Alcohols and Ethers Part 2 ROHAZITA BAHARI School of Bioprocess Engineering University Malaysia Perlis (UniMAP)

Reaction of Alcohol Others OXIDATION ALKYL HALIDE ALKENE SUBSTITUTION ELIMINATION (DEHYDRATION) OXIDATION SUBSTITUTION Others ALKYL HALIDE SULFONATE ESTER KETONE ALDEHIDE CARBOXILIC ACID ALKENE

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 strong base poor leaving group no reaction in either case

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

Electrophiles Molecules that contain atoms with empty orbital, which can accommodate electrons. Typically, these are positively charged. Examples: Boron has only 6 valence electrons. BF3 is a Lewis acid.

Nucleophiles Examples: 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:

Nucleophilic substitution of Alcohol An alcohol has a strongly base leaving group (HO-) therefore alcohol cannot undergo a nucleophilic substitution reaction Convert the strongly basic leaving group (OH–) into the good leaving group, H2O (a weaker base):

Primary, secondary, and tertiary alcohols all undergo nucleophilic substitution reactions with HI, HBr, and HCl:

SN1 reaction The SN1 reaction is a substitution reaction in organic chemistry. "SN" 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.

SN2 reaction The SN2 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 SN2. The somewhat more transparently named analog to SN2 among inorganic chemists is the interchange mechanism.

Nucleophilic Substitution

Examples

Mechanism of Substitution Secondary and tertiary alcohols undergo SN1 reaction.

Mechanism of Substitution Primary alcohols undergo SN2 reaction. Primary carbocations are too unstable to be formed. Attack from back-side

SN1 REACTION OF ALCOHOL Secondary and tertiary alcohols undergo SN1 reactions with hydrogen halides:

Look out for rearrangement product in the SN1 reaction of the secondary or tertiary alcohol:

SN2 REACTION OF ALCOHOL Primary alcohols undergo SN2 reactions with hydrogen halides:

When HCl is used; SN2 reaction is slower, but the rate can be increased using ZnCl2 as catalyst . ZnCl2 functions as a Lewis acid that complexes strongly with the lone-pair electrons on oxygen:

Other Methods for Converting Alcohols into Alkyl Halides Utilization of phosphorus tribromide: Other phosphorus reagents can be used: PBr3, phosphorus tribromide PCl3, phosphorus trichloride PCl5, phosphorus pentachloride POCl3, phosphorus oxychloride

SUMMARY When treated with HBr or HCl alcohols typically undergo a nucleophilic substitution reaction to generate an alkyl halide and water Alcohol relative reactive order : 30>20>10>methyl Hydrogen halide reactively order: Hi>HBr>HCl>HF (paralleling acidity order) Reaction usually proceeds via an SN1 mechanism which proceeds via a carbocation intermediate, that can also undergo rearrangement.

SUMMARY Methanol and primary alcohols will proceed via an SN2 mechanism since these have highly unfavorable carbocations The reactions of alcohols with HCl in the presence of ZnCl2 (catalyst) forms the basis of the Lucas test for alcohols.

Reactions of Alcohols with other Halogenating agents (SOCl2, PX3)

Alcohols can also be converted to alkyl cloride using thionyl chloride,SOCl2, or phosphorous trichloride, PCl3. Alkyl bromides can be prepared in a similar reaction using PBr3 Used mosty for 10 and 20 ROH In each case a base is used to ‘mop-up’ the acidic by-product

Common bases are tiethylamine,Et3N, or pyridine, C6H5N In each case the –OH reacts first as a nucleophile, attacking the electrophilic center of the halogenating agent A displaced halide ion then completes the substitution displacing the leaving group

Activation by SOCl2 Pyridine is generally used as a solvent and also acts as a base:

Summary: Converting of Alcohols to Alkyl Halides Recommended procedures:

Converting Alcohols into Sulfonate Esters

Several sulfonyl chlorides are available to activate OH groups:

The elimination of water from an alcohol is called DEHYDRATION.

Elimination 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 REACTION OF ALCOHOL (DEHYDRATION) Dehydration of alcohol requires acid catalyst and heat Dehydration of Secondary and Tertiary Alcohols by an E1 Pathway

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

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.

Mechanism of E1 Dehydration of an Alcohol

The major product is the most stable alkene product: The most stable alkene product has the most stable transition state

Elimination In case we have a choice between several b-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.

The rate of dehydration reflects the ease with which the carbocation is formed:

Look out for carbocation rearrangement:

Pinicol Rearrangement Protonate alcohol: Eliminate water: Rearrange carbocation: Deprotonate: Resonance-stabilized oxocarbocation

Ring Expansion and Contraction Mechanism for this reaction: Protonate the alcohol. Eliminate water. Rearrange carbocation to afford the more stable cyclohexane ring. Deprotonate.

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.

Primary Alcohols Undergo Dehydration by an E2 Pathway

A Milder Way to Dehydrate an Alcohol

ETHER

Nucleophilic substitution reaction of Ether Ethers, like alcohols, can be activated by protonation: Ether can undergo nucleophilic substitution with HBr and HI only (HCl cannot be used because Cl- too poor nucleophile

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

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

Ether cleavage: an SN1 reaction:

Reagents such as SOCl2 and PCl3 can activate alcohols but not ethers Ethers are frequently used as solvents because only they react with hydrogen halides

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 tertiary carbocation Now we have carbocation-type carbons that can be distinguished via their stability.

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.

Nucleophilic Substitution Reactions of Epoxides Acidic condition; HBr: Aqueous acid:

Reaction of an epoxide in different substituent Regioselectivity: Mechanism:

Neutral or Basic condition: When a nucleophile attacks an unprotonated epoxide,the reaction is a pure SN2 reaction: Therefore: