Chap 7. Acid and BasesBrønsted Acid：Proton donor

Base：Proton acceptor

Solvent usually acts as an acid (to donate H+) or as base (to accept H+)

][][loglog

][]][[

−

+−

−+=−=

−=

AHApHKpK

HAHAK

aa

a

AH

HAa

AH

HA

AH

HAa

rrr

K

HArHrAr

aaa

K

+−

+−+−

⋅=

−

⋅=

⋅=

+−

][][][*

CH3COH

O

+ H3O+ + CH3 CO-O

H2Oacid base conj. acid conj. base

CH3COH

O

+ HSO4-+H2SO4

acidbase conj. acid conj. baseCH3COH

+OH

C6H5NH2 + NH3+-NH2

acid base conj. acidconj. baseC6H5NH-

For A-H A- + H+

solvated

The stronger the acid is, the weaker the conjugate base is.The stronger the base is, the weaker the conjugate acid is.

activity activity coefficient

Leveling effect：

M101.005][ M103.11][

0.5by differ the,5,4if3-3-

21

×=×=

==++ HH

pHpKpK aa 　　　　　　measurable

000043.1 )10

10(099990][HA ofn sol' M 0.1for

3,1000043.1

)1010

(099900][HA ofn sol' M 0.1for

2,10

32

2

3

22

1

2

1

1

=

==

−===

==

−==

+

+

pH-x.

xM　　.H

pKKpH

-x.xM　　.H

pKK

a

a

　　　　　　　　　　　　

　　　　　　　

　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　

　　　　　　　

　　　　　　　　　　　　　　　　　　　　　if H-A1 A-++ H2O H3O+

if H-A2 A-++ H2O H3O+

no measurable difference

pKa(H2O) = 15.75pKa(H3O+) = -1.75

pH=2.507 pH=2.998

Lewis Acid：electron pair acceptor

Base：electron pair donorLewis acid + Lewis base adductBMe3 + NH3 Me3B:NH3

BF3 + OEt2 F3B:OEt2

Li + OMe

HLi:O

Me

H

+

Lewis acids: SO3, BF3, AlCl3, SnCl4, FeCl3, ZnCl2, H+, Ag+, Ca+2

Lewis bases: C6H5N, (C2H5)2O, NH3, OH-, CO32-, HCO2-, SH-, CH3CO2-

Brønsted base can be Lewis base, e.g. OH-

Brønsted acid may not be Lewis acid, e.g. AlCl3, or HCl

The ionization of an acid (base) depend on the basicity(acidity) of the medium in which it is ionizing.

→ 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 acidsof a solvent cannot be determined in that solvent.

→ Relative strengths of bases stronger than the conjugate basesof 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/H2SO4To measure very weak acid → NH3, DMSO…

For a base with known pKBH+, in a series of acid sol’n measure I → H0 for the series of acid sol’n

use H0 to measure the pKB2H+ of a weaker base from pKB2H+ to measure H0 for even more acidic sol’n from H0 of these sol’n to measure pKB3H+ even weaker base

][][,loglog

log]log[][

][loglog

][][][

BBHI

rrr

pHIpK

rrr

HBH

BK

BHrHrBr

aaa

K

BH

HBBH

BH

HBBH

BH

HB

BH

HBBH

+

++

+

+

=⋅

−+=

⋅++=

⋅=

⋅=

+

+

+

+

+

+

+

+

+

+

+

　　

H0, if activity co. rB-, rBH+, rH+→ 1then H0→ pH

BH+ B + H+KBH+

Acidity Function, H0

Acid-Base Catalyzed Reactionsacid-catalyzed

base-catalyzed

Specific acid catalysis

General acid catalysis

Similar for general base (or specific base catalysis)To differentiate specific or general acid catalysis

use buffer to keep [H+] const, with changing bufferconstant rate → specific acid catalysischanging rate → general acid catalysis

R C

O

R + H+ R C

+OH

R

R C

+OH

R + Nu R C

OH

R+Nu

→ product

more reactive

Ph C

O

CH3 + B- Ph C

-OCH2

Ph C

-OCH2 + PhCH O

+ BH

PhCHCH2CH2PhO -O

→ product

more nucleophilic

S + HA SH+

SH+ P　.......　fast

k1

k-1k2

+ A-　.......　r.d.s

]][[][1 HASk

dtPdrate ==

]][[][1 i

iHASk

dtPd

==∑if more than one acid available in sol’n,

general

S + H+ SH+　.......　fast

SH+ P　.......　r.d.s

k1

k-1k2]][[

][

1

1+

+

−

==HS

SHkkK

]][[]][[][][22

++++==== HSkHSKkSHk

dtPdrate SH

reaction proceed only through protonated species

depends only on the conc’nof H+, not the donor in sol’n

Brønsted Catalysis Law

For general acid catalysis, the acidity of each acid will affectthe rate.

ka = Ga(Ka)α

plot log ka v.s log Ka for a series of related acid gives a linear curve with slope of α

log kHA = αlog Ka + constant

( log kHB = βlog Kb + constant )

sensitivity of the rate constant to structural change

O CH

OEt

OEt

H+

slowH2O/Dioxane

OH

CH

OEt

OEt

OH

CH

OEt

OEt

fastCHO

OEt

Substituent Effect on acidity

the acid strengthening effect of ortho-substituent

the ortho group remove the planarity

resonance effect：decrease the acidity

inductive effect：acid strengthening

C

O-

O

X

C

O-

O-

C

O-

O

Addition to Carbonyl GroupHydration of aldehyde and ketone

General base catalysis and general acid catalysisbase-catalysis

acid-catalysis

for the equilibrium the catalytic efficiency depends on acid strengthening

e--withdrawing group favors hydrate

angle strain favors hydrate

HO OH O

∆θ = 49°/2 ∆θ = 60°/2

60° 60°

O

HO

H

O

H

O

H

Steric effcet

bulky group favors ketone

conjugate aromatic group favors ketone

increasing alky substitution

CH3C COCH3

O O

The hydration may be unfavorable, but the equilibrium is established fast

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

hemiketal, hemiacetal, ketal, acetal

To drive equilibrium to ketal, dehydration or azeotrope are used

O

O

OO

O

O

in general less favorable than methanol for steric reason

R2C O + H2O* R2C OH

*OH

R2C O* + H2O

R2C OHOR'

Kd R2C O + R'OHFor

hemiketal→ can be catalyzed by acid or base

can only be catalyzed by acidso stable in base

R2C O + R'OH R2C OR'

OH

R2C OR' + H2O

R2C OR'

OH

+ R2C OR'

OH2

R2C OR'

OH2

R2C OR' + R'OH R2C OR'

HOR'

R2C(OR')2 + H+

H+

ketal

Enolization of Carbonyl Compounds

1. catalyzed by acid or base2. 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

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. Hammetρ value

3. ΔS┿ nearly zero or slightly positive

4. kinetic solvent isotope effect kD3O+/ kH3O+ ~ 2-3

5. the reaction is specific acid catalyzed→ a pre-equilibrium exist for protonation of ketal/acetal

X

CH

OEt

OEt X

CH

O

+ 2 EtOH

ρ = -3.35

R

C

R

OR'

OR'

R

C

R

HOR'

OR'

H+

fast

R

C

R

OR'slow

H2O

Possible Transition State

r.d.s. add’n of amine to carbonyl

r.d.s. acid-catalyzed dehydration

General Acid catalysis for some “reactive” acetal-ketal

the rate-determining step changes depending on pH

different ρ may be observed for at different pH

reactive due tostable carbonium (stabilized by alkoxyand aromaticity)

good leaving group

ring strain relived

stable carbonium

aryl stabilization and relief of steric strain

protonation partially rate-determining step

OC2H5

OC2H5

O O

NO2

O

OC2H5

(Ar)2C(OC2H5)2

PhCH[OC(CH3)3]2

addition dehydration

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

evidence for switching of mechanism kinetic parameters, exchange experiment

CH3 CO

ORH2SO4 CH3 C

OOH + ROH

CH3 CO

OEtH2SO4 CH3 C

OOH + EtOH

2.32.798.4-17.016.362.2-15.316.940.0ΔS┿

ΔH┿% H2SO4

Base-Catalyzed Hydrolysis of EsterBAl2 Mechanism

Ruled out for most ester by labeling experiment

but in highly strained case

BAc2 Mechanism

Substituent effect：Electron-withdrawing groups in R and R’favor hydrolysis

Evidences：kinetics, isotope labelingdependence of [OH-], activation parameters

Acyl-O cleavage, exchange with solvent…

O*H

CH3

O

H2Oneutral pH

*OH

O OH

H2Oacidic (pH<1)basic (pH>9)

OH

O OH

OH

CH3

O

H2Oneutral pH

H2Oacidic (pH<1)basic (pH>9)

OH

O OH

OH

O OH

(+)-β-butyrolactone(-)-hydroxy butyric acid

(+)-hydroxy butyric acid

R

O

OR'

k1

k-1R OR'

O

OH

1818

R

O

OH

18

+ R'O-

R OR'

OH

OH

18

R OR'

OH

O-

18

R

O

OH18 + R'O-

R

O

OR'

18+ H2O

OH-

k3

k-3

k4, H2Ok-4, OH-

k-4, OH-

k1

k-1

k3

k-3

18

Isotope labeling experiment for BAC2 mech.

If the recovered ester loses 18O, a tetrahedral intermediate is indicated.If no loss of 18O, the BAC2 mechanism can not be eliminated yet (k4<<k3, k-1)

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

O

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

Nucleophilic Catalysis

COOH

COOR

OH- COOH

COO-

R =　　　　　　　　　　　　,　　　　　　　　　,　racemization occursCH3 O *CH *CHCH3

Mixed anhydride