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Nucleophilic Addition To Carbonyls

Lewis basic site-reacts with electrophiles

R Y

O

!

!

R Y

O

electron-deficient carbon-reacts with nucleophiles overall reaction:

R

O

Nuc:

E+

R

NucO

E

this can occur by either of three mechanisms:

:O:

R

O

Nuc:

E+

R

NucO

E

1) simultaneous

2) or

R

E+

R

O

E

:NucO

R

Nuc

E

electrophilicattack

3)or

R

:Nuc O

R

Nuc

E+ O

R

Nuc

E

nucleophilicattack

O__

which mechanism is operative will depend on electrophilicity of E+, and nucleophilicity

of Nuc: general rule: when E+ is H+ or strong Lewis acid, Nuc is neutral

⇒ choose mechanism #2

when E+ = Li+, Na+, K+ ; Nuc is anionic ⇒ mechanism #1

when E+ = R4N+ ; Nuc is anionic ⇒ mechanism #3

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Case study - hydration of carbonyls:

R R'

O

+ H2O

R R'

HO OH

normally Keq (ketones < 10-5) (aldehydes 10-3 to 103)

Ex:

CCl3 H

O

+ H2O

Cl3C H

HO OH

Keq = 3 x 104

Why do EWG’s favor hydrates?

Kinetics of hydration

R H

O H2O)

R H

HO OH

k1(+

H2O)(-k-1

How to measure k1? Look at carbonyls with Keq << 1 look at oxygen isotope exchange rate:

R1 R2

O

R1 R2

H*O OHk1

k-1 k1

k-1

R1 R2

O*

H2O* + + H2O

so, since k1 << k-1 ,

R1 R2

O*

d

dt

~d

dt

R1 R2

HO* OH

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look at effect of pH on rate:

7 131

log(rate)

pH

What's going on here?

rate increases with increasing [H+], [OH-]

Implication: 2 different mechanisms, one in acid,

one in base

acid catalysis- 2 choices specific acid catalysis - protonation occurs before R.D.S.:

-H+

H+

R1 R2

O

R1

R2

HO OH2slow

+ + H2Ofast

R1 R2

OH

R1 R2

HO OH

+ H+

k2

R1 R2

OH

! = k2[H2O] [ ] ~ k1[ R1 R2

OH

]

alternative #2 - general acid catalysis

R1 R2

O

R1 R2

HO Oslowfast

R1

R2

HO OH

+ HA

+ H-AR1

R2

O

H A

Hydrogenbondedcomplex

+ H2OH

H

+ A-

in this case, proton transfer occurs in R.D.S.

[HA]R1 R2

O

! = k3 ][ [HA] [H2O] ~ k2 R1 R2

O

][

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in basic solution, we can change nucleophiles:

H-O-H-OH

R1 R2

O

R1 R2

HO OHfast+ slow+ OH

-

R1 R2

HO O-

+

[_OH]R1 R2

O

! = k2 ][ base-catalyzed hydration (nucleophilic catalysis) can also be viewed as:

Na+

-OH

R1 R2

O

R1 R2

HO OHfastslow

+ Na+OH

-

R1 R2

HO O-Na

+O

H

H

+ H2O

these really represent examples of specific base & general base catalysis so, which mechanisms are operative? It will depend on nature of acid, base, and/or carbonyl; all mechanisms have been observed in carbonyl hydration see Jencks, JACS, 1978, 100, 5444

McClelland, JACS, 1983, 105, 2718

Case Study #2 - Cyanohydrin Formation

R H

OH CN

RCHO + HCN

kinetics of this reaction were studied by Lapworth; he found that rate was not ∝ [HCN], but rather: ν = k [RCHO] [CN-] (Lapworth, JCS, 1903, 83, 998)

so, mechanism is:

R H

Ofastslow

R H

NC O-

+ H-CNR H

NC OH-C N

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tertiary amines were also shown to catalyze reaction:

R H

HO CN

RCHO + HCN +R3N + R3N

Does it just increase [CN-]? No . . . look at kinetics: ν = k4 [RCHO] [HCN] [R3N]2 ← bimolecular in amine

Why?

HCN +R3N R3NH CN

R3NH CN

H-NR3CN

+NR3

R H

HO CN

R H

O

+

R H

O

+ HNR3 CN

+ HNR3 CN this is an example of general acid catalysis Prelog & Wilhelm, Helv. Chim. Acta, 1954, 192, 1634

Scope of Nucleophilic Addition nucleophiles that add readily: C-, H-, :NR3 (R=H, alkyl) nucleophiles that add under acid catalysis: ROH, RSH, HNR2

Addition of Carbon Nucleophiles While all carbanions are nucleophilic enough to add to carbonyls, they are also basic enough to deprotonate carbonyl α-protons; thus, we will often observe competing modes of reaction Common carbanion nucleophiles: R-CC-, -CN, R-Li, R-MgBr Mechanism usually involves a 4-center transition state:

O

RR'

M

CR''

R'''

!"

!"

!+

because of the compact nature of the transition state, reaction rate will be very sensitive to steric factors

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Chemoselectivity of Grignard Additions

O

RMgX

OH R OH O

+ +

1,2 addition reduction enolization

R X 1,2 addition reduction enolization

Et Br 80 15 1

n-Pr Cl 51 46 2

n-Pr Br 35 64 1

n-Pr I 30 69 1

i-Pr Cl 0 72 28

i-Pr Br 0 65 29

i-Pr I 0 70 30

Mosher, JOC, 1962, 27, 1

Where does product #2 come from? β - hydride transfer

MgX

R1 R2

O

Mg

CH

H HH

CH3O

R1

R2 H

+HC

CH3

HH -this is related to the Meerwein - Pondorf - Verley reaction conclusion: only CH3, 1˚, sp2, & sp Grignards add cleanly to ketones (but all Grignards, RLi add to aldehydes) Typically, small M+ (Li+, CeIII ) promote 1,2 addition to carbonyls

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Addition of Enolates to Carbonyls - The Aldol Reaction

R1

O

R2 +H R3

O

R1 R2

R2

O O

original version:

R1

O

R2 +H R3

O

R1 R3

R2

O O

RCH2CHONaOEt

EtOH

RH

H

O Na

+RCH2C H

O

R H

R

O ONa

EtOH

R CHO

OH

H REtO-

only irreversiblestepR

R

CHO

- this reaction is made

irreversible only by the final

! - elimination

",! - unsaturated aldehyde

the use of irreversible deprotonation using strong bases created a new version

R1

R2

O Li

+ R3CHOR1 R3

R2

O LiO

+R1 R3

R2

O LiO

syn anti

( "threo" ) ( "erythro" ) - we stop at β - hydroxy carbonyl compounds; diastereoisomers possible

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Observations: 1) Z - enolates give mainly syn aldol products R OM

R'

R''-CHO

R'' R'

OH

R

O

OM

R'

R''-CHO

R'' R'

OH

R

O

R

2) E - enolates give mainly anti aldol

3) stereoselectivity (for syn) of Z - enolates is better than that of E (for anti) 4) stereoselectivity is better for both when R’ is large 5) stereoselectivity is better for both when when R’’ is large (mostly when M = boron) 6) correlation reversed when R is large how to explain? Zimmerman-Traxler model JACS, 1957, 79, 1920 Z - enolate:

R''-CHOR OM

R'

+aldol

O OM''R

HH

R'

R

O OMH

R''H

R'

R

favored

disfavored

syn

anti

O O''R

HH

R'

M R

''R R'

OM

R

O

syn

O OH

R''H

R'

M R

''R R'

OM

R

O

anti

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E - enolate:

R

OM

R'

O OMR''

HR

H

R'

O OMH

R''R

H

R'

M

M

O OH

H

R''R

R'

O OH

R''

HR

R'

R'' R'

OM

R

O

R'' R'

OM

R

O

R''-CHO +aldol

favored

disfavored

anti

syn

anti

syn - now return to observations: 1,3-diaxial interaction between R’ & R’’ controls stereochem.

R

H

H

O

''R

R'

O

M

R

H

R''

O

H

R'

O

Mso large R' & R'' increases stereoselectivity

-favored/disfavored difference not as greatfor E-enolate (1,3-diaxial vs. gauche)

When R is large, anti T.S. for Z looks better '' syn T.S. for E '' ''

E anti

vs.

E syn

Allyl Nucleophilic Addition

M+

H R

O OM

R this looks simple, but there are 2 possibilities:

M+

H R

O

!"

M

O

R

4 - center T.S.

R

OH

!"

M+

H R

O

!"

OM

R

6 - center T.S.

R

OH

! "

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which mechanism prevails depends on M: 6 - center: M = B, Cr, SiX3 4 - center: M = BaCl both: M = Li, MgX neither: M = SnR3

⇒ 6 - center transition state looks like Zimmerman - Traxler:

B

O

O

E

+ CHO

OH anti

B

O

O

+ CHO

OH

Zsyn

Hoffman, JOC 1981, 46, 1309 also:

B

O

O

+ CHO

OH

•

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Addition/Elimination Mechanism Variant #1 - Addition of Nitrogen Nucleophiles to Aldehydes & Ketones

R1 R2

O H2N-Z

H

R1 R2

HO N

H H

Z-H

+ H R1 R2

H2ON Z

H

R1 R2

NZH

R1 R2

NZ

Z = R, OR, NR2

- this process is typically reversible; equilibrium can favor either s.m. or product, depending on choice of conditions

look at pH - rate profile of

O

+ H2NOH

NOH

+ H2O

1 2 3 4 5 6 7 8

kobs

pH

Why a bell - shaped pH rate profile? look at kinetics

vmax at pH 4.8

O

+ H2NOHformulate reaction as

fast

k1

k-1 NH

OH

OH

slow

k2

H+ N

OH

+ H2O

H2NOHO

! = k2

k1

k-1

H+

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H3NOH

H2NOH H3NOH

H2NOH H3NOH

but since we have a second equilibrium: H + H2NOH

Ka

O! =

k1

k-1

k2+ when [H+] Ka

O! =

k1

k-1

k2+ Ka when [H+] Ka

H+

so this gives the following pH - rate profile:

kobs

pH

something's wrong here . . . what is it?

H2NOH H3NOHO

! = k1 +

Ka

kobs

pH

so, now combine the two curves

O

+ H2NOHNH

OH

OH

fast

NOH

+ H2O

What aboutslow

1 +H+

H+

kobs

pH

pH - rate behavior indicatesa change in rate - determiningstep at pH ~ 5

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Variant #2 - Addition to Carboxylic Acid Derivatives

R Y

O O

R

Nuc

+ Nucaddition

Y

elimination

R Nuc

O

tetrahedral

intermediate -this is sometimes referred to as nucleophilic acyl substitution, but more properly thought of as addition/elimination alternate version:

R Y

O Nuc

R Y

O

H

H

O

R

Nuc

Y

H

-H

-YR Nuc

O

Y = OR, O2CR, NR2, Cl, Br, F, SR order of reactivity:

RCHO

R X

O

R O R'

O O

R R'

O

R SR'

O

R OR'

O

R NR2

O

> > > > >~

(based on electronegativity and π - donation of Y) Mechanism #1 - saponification

NaOH

H2O

NaOH

R OR'

O O

R

OH

ORR O-H

O

R O

O

- OR

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Mechanism #2 - Fischer esterification

H

MeOH

-H+H

HCl

MeOH

-H

R OH

O

R OH

O

H

O

R

O-Me

OH

H

+

H

OH

R

OMe

OH2R OMe

O-H

R OMe

O

- H2O

an alternative mode of catalysis - nucleophilic catalysis

Cl

O

+

OH

Cl

O

+

OHN

O

O

very slow reaction (t 1/2 > 24h)

(t1/2 ~ 1h)

Why does pyridine accelerate the reaction? it’s not going to deprotonate cyclohexanol (Keq = 105-17 = 10-12) So, look at alternative mechanisms:

Cl

O

N

O

O

N O Cl

N

O

OH

N

O O

H

H

O

O

A

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So why is this any faster? reason 1: pyridine is a far better nucleophile than an alcohol reason 2: acyl pyridinium ion A is far more reactive than the acyl chloride (Why? better leaving group) ⇒ combine better nucleophilicity with better leaving group ability & you have nucleophilic catalysis

better nucleophilic catalysts than pyridine: N

NMe2

(DMAP), PBu3 (NEt3 also used) Conjugate (1,4) Addition

O1

23

4

Nuc

!," - unsaturated carbonyl compounds have 2 sites of attack

by nucleophiles: C-2 or C-4 (C ")

Addition to Cβ is referred to as 1,4-addition (conjugate addition):

Nuc

O O

Nuc

H

O

Nuc What factors govern 1,2- vs. 1,4 - addition?

O

Nuc

1,2

Nuc

1,4

ONucO

Nuc

enolate

(more stable)

thermodynamic product

alkoxide

(less stable)

kinetic product

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Why is 1,2-adduct the kinetic product? look at transition states

O

E

OO

E!

A

Nuc

Nuc

E

unless there is a high concentration of E+, 1,4-addition is slower in general Examples of 1,4 - additions:

O O

NCor

Et2AlCN

O

O

O

O

MeO2C

CO2Me

MeO2C CO2Me

NaOMe,MeOH

SiMe3

reversible reactions

(note, not NaCN or KCN

"Michael Addition" Org. React., 1959, 10, 179

"Sakurai reaction"

Sakurai, JACS, 1977, 99, 1673

HCN

TiCl4

Why 1,4 - addition?

TiCl4

Cl Cl

Cl

O

OOTiCl3O

TiCl3O

TiCl3

SiMe3no longer a cyclic transition state,so 1,2 & 1,4 are kinetically similiar

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One major category of 1,4 - additions is the addition of organocuprate reagents to α, β − unsaturated carbonyl compounds: O

LiCuMe2

O

Gilman'sreagent

How does this work & why does it give 1,4 - addition? - all organocopper reagents are CuI species - free radicals so, probably the mechanism involves free radical intermediates: JACS, 1994, 116, 2902-2913

1,2 vs. 1,4 Addition

R

O

Ph RPhR

OH

Ph

R'HO R'

R'-M+

R R’ M 1,2 addition 1,4 addition

i-Pr Me MgCl 50 50

t-Bu Me MgCl 67 33

i-Pr Ph MgCl 34 66

t-Bu Ph MgCl 33 67

t-Bu Me Li 85 15