Chap 7. Acid and Bases Brønsted Acid：Proton donor Base：Proton acceptor O O + - CH3COH + H2O H3O +CH3 CO acid base conj. acid conj. base O +OH - CH3COH +HSOH2SO4 CH3COH + 4 base acid conj. acid conj. base - - C6H5NH2 +NHNH2 C6H5NH + 3 acid baseconj. base conj. acid For A-H A- + H+ solvated

[A− ][H + ] K = a [A − H ] [A − H ] pK = −log K = pH + log a a [A− ] Solvent usually acts as an activity coefficient acid (to donate H+) or as activity + a a r [A− ] r [H + ] base (to accept H ) * A− ⋅ H + A− ⋅ H + Ka = = aAH rAH [A − H ] r r A− ⋅ H + = Ka rAH

The stronger the acid is, the weaker the conjugate base is. The stronger the base is, the weaker the conjugate acid is. Lewis Acid：electron pair acceptor Base：electron pair donor Lewis acid + Lewis base adduct

BMe3 + NH3 Me3B:NH3

BF3 + OEt2 F3B:OEt2 Me Me + + Li O Li:O H H

+ + +2 Lewis acids: SO3, BF3, AlCl3, SnCl4, FeCl3, ZnCl2, H , Ag , Ca - 2- 2- - 2- Lewis bases: C6H5N, (C2H5)2O, NH3, OH , CO3 , HCO , SH , CH3CO Brønsted base can be Lewis base, e.g. OH-

Brønsted acid may not be Lewis acid, e.g. AlCl3, or HCl Leveling effect： The ionization of an acid (base) depend on the basicity(acidity) of the medium in which it is ionizing.

pKa(H2O) = 15.75 + pKa(H3O ) = -1.75 2 if H-A + H O + - K =10 , pK = −2 1 2 H3O + A a1 x2 for 0.1 M sol'n of HA [H + ] = 0.09990M ( =102 ) 1 0.1-x pH =1.00043 + - 3 if H-A2 + H2O H O + A K =10 , pK = −3 3 a1 x2 for 0.1 M sol'n of HA [H + ] = 0.09999M ( =103 ) 2 0.1-x pH =1.000043 no measurable difference

if pK = 4, pK = 5, the pH differ by 0.5 a1 a2 measurable [H + ] = 3.11×10-3 M [H + ] =1.005×10-3 M pH=2.507 pH=2.998 → 1. No acid stronger than the conjugate acid of a solvent can exist in appreciable concentration in that solvent. → 2. No base stronger than the conjugate base of a solvent can exist in appreciable concentration in that solvent → Relative strengths of acids stronger than the conjugate acids of a solvent cannot be determined in that solvent. → Relative strengths of bases stronger than the conjugate bases of the solvent cannot be determined in that solvent + (acidity can be measured for acid stronger than H2O, and weaker than H3O )

The acidity range varies dramatically. strong acid HI, HClO4… weak acid methane,

To measure very strong acid → use mix of H2O/H2SO4 To measure very weak acid → NH3, DMSO…

Acidity Function, H0 K BH+ BH+ B+H+ + a a + r [B] r + [H ] B ⋅ H B ⋅ H K + = = BH a r [BH + ] BH + BH +

r r + [B] + B ⋅ H log K BH + = log + + log[H ]+ log [BH ] r + BH + r ⋅r + [BH ] pK log I pH log B H , I BH + = + − = rBH + [B]

H0, if activity co. rB-, rBH+, rH+ → 1 then H0 → pH For a base with known pKBH+, in a series of acid sol’n measure I → H0 for the series of acid sol’n use H to measure the pK + of a weaker base 0 B2H from pK + to measure H for even more acidic sol’n B2H 0 from H of these sol’n to measure pK + even weaker base 0 B3H Acid-Base Catalyzed Reactions acid-catalyzed + O OH more reactive R C R + H+ R C R +OH OH R C R + Nu R C R → product base-catalyzed +Nu O -O more nucleophilic - Ph C CH3 + B Ph C CH2 + BH -O O -O

Ph C CH2 + PhCH O PhCHCH2CH2Ph → product Specific acid catalysis + k1 k [SH ] + + + 1 S H SH ...... fast K = = + k-1 k [S][H ] k −1 SH+ 2 P ...... r.d.s d[P] + + + rate = = k [SH ] = k K[S][H ] = k + [S][H ] dt 2 2 SH reaction proceed only depends only on the conc’n through protonated species of H+, not the donor in sol’n General acid catalysis k1 + S + HA SH + A- ...... r.d.s k-1 k SH+ 2 P ...... fast d[P] rate = = k [S][HA] dt 1 if more than one acid available in sol’n, d[P] = ∑ = k1[S][HAi ] dt i general Similar for general base (or specific base catalysis) To differentiate specific or general acid catalysis use buffer to keep [H+] const, with changing buffer constant rate → specific acid catalysis changing rate → general acid catalysis Brønsted Catalysis Law For general acid catalysis, the acidity of each acid will affect the rate.

α ka = Ga(Ka)

plot log ka v.s log Ka for a series of related acid gives a linear curve with slope of α sensitivity of the rate constant log kHA = αlog Ka + constant to structural change

( log kHB = βlog Kb + constant )

H + H OEt H OEt O C slow O C OEt H OEt H2O/Dioxane

H O OEt fast O C H C OEt H OEt Substituent Effect on acidity

the acid strengthening effect of ortho-substituent O O- O C C C O- O- O- X the ortho group resonance effect： inductive effect： remove the planarity decrease the acidity acid strengthening Addition to Carbonyl Group Hydration of aldehyde and ketone General base catalysis and general acid catalysis base-catalysis

acid-catalysis

the catalytic efficiency for the equilibrium depends on acid strengthening

HO OH O

60° 60° angle strain ∆θ = 49°/2 ∆θ = 60°/2 favors hydrate e--withdrawing group favors hydrate

O O

CH3C COCH3

O O bulky group increasing alky H H favors ketone O O substitution

H H Steric effcet

conjugate aromatic group favors ketone The hydration may be unfavorable, but the equilibrium is established fast *OH

R2CO+H2O* R2COH R2CO*+H2O

t1/2 ~ 1min in neutral condition << 1 min in acidic or basic condition

hemiketal, hemiacetal, ketal, acetal

OH

R2CO+R'OH R2COR' hemiketal → can be catalyzed by acid or base OH OH2 + R2COR'+ H R2COR' can only be catalyzed by acid OH2 so stable in base R2COR' R2COR'+ H2O HOR' + R2C OR' + R'OH R2COR' R2C(OR')2 +H ketal

For OR' Kd R2COH R2CO+R'OH

O

O in general less O favorable than methanol for steric reason O

O O

To drive equilibrium to ketal, dehydration or azeotrope are used Enolization of Carbonyl Compounds

1. catalyzed by acid or base

2. first order in ketone, zero order in X2 3. if chiral at α-carbon, the rate of bromination is the same as rate of racemization and rate H-exchange → rate-determining step is the formation of enol or enolate in acid-catalysis

in base-catalysis For unsymmetrically substituted ketone, the enolization / halogenation depends on condition in acid-catalysis, more substituted enol is formed

in base-catalysis, less substituted enolate is formed

the preference is based on both kinetic and thermodynamic reasons

Kinetic reason：

Thermodynamic reason：

favored Hydrolysis of Acetal by acid-catalysis Possible Transition State

Mechanistic Evidences 1. C-O cleavage between carbonyl C and O is shown by isotope labeling experiment, stereochemistry of R group. (no racemization or inversion) 2. Hammet ρ value

OEt O CH CH + 2 EtOH

X OEt X ρ = -3.35

3. ΔS┿ nearly zero or slightly positive

4. kinetic solvent isotope effect k +/ k + ~ 2-3 D3O H3O 5. the reaction is specific acid catalyzed → a pre-equilibrium exist for protonation of ketal/acetal

R OR' R HOR' R + H H O C C C OR' 2 fast slow R OR' R OR' R General Acid catalysis for some “reactive” acetal-ketal reactive due to

OC2H5 stable carbonium (stabilized by alkoxy and aromaticity) OC2H5

NO protonation 2 good leaving group partially OO rate- determining O step ring strain relived OC2H5

(Ar)2C(OC2H5)2 stable carbonium

PhCH[OC(CH3)3]2 aryl stabilization and relief of steric strain

addition dehydration

r.d.s. add’n r.d.s. of amine to acid-catalyzed the rate-determining step carbonyl dehydration changes depending on pH

different ρ may be observed for at different pH Acid-catalyzed Hydrolysis of Ester

AAc2 Mechanism

AAc1 Mechanism

┿ at 9.8M H2SO4, ΔS +17eV (support AAc1) ΔH┿ 28.4kcal

No carbonyl oxygen exchange (rule out AAC2) AAl1 Mechanism

the hydrolysis mechanism depends on structure and condition

O O H2SO4 CH3 C OR CH3 C OH +ROH

evidence for switching of mechanism kinetic parameters, exchange experiment O O H2SO4 CH3 C OEt CH3 C OH +EtOH

┿ ┿ % H2SO4 ΔH ΔS 40.0 16.9 -15.3 62.2 16.3 -17.0 98.4 2.7 2.3 Base-Catalyzed Hydrolysis of Ester

BAl2 Mechanism

Ruled out for most ester by labeling experiment

but in highly strained case *OH H H2O neutral pH O* CH O OH 3 OH H2O O acidic (pH<1) O OH basic (pH>9)

OH H H2O O CH neutral pH 3 O OH OH (+)-hydroxy butyric acid H O O 2 acidic (pH<1) O OH (+)-β-butyrolactone basic (pH>9) (-)-hydroxy butyric acid

BAc2 Mechanism

Evidences：kinetics, isotope labeling dependence of [OH-], Acyl-O cleavage, activation parameters exchange with solvent… Substituent effect：Electron-withdrawing groups in R and R’ favor hydrolysis Isotope labeling experiment for BAC2 mech.

18 18 O 18O O k1 ROR' k3 + R'O- R OR' k-1 R OH OH k-3

k4, H2O k-4, OH-

18 OH ROR' OH

k-4, OH-

18OH O k3 k + R'O- O 18 1 ROR' 18 + H2O k-3 R OH k O- R OR' -1 18OH-

If the recovered ester loses 18O, a tetrahedral intermediate is indicated. 18 If no loss of O, the BAC2 mechanism can not be eliminated yet (k4<

O If the 18O is labeled as R C-18OR, loss of 18O in the product should be observed. BAl1 Mechanism

for eater from a strong acid (carboxylate ion stable) for R’ a tertiary or benzylic alky group (carbocation stable) or conc’n of base too low

with BAl1 mechanism, R’OH will be racemized COOH COOH OH-

COOR COO-

R = CH3 O*CH, CH3 *CH , racemization occurs

Nucleophilic Catalysis

Mixed anhydride