An alternative to making the halide: ROH  ROTs Preparation from alcohols. p-toluenesulfonyl chloride Tosyl chloride TsCl Tosylate group, -OTs, good leaving group, including the oxygen. The configuration of the R group is unchanged.

Example Preparation of tosylate. Retention of configuration

Substitution on a tosylate The –OTs group is an excellent leaving group

Acid Catalyzed Dehydration of an Alcohol, discussed earlier as reverse of hydration Secondary and tertiary alcohols, carbocations Protonation, establishing of good leaving group. Elimination of water to yield carbocation in rate determining step. Expect tertiary faster than secondary. Rearrangements can occur. Elimination of H+ from carbocation to yield alkene. Zaitsev Rule followed.

Primary alcohols Problem: primary carbocations are not observed. Need a modified, non-carbocation mechanism. Recall these concepts: Nucleophilic substitution on tertiary halides invokes the carbocation but nucleophilic substitution on primary RX avoids the carbocation by requiring the nucleophile to become involved immediately. The E2 reaction requires the strong base to become involved immediately. Note that secondary and tertiary protonated alcohols eliminate the water to yield a carbocation because the carbocation is relatively stable. The carbocation then undergoes a second step: removal of the H+. The primary carbocation is too unstable for our liking so we combine the departure of the water with the removal of the H+. What would the mechanism be???

Here is the mechanism for acid catalyzed dehydration of Primary alcohols 1. protonation 2. The carbocation is avoided by removing the H at the same time as H2O departs (like E2). As before, rearrangements can be done while avoiding the primary carbocation.

Principle of Microscopic Reversibility Same mechanism in either direction.

Pinacol Rearrangement: an example of stabilization of a carbocation by an adjacent lone pair. Overall:

This is a protonated ketone! Mechanism Reversible protonation. Elimination of water to yield tertiary carbocation. This is a protonated ketone! 1,2 rearrangement to yield resonance stabilized cation. Deprotonation.

Oxidation Primary alcohol Na2Cr2O7 Na2Cr2O7 RCH2OH RCH=O RCO2H Na2Cr2O7 (orange)  Cr3+ (green) Actual reagent is H2CrO4, chromic acid. Secondary Na2Cr2O7 KMnO4 (basic) can also be used. MnO2 is produced. R2CHOH R2C=O Tertiary The failure of an attempted oxidation (no color change) is evidence for a tertiary alcohol. R3COH NR

Example…

Oxidation using PCC Primary alcohol Stops here, is not oxidized to carboxylic acid PCC RCH2OH RCH=O Secondary PCC R2CHOH R2C=O

Periodic Acid Oxidation

Mechanistic Notes Cyclic structure is formed during the reaction. Evidence of cyclic intermediate.

Sulfur Analogs, Thiols Preparation RI + HS-  RSH SN2 reaction. Best for primary, ok secondary, not tertiary (E2 instead) Oxidation Acidity H2S pKa = 7.0 RSH pKa = 8.5

Ethers, Sulfides, Epoxides

Variety of ethers, ROR Aprotic solvent

Regard as leaving group. Compare to OH, needs protonation. Reactions of ethers Ethers are inert to (do not react with) Common oxidizing reagents (dichromate, permanganate) Strong bases Weak acids. But see below. HX protonates ROH, set-up leaving group followed by SN2 (10) or SN1 (20 or 30). Ethers do react with conc. HBr and HI. Recall how HX reacted with ROH. Look at this reaction and attempt to predict the mechanism… Regard as leaving group. Compare to OH, needs protonation. Expectations for mechanism Protonation of oxygen to establish leaving group For 1o alcohols: attack of halide, SN2 For 2o, 3o: formation of carbocation, SN1 Characterize this reaction: Fragmentation Substitution

Mechanism This alcohol will now be protonated and reacted with halide ion to yield RX. Inversion will occur. Inversion of this R group This alcohol is protonated, becomes carbocation and reacts with halide. Loss of chirality at reacting carbon. Possible rearrangement.

Properties of ethers Aprotic Solvent, cannot supply the H in H-bonding, no ether to ether hydrogen bonding Ethers are polar and have boiling points close to the alkanes. propane (bp: -42) dimethyl ether (-24) ethanol (78)

Hydrogen Bonding Requirements of Hydrogen Bonding: Need both H acceptor and donor. protic Ethers are not protic, no ether to ether H bonding However, ethers can function as H acceptors and can engage in H bonding with protic compounds. Small ethers have appreciable water solubility.

Synthesis of ethers Williamson ether synthesis RO- + R’X  ROR’ nucleophile electrophile Characteristics RO-, an alkoxide ion, is both a strong nucleophile (unless bulky and hindered) and a strong base. Both SN2 (desired) and E2 (undesired side product) can occur. Choose nucleophile and electrophile carefully. Maximize SN2 and minimize E2 reaction by choosing the R’X to have least substituted carbon undergoing substitution (electrophile). Methyl best, then primary, secondary marginal, tertiary never (get E2 instead). Stereochemistry: the reacting carbon in R’, the electrophile which undergoes substitution, experiences inversion. The alkoxide undergoes no change of configuration.

or Analysis (devise reactants and be mindful of stereochemistry) Use Williamson ether synthesis. Which part should be the nucleophile? Which is the electrophile, the compound undergoing substitution? Electrophile should ideally be 1o. Maximizes subsitution and minimizes elimination. Provide a synthesis starting with alcohols. We can set it up in two different ways: Nucleophile Electrophile, RX undergoing substitution Remember: the electrophile (RX) will experience inversion. Must allow for that! 1o 1o or Nucleophile Electrophile, RX undergoing substitution 2o 2o

Note allowance for inversion Electrophile (RX) 1o SN2 Note allowance for inversion Nucleophile 2o Preferably use tosylate as the leaving group, X. Thus…. TsCl { retention SN2 Done! inversion K retention

Acid catalyzed dehydration of alcohols to yield ethers. Key ideas: Acid will protonate alcohol, setting up good leaving group. A second alcohol molecule can act as a nucleophile. The nucleophile (ROH) is weak but the leaving group (ROH) is good. Mechanism is totally as expected: Protonation of alcohol (setting up good leaving group) For 2o and 3o ionization to yield a carbocation with alkene formation as side product. Attack of nucleophile (second alcohol molecule) on carbocation. For 1o attack of nucleophile (second alcohol molecule) on the protonated alcohol.

Mechanism For primary alcohols. For secondary or tertiary alcohols. SN1 substitution H-O-H leaves, R-O-H attached. E1 elimination

Use of Mechanistic Principles to Predict Products protonate Have set-up leaving group which would yield secondary carbocation. Check for rearrangements. 1,2 shift of H. None further. Carbocation reacts with nucleophile, another alcohol. deprotonate

Acid catalyzed addition of alcohol to alkene Recall addition of water to an alkene (hydration). Acid catalyzed, yielded Markovnikov orientation. Using an alcohol instead of water is really the same thing!! Characteristics Markovnikov Alcohol should be primary to avoid carbocations being formed from the alcohol. Expect mechanism to be protonation of alkene to yield more stable carbocation followed by reaction with the weakly nucleophilic alcohol. Not presented.