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Organic Chem/Beauchamp C=O and mechanisms in 1

Weak / (and strong acid) Conditions (H2O and ROH) with Carbonyl Compounds and Compounds

Weak (, H2O and , ROH in our course) react with secondary and tertiary RX compounds (SN1 > E1 reactions). Also, methyl and primary alcohols react under strong HX acid conditions via SN2, while secondary, and tertiary alcohols react under strong HX acid conditions via SN1 (HX = HCl, HBr, HI). All alcohols react via E1 reactions with H2SO4/. Rearrangements are always a possibility in . Weakly electrophilic carbonyl, and epoxide compounds also become strongly electrophilic in strong acid and protic . We will only use limited examples (H2O, ROH and ) to introduce these reactions. In weak base/nucleophile reactions (strong acid) the order of events is usually 1. Add a proton, 2. add weak nucleophile and 3. lose extra proton). Because the acidic conditions are usually strong protic acid, the solvents + + used are typically protic (H2O/H2SO4 = H3O /H2O or ROH/TsOH = RO H2/ROH). Carbonyl reactions with water and alcohols often have products and reactants in equilibrium with one another, while with epoxide reactions are irreversible, due to the release of large ring strain. Writing mechanisms in acid is often longer (than base) because there is an initial protonation step, sometimes intermediate structures, and a final deprotonation step required. One final point is that water is often used to shift the equilibrium, in acid, to one side or the other by adding water (hydration) or removing water (dehydration). The acid we will use when water is the will be (H2SO4) and the acid we will use when an is the solvent (nonaqueous) will be toluenesulfonic acid (TsOH). You can think of TsOH as ‘organic’ sulfuric acid. Other are possible, but not discussed here.

Very strong acids used in our course.

H OTs H OSO3H O O H H O Ts H O SO H H O S = H O S O = 3 pK -1 a pKa -3 O O used in nonaqueous conditions used in aqueous conditions toluenesulfonic acid = TsOH (it's like "organic" sulfuric acid) sulfuric acid = H2SO4

Generic Carbonyl Addition Reactions of and in Aqueous Acid (= hydration) Write a step-by-step mechanism for O H H the addition of water to an O O H H H2SO4 or = carbonyl hydrates. This C O C is a reversible reaction that favors R R' the C=O side of the equilibrium. R R' Possible mechanism without details (you add those)

H O SO H 3 OSOH H H3O H H 3 H O O O O O R C R' R C R' C C resonance C R R' H H H H R R' R R' O O O O H H H Possible mechanism with details. H O SO H 3 OSOH H H3O H H 3 H O proton O O O O add nucleophile to carbocation transfer R C R' R C R' C proton C resonance C R R' H H H H R R' transfer R R' O O O O carbonyl H H H compound carbonyl equilibrium reaction, usually favors carbonyl compounds, except when R = R' = H hydrate Write a mechanism for the reverse reaction = dehydration of carbonyl hydrate to carbonyl and water. Organic Chem/Beauchamp C=O and epoxides mechanisms in acid 2

Write a step-by-step mechanism H H O O O for the elimination of water from H2SO4 H H a carbonyl hydrate. C C O R R' R R' Possible mechanism without details (you add those). H H H H OH2 O H OH2 O O H H O O O R C R' R C R' C resonance C C O O R R' R R' R R' H OH H 2 H H equilibrium reaction, usually favors carbonyl compounds, except when R = R' = H Possible mechanism with details.

H OH2 H H H H H O O O H OH2 O O O R C R' R C R' C C resonance C R R' O O R R' R R' H OH2 H H H

Carbonyl in Alcoholic Acid (forms a hemi-/ketal), followed by an SN1 reaction (forms an acetal/ketal). To form the acetal/ketal requires the removal of water to shift the equilibrium to the right. If water is added the equilibrium will shift to the left, reforming the and 2 x ROH. This is an equilibrium reaction that can be pushed in either direction. That turns out to be a very valuable feature of this reaction, called protection/deprotection that we will study more later.

Write a step-by-step mechanism for the addition of an alcohol to an aldehyde (or ketone) = hemi-acetal O TsOH H3C CH3 (hemi-ketal). Removal of water forces and additional (-H2O) O O H C H SN1 step with a second leading to C 2 3 O C an acetal (or ketal). Addition of water forces the R R' H2SO4 R R' equilibrium back to the aldehyde or ketone. H2O

Possible mechanism without details (you add these). OTs Ts OH H H H H O Ts H O O O O O R C H R C H C C C R H H3C H H CH R H R H O 3 O O O H C H H C carbonyl = A 3 3 compound hemi-acetal = B equilibrium is controlled by water, removing water shifts it to the right and adding water shifts it to the left

CH3 H3C H H3C H3C H O O H H O O H H R H R H O O H C C R C H R C H R C H O O O O H C H C remove H O H3C H C 3 3 2 O 3 add H O acetal = C acetal hemi-acetal = S 1 reaction 2 H3C N Organic Chem/Beauchamp C=O and epoxides mechanisms in acid 3

possible mechanism with details Ts OH H O Ts OTs H H H H O O O add nucleophile proton O O to carbocation transfer R C H R C H C C resonance C proton R H H3C H H CH R H R H O 3 O transfer O O H C H H C carbonyl = A 3 3 compound hemi-acetal = B equilibrium is controlled by water, removing water shifts it to the right and adding water shifts it to the left proton CH3 H3C H H H transfer H3C H C H 3 O O O O O H H R H R H water is a good O H C R C H R C H C resonance R C H proton O O transfer O O H C H3C H3C 3 H3C remove H2O O acetal = C acetal hemi-acetal = S 1 reaction add H2O H3C N

Similar mechanisms with a = glycol (protection of a C=O, aldehydes and ketones)

O TsOH Write a similar mechanism when H2 O H (-H2O) O H H both alcohols are in the same C C O H C O C O molecule (= ). R R' H 2 R R'

Possible mechanism without details (you add these). H H Ts OH toluenesulfonic O acid H H O O O O H O Ts resonance O O H H H O aldehyde H O O hemi-acetal or ketone O H OTs hemi-ketal ethylene glycol

H H (remove) H H O OTs Ts O O

O H resonance O O O O O O H H H O O acetal or ketal O equilibrium is controlled by water, removing water shifts it to the right and adding water shifts it to the left

Organic Chem/Beauchamp C=O and epoxides mechanisms in acid 4

possible mechanism with details H OTs H toluenesulfonic Ts OH O acid H H O O O O H O Ts resonance O O H H H O aldehyde H O O hemi-acetal or ketone O H hemi-ketal OTs ethylene glycol

OTs H H (remove) H H O Ts O O

resonance O H O O O O O O H H H O O acetal or ketal O

Write a mechanism for the reverse reaction (deprotection of a carbonyl).

O Write a mechanism for H SO H2 O O H H 2 4 C O C H the reverse reaction using C O R R' H C O H2SO4 / H2O. R R' H2 Possible mechanism without details (you add these). O H H H H O O H OH2 H H resonance O H O O O O O O H H H O acetal or ketal O O

equilibrium is controlled by water, removing water shifts it to the right and adding water shifts it to the left H H O O H H O O O resonance O H aldehyde O H H O or ketone O H O H O hemi-acetal H2OH ethylene glycol hemi-ketal

Possible mechanism with details O H H H H O O H OH2 resonance H H O H O O O O O O H H H O acetal or ketal O O equilibrium is controlled by water, removing water shifts it to the right and adding water shifts it to the left H H O O OH H H 2 O O O resonance O H aldehyde O H O or ketone H O H O H O H2OH ethylene glycol hemi-acetal hemi-ketal

Organic Chem/Beauchamp C=O and epoxides mechanisms in acid 5

S 1 reaction addition reaction N A The equilibrium is controlled B C here. Removing water pushes carbonyl compound acid hemi-acetal or ketal acid acetal or ketal the reaction toward the acetal or + catalyzed + catalyzed ketal, and adding water pushes alcohol + alcohol water the reaction toward the carbonyl and alcohols SN1 reaction

Carbonyl groups are very susceptible Acetal/ketal groups are very inert to attack to attack by strong nucleophile/bases by strong nucleophile/bases such as the such as the n-butyl or LDA. n-butyl carbanion or LDA. The diol is also Also, alcohols are weakly acidic. The protected. This protects the organic compounds acetal/ketal takes care of both problems. from either point of view.

Formation of a THP protected alcohol. DHP is an , which a condensation of an aldehyde and a single alcohol. When a second alcohol is added to DHP in the presence of an acid catalyst (TsOH) and acetal forms, which protects the alcohol (instead of the carbonyl group). A similar strategy is used, but protects a different functionality (the alcohol).

overall mechanism for protection of an alcohols as a THP ether (tetrahydropyran, using DHP = dihydropyran and TsOH)

H O H R O Ts R THP O H O O sometimes O R written this way DHP = dihydropyran alcohol acetal (enol ether) possible mechanism without the details H H H H H H alcohol O HOTs resonance H H R O O R O H H R O O H O H O THP protected alcohol DHP = O R as an acetal H dihydropyran H R (enol ether) O

H possible mechanism with the details H H H H H H alcohol O HOTs resonance H H R O O R O H H R O O H O H O THP protected alcohol DHP = O R as an acetal H dihydropyran H R (enol ether) O

H

Organic Chem/Beauchamp C=O and epoxides mechanisms in acid 6

Deprotection of a THP protected alcohol

overall mechanism for protection of an alcohols as a THP ether (tetrahydropyran, using DHP = dihydropyran and TsOH)

O H H O R H H O H OH HO O H O 2 alcohol R alcohol + aldehyde acetal (discard) possible mechanism without the details

O resonance H H H H O H O H H H H O O H O O O O R O O acetal O R R H H H H H alcohol O H2OH H H O H H H resonance H O O H HO O H O H H H O O alcohol + aldehyde H H O O (discard) O O H H H H possible mechanism with the details

O resonance H H H H O H O H H H H O O H O O O O R O O acetal O R R H H H H H alcohol

H H O H2OH O H H H resonance H O H O H H HO O H O O H O O O alcohol + aldehyde H H O O (discard) H H H H Organic Chem/Beauchamp C=O and epoxides mechanisms in acid 7

Fischer Synthesis Reaction - In a closely related series of steps it turns out that carboxylic acids and alcohols can form and water (which is removed) using catalytic . Using aqueous sulfuric acid and lots of water will hydrolyze the ester back to the and the alcohol. This is again an equilibrium controlled by the removal or addition of water. If you can write a mechanism from the overall reaction. If you need help, use the reactions mechanism written without the details. If you need more help, study the proposed mechanism and then try the other approaches.

overall mechanism for Fischer esterification O O TsOH H3C H C H (-H2O) C CH O O 3 R O R O H H carboxylic = A alcohol ester = C water acid possible mechanism without the details H O Ts H H H H resonance O O O O resonance O H R C O C H C H C H C H H3C H R O R O R O R O O O carboxylic H3C H acid proton OTs equilibrium is controlled by water, removing water shifts it to the right and adding water shifts it to the left transfer

OTs Ts OH H H H H O H H O resonance O O resonance O H C CH3 H C CH3 C CH R C O R O 3 R C O R O R O O O H3C H3C T.I. O H H O C CH 3 water can be distilled out and R O removed from the equilibrium ester

Organic Chem/Beauchamp C=O and epoxides mechanisms in acid 8

possible mechanism with the details

H O Ts H H H H add nucleophile resonance O O O O resonance O to carbocation H R C O C H C H C H C H H3C H proton R O R O R O transfer R O O O H C H carboxylic = A 3 acid proton OTs equilibrium is controlled by water, removing water shifts it to the right and adding water shifts it to the left transfer

OTs Ts OH H H H water is a good H O H H O resonance O leaving group, and O resonance O a good carbocation H C CH3 H C CH3 C CH forms R C O R O 3 R C O R O R O O proton O H3C transfer H3C T.I. = B O water can be distilled out H H and removed O C CH3 R O from the equilibrium ester = C

Propose a mechanism for the reverse reaction: acid of an ester.

overall mechanism for hydrolysis of an ester to an alcohols and carboxylic acid

O O TsOH H C H (-H O) C H 3 C CH O 2 O 3 R O R O H H ester water carboxylic acid alcohol possible mechanism without the details H OH H H O 2 H H H O O O O resonance H C CH3 resonance R C O R O C CH C CH3 C CH3 3 ester R O R O R O H H O O H3C

equilibrium is controlled by water, removing water shifts it to the right and adding water shifts it to the left H H O H H H O O O O O H H C H resonance resonance R C O R C O R O C H C H C H R O R O R O T.I. carboxylic acid O O H C O H3C H 3

H3C H H2OH

Organic Chem/Beauchamp C=O and epoxides mechanisms in acid 9

possible mechanism with the details H H H H H H O O H OH2 O O O O resonance resonance H CH3 CH3 O O O O O O H O H C ester CH3 CH 3 H H 3 water O H H H H H H C OH H O H O 3 H H alcohol O O O H H H H O O O H resonance resonance O O H O O H H H O H C H O O O H3C H 3 carboxylic acid H O

H There are many examples of carbonyl groups reacting with primary RNH2 The following reaction shows the formation of simple with carbonyl groups. Reaction with (H2NNH2) is similar.

Write a mechanism for H R formation usingTsOH (-H2O). O Neutral is a good enough N R HOTs N O nucleophile to attack without H H protonating the carbonyl group. H (remove)

possible mechanism without the details H H H H H H O O TsO H O O (remove) O H N R N N N H H N R R R R NH2 H H H R H equilibrium is controlled by water, removing water shifts it to the right and adding water shifts it to the left resonance Imines can be made into amines using sodium 1. NaH3BCN 2. workup cyanoborohydride (NaH3BCN),followed by workup. H HN Reaction with hydrazine, followed by strong base R R'ONa /  N and heat can reduce the C=O to a CH2. This N when R = NH2 R reaction is called the Wolff-Kishner reduction. C R R NH H H2 2 possible mechanism with the details H H H H H H O O TsO H O O (remove) O H N R N N N H H N R R R R NH2 H H H R H equilibrium is controlled by water, removing water shifts it to the right and adding water shifts it to the left resonance

R NH3 N N R R R NH2 H

Organic Chem/Beauchamp C=O and epoxides mechanisms in acid 10

When carbonyl groups react with secondary amines, R2NH, enamines form. Enamines are nucleophilic on the second of the C=C . They are neutral versions of chemistry in reactions with common , and very similar to biochemical examples in nature. The following reaction shows the formation of simple enamines with carbonyl groups. After reaction with an they can be hydrolyzed back to a carbonyl group.

Write a mechanism for enamine H o formation using 2 amines and TsOH O N O (-H2O). Neutral nitrogen is a good HOTs N H H enough nucleophile to attack without (remove) protonating the carbonyl group. H possible mechanism without the details H H H H O H (remove) O TsO H O O O H N N N N N H R2NH

equilibrium is controlled by water, removing water shifts it to the right and adding water shifts it to the left resonance

Br H C 3 CH H H O 3 H3C 2 N N N O hydrolyze can react back to C=O with good R NH2 electrophiles enamine possible mechanism with the details H H H H H H O O TsO H O O O H (remove) N N N N H N R2NH

equilibrium is controlled by water, removing water shifts it to the right and adding water shifts it to the left resonance

Br H3C H H2O CH3 H C N 3 N N hydrolyze O back to C=O can react R NH mechanism with good 2 not shown electrophiles enamine

Organic Chem/Beauchamp C=O and epoxides mechanisms in acid 11

Nitriles can be hydrolyzed in milder acid (HCl/H2O) to primary and in stronger acid (H2SO4/H2O/) to carboxylic acids.

Write a mechanism for an acid O hydrolysis of a nitrile group to O H OH2 H OH a primary in HCl/H2O N H 2 O or a carboxylic acid in C N H H H H SO /H O/ (harsher conditions). O 2 4 2 HCl/H O 2 H H2SO4/H2O/ possible mechanism without the details H H2OH H H N N N N C H OH2 C O H H H H O O nitrile OH2 H

O H H H H H H H N N N N resonance resonance H H H amide H O O O

possible mechanism with the details H H2OH H H N N N N C H OH2 C O H H H H O O nitrile OH2 H

O H H H H OH2 H H H N N N N resonance resonance H H H amide H O O O

possible mechanism without the details O H H H O O O H OH2 H resonance resonance N H H H N N N amide H H H H

O H H H H H H N H O O O H O H H H H H N N O H N O H H O O H H H2O H resonance H H

H H O O OH2 O resonance H H H O O O

Organic Chem/Beauchamp C=O and epoxides mechanisms in acid 12

possible mechanism with the details

O H H H O O O H OH2 H resonance resonance N H H H N N N amide H H H H

H O H H N H H H H O H OH2 O H O O H H H H H N N O H N O H H O O H H H H resonance H2O H

H H O O OH2 O resonance H H H O O O

Epoxides in Acid Solution

As was the case with carbonyl compounds in acid, epoxides first add a proton. The positive charge in the intermediate is distributed over the and both carbon (Ca and Cb, below). The weak nucleophile is attracted to the backside of the more substituted carbon because it carries a larger partial positive charge than the less substituted carbon (just like ). This is the opposite epoxide carbon to what was attacked in strong base (but still backside attack because of the bridging oxygen ). If the more substituted carbon is chiral, we should see a change in the (from R to S or S to R).

overall mechanism for epoxides in aqueous acid (H2SO4 / H2O = hydration conditions) H O O H H OH2 CH3 Cb Ca C C H H H H H b a H CH3 O H diol compound epoxide compound O R absolute configuration S absolute configuration H possible mechanism without the details

H O SO H 3 H H H O O H O H proton O CH CH3 transfer C C 3 Cb Ca H b a Cb Ca H H H Cb Ca H H H H H O H H H O H CH3 O H H CH3 O H H

Organic Chem/Beauchamp C=O and epoxides mechanisms in acid 13

possible mechanism with the details H O SO H 3 H H H O O H O H proton O CH CH3 transfer C C 3 Cb Ca H b a Cb Ca H H H Cb Ca proton H H H H H O H H H O transfer H CH3 O H H CH3 O H H epoxide compound inversion of diol compound S absolute configuration configuration R absolute configuration

Ca has greater partial positive charge than Cb because it is more substituted, so the weak nucleophile attacks it faster. Notice that a different carbon of the unsymmetrical epoxide was attacked than was the case in strong nucleophile/base conditions. Because that carbon is chiral in this example, we can see the inversion of configuration (from S to R), even though there is an "OH" on both carbon atoms.

overall mechanism for epoxides in alcoholic acid (TsOH / ROH)

H O O H H C OH CH3 Cb Ca 3 2 C C H H H3C H H b a H CH3 O H hydroxy ether compound epoxide compound O R absolute configuration S absolute configuration H3C possible mechanism without the details

H O Ts OTs H H H O O H O H proton O CH CH3 transfer C C 3 Cb Ca H b a Cb Ca H CH3 H Cb Ca H H H H H O H H H O H CH3 O H H CH3 O H C H3C 3 possible mechanism with the details H O Ts OTs H H H O O H O H proton O CH CH3 transfer C C 3 Cb Ca H b a Cb Ca H CH3 H Cb Ca proton H H H H H O H H CH3 O transfer H CH3 O H H CH3 O H C H3C epoxide compound inversion of 3 S absolute configuration hydroxy ether compound configuration R absolute configuration

Ca has greater partial positive charge than Cb because it is more substituted, so the weak nucleophile attacks it faster. Notice that a different carbon of the unsymmetrical epoxide was attacked than was the case in strong nucleophile/base conditions. This is easy to see in this example because "methoxy = -OCH3" (from the attacking weak nucleophile) is different than "hydroxy = -OH" (from the epoxide oxygen).