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Weak Nucleophile/Base (And Strong Acid) Conditions (H2O and ROH) with Carbonyl Compounds and Epoxide Compounds

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Weak Nucleophile/Base (And Strong Acid) Conditions (H2O and ROH) with Carbonyl Compounds and Epoxide Compounds Organic Chem/Beauchamp C=O and epoxides mechanisms in acid 1 Weak Nucleophile/Base (and strong acid) Conditions (H2O and ROH) with Carbonyl Compounds and Epoxide Compounds Weak nucleophiles (water, H2O and alcohols, 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 carbocation chemistry. Weakly electrophilic carbonyl, nitrile and epoxide compounds also become strongly electrophilic in strong acid and protic solvents. We will only use limited examples (H2O, ROH and amines) 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 resonance 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 solvent will be sulfuric acid (H2SO4) and the acid we will use when an alcohol is the solvent (nonaqueous) will be toluenesulfonic acid (TsOH). You can think of TsOH as ‘organic’ sulfuric acid. Other acids 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 Aldehydes and Ketones in Aqueous Acid (= hydration) Write a step-by-step mechanism for O H H the addition of water to an aldehyde O O H H H2SO4 or ketone = 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 Addition Reaction in Alcoholic Acid (forms a hemi-acetal/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 carbonyl group 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 methanol molecule 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 leaving group 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 diol = ethylene 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 (= ethylene glycol). 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.
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