst.  The acid is mandatory to convert the poor leaving group OH – into a good leaving group H 2 O.

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

Elimination ► Second, a base removes a proton  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  -hydrogens, the most stable alkene is formed preferentially. 84 %16 %

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

Substitution of Ethers ► The behavior of ethers is comparable to alcohols.  pK a of the leaving group is comparable.  Activation by acid allows substitution.

Substitution of Ethers ► The mechanism involves first a protonation step.  The subsequent steps are determined by the stability of the intermediates. Stable carbocation  S N 1 Unstable carbocation  S N 2

Substitution of Ethers ► Examples attack of nucleophile stable carbocation

Substitution of Ethers Primary carbocations are unstable; thus, reaction proceeds via S N 2. Reaction takes place on the less hindered of the two alkyl groups.

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

Epoxides ► A special group of ethers are epoxides. ► Here the oxygen is incorporated into a three- membered ring.  We name epoxides commonly by using the name of the parent alkene followed by oxide.

Epoxides ► Alternatively we can use the name of the parent alkane with an “epoxy” prefix  Formation of epoxides can be accomplished by a reaction of a peracid with an alkene

Epoxides ► Reaction with hydrogen halides proceeds as with other ethers.

Epoxides ► Reaction with water and alcohols can be accomplished via acid catalysis.

Epoxides ► For unsymmetrical epoxides we have to inspect the individual steps in the reaction more carefully. acidic conditions basic conditions  We obtain different results depending on the reaction conditions used.

Epoxides ► Acidic conditions:  First step is the formation of an oxonium species. Attack of the nucleophile can take place at two positions.

Epoxides ► For the process of breaking the C-O bond of the epoxide we have to assume that the oxygen is keeping the bonding electrons, thus creating a partial positive charge on the neighboring carbon. secondary carbocation  Now we have carbocation-type carbons that can be distinguished via their stability. tertiary carbocation

Epoxides ► Reaction proceeds at the tertiary center

Epoxides ► Under basic reaction conditions the situation changes.  First we generate an alcoholate anion  Attack takes place on the less hindered side.

Epoxides ► Finally, the reaction is completed by taking up a proton.

Epoxides ► Ring opening of epoxides is an important reaction in organic chemistry. A wide variety of nucleophiles can be used for this reaction.