Nucleophilic Substitution and b-elimination

Nucleophilic Substitution and b-elimination

An alternative to making the halide: ROH ROTs CH3 CH3 Preparation from alcohols. ROH + O S O Cl p-toluenesulfonyl chloride Tosyl chloride TsCl The configuration of the R group is unchanged. O S

O O R Tosylate group, -OTs, good leaving group, including the oxygen. Example CH3 CH3 H TsCl OH C3H7 CH3 C2H5 H

OTs C3H7 CH3 Preparation of tosylate. Retention of configuration C2H5 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: 1. 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. 2. 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: Mechanism Reversible protonation. Elimination of water to yield tertiary carbocation. 1,2

rearrangement to yield resonance stabilized cation. Deprotonation. This is a protonated ketone! Oxidation Primary alcohol RCH2OH Na2Cr2O7 Na2Cr2O7 RCH=O RCO 2H Na2Cr2O7 (orange) Cr3+ (green) Actual reagent is H2CrO4, chromic acid. Secondary Na2Cr2O7 R2CHOH R2C=O

KMnO4 (basic) can also be used. MnO2 is produced. Tertiary R3COH NR The failure of an attempted oxidation (no color change) is evidence for a tertiary alcohol. Example OH OH Na2Cr2O7 acid HO CH2OH O CO2H Oxidation using PCC

Primary alcohol RCH2OH PCC RCH=O Secondary PCC R2CHOH R2C=O Stops here, is not oxidized to carboxylic acid Periodic Acid Oxidation OH O OH HIO4 glycol O + HIO3

two aldehydes OH O HIO4 O HO O + HIO3 aldehydes O carboxylic acid O O HO HIO4 O + HIO3

OH carboxylic acid carboxylic acid OH O 2 HIO4 O HO O + 2 HIO3 OH OH O 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 Reactions of ethers Ethers are inert to (do not react with) Common oxidizing reagents (dichromate, permanganate) Strong bases

HX protonates ROH, set-up leaving group followed by SN2 (10) or SN1 (20 or 30). Weak acids. But see below. Ethers do react with conc. HBr and HI. Recall how HX reacted with ROH. Look at this reaction and attempt to predict the mechanism Characterize this reaction: Fragmentation Substitution 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 Mechanism H + H R-O-R

H XO R R R primary R O R X Inversion of this R group Secondary, Tertiary R H R This alcohol is protonated, becomes

carbocation and reacts with halide. This alcohol will now be protonated and reacted with halide ion to yield RX. Inversion will occur. O X- R R X Loss of chirality at reacting carbon. Possible rearrangement. Properties of ethers Aprotic Solvent, cannot supply the H in Hbonding, 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 R Requirements of Hydrogen Bonding: Need both H acceptor and donor. R O H O protic H H acceptor 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. H donor Synthesis of ethers Williamson ether synthesis RO- + RX 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 RX 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. Analysis (devise reactants and be mindful of stereochemistry) C2H5 Provide a

synthesis starting with alcohols. H3C H Use Williamson ether synthesis. D H Which part should be the nucleophile? O H CH3 H CH3 C2H5 Which is the electrophile, the compound undergoing substitution? Electrophile should ideally be 1o. Maximizes subsitution and minimizes elimination.

We can set it up in two different ways: C2H5 Electrophile, RX undergoing 1o substitution C2H5 H3C H D H O Nucleophile H 2 o CH3 H

CH3 C2H5 Nucleophile H3C H Remember: the electrophile (RX) will D inversion. H experience Must1oallow for that! O or H CH3 H CH3 C2H5 Electrophile, RX undergoing substitution 2o

C2H5 C2H5 Electrophile (RX) H3C H D H 1o H3C H H D SN2 X O

Nucleophile H 2 o CH3 H O CH3 C2H5 Preferably use tosylate as the leaving group, X. Thus. C2H5 H3C H O H CH3 H

CH3 C2H5 SN 2 { inversion H CH3 H CH3 C2H5 C2H5 H3C H D Note allowance for inversion

C2H5 H H D TsCl H3C H H D retention OTs OH OH O H CH3 H

CH3 C2H5 K retention H CH3 H CH3 C2H5 Done! Acid catalyzed dehydration of alcohols to yield ethers. 2 ROH H ROR + H2O 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. RCH2OH RCH2OH RCH2OCH2R RCH2 - OH2 primary alcohols H RCH2OCH2R ether For secondary or tertiary alcohols. ROH ROH2 H2O + carbocation

- H+ alkene E1 elimination ROH ether SN1 substitution H-O-H leaves, R-O-H attached. Use of Mechanistic Principles to Predict Products acid C10H22O OH H+ H OH OH2+ protonate Have set-up leaving group which would yield secondary carbocation.

H Check for rearrangements. 1,2 shift of H. None further. O OH O H Carbocation reacts with nucleophile, another alcohol. deprotonate H H 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!! OH

OR HOH ROH acid acid alcohol ether 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.

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