Topic 12: Addition to π*

Tetrahedral intermediates

Read: F. A. Carey & R. J. Sundberg Advanced Organic Chemistry, Part A: Structure and Mechanisms. 5th Ed. Ch. 7I. Fleming Molecular Orbitals and Organic Chemical Reactions, 5.1.3.1, 5.1.4, 5.2.1

Professor David L. Van VrankenChemistry 201: Organic Reaction Mechanisms I

Nu .. Nu

-..

Addition of Nucleophiles to Simple C=C Bonds is Not Common

■ Addition to C=C much slower than addition to C=O

Felkin, H. et. al. Tetrahedron Lett. 1969, 707.

Bartlett, P. D.; Tauber, S. J.; Weber, W. P. J. Am. Chem. Soc. 1969, 91, 6362.

■ Directed addition: 5-membered T.S. confers an entropic advantage

■ Requires 2° or 3 ° alkyllithiums + ether or amine additives

O O Li

Li1°

but...Li

Li

Fast if: • 2° & 3° R-Li • H2C=CH2 • cat. R3N • ROR solvent

always fast

E Nu

π*CC

π*CN

π*CO

MO lowerLUMO

more charge

Why is C=O more electrophilic than C=C?There are two reasons...

Oδ+ δ−

2 equiv.i-PrLiLi LiEt2O

OEt2

OEt2-30 °C

OLi Li

2 equiv.i-PrLi

Li

OHO

Li

OLi

Li

Addition of Nucleophiles to C=O

■ The C=O bond is polarized

Burgi, H. B.; Dunitz, J. D. Acc. Chem. Res. 1983, 16, 153.

(Crystal structures confirm attack trajectory)

■ Electronegative atoms distort the HOMO and LUMO

Dipole Moment:µ = ∆q × dist. = 2.7 D suggests ± 0.23 charges

■ "Coefficients" describe the relative size of p orbitals in π and π*■ The coefficient is bigger on carbon in π*C=O

■ The Bürgi-Dunitz Angle = Preferred Nu—C — O angle = 109°

HF/STO-3G

1.22 Å

O O.... .. -

+

C O

E

C Oπco

π*co

Nu..

π: electronegative atom gets larger coeff.

π*: electropositive atom gets larger coeff.

C ORR

109°Me2N

R O

N-C-O distortions = 109 ° = maximum overlapX-ray

Nu

The Felkin-Anh Analysis*

■ Chiral centers adjacent to carbonyls control the stereoselectivity of Nu addition(The selectivity is usually modest.)

■ Strong nucleophiles = early, reactant-like transition states (= Felkin,Cram)■ Nucleophiles attack opposite side of large groups (= Dauben)

■ Nucleophile attacks on the opposite side of electronegative groups

Compare Two Newmans: here’s how

■ Forming bond eclipses small rather than medium group

Nguyên, T. A. Topics Curr. Chem. 1980, 88, 145. Chérest, M.; Felkin, H. Tetrahedron Lett. 1968, 2205

■ Attack from Bürgi-Dunitz angle (= Anh)

JACS 1956, 2579

*His last name is Nguyen, not Anh

S

Med

BIG

Med

S

BIG

better TS

vs.Nu

O

RNu

O

RMe Me

Cost = 5.5 kcal/mol

Med

s

OMe

Nu

OMeO-

sMedR forming bond

donates into σ*

σ*

Me

O

Me

Ph

MeMe

PhEt2O35 °C

OHHPh

MeMe

HHO

74 : 26

LiAlH4

Nu

O

R

Med S

BIG

Cram modelnot quite right

Chelation Control and Lewis Acids

■ Gives opposite of Felkin-Anh (= Cram's chelate model)

■ Good chelating metals: TiX4, ZnX2, MgX2, LiXMengel, A.; Reiser, O. “Around and beyond Cram's Rule.” Chem. Rev. 1999, 99, 1191.

Carey & Sundberg Advanced Organic Chemistry. Part A: Structure and Mechanism, 4th Ed. Table 4.9, p. 236.

■ Lewis Acidity Scales■ Lewis Acids: Increase δ+ and lower LUMO, thus chlelated form is more reactive than un-chelated.

■ Bad solvents for chelation control: DMSO, DMF, ROH, DME, THF(compete with substrate for chelation to metal)

■ Siloxy groups are poor for chelation: RO >> R3SiO

BCl3 1.00

AlCl3 0.91

BF3 0.76AlEt3 0.63

SnCl4 0.61

-6.6

-25.6

+4.1-10.1

+10.0

O OL.A.+ L.A.

L.A. ∆H LUMO lowering

H H

∆δ(H-3)1.35

1.23

1.170.63

0.87

TiCl4OBF3+ OO

OR

Ti-Cl Cl

Cl Cl-2

++

O

C7H15

OBnR1

C7H15

OBn -O Bu

Et2O-20 °C

99 : <1

MgBuMgBr

BrMgBu

RMgBr =BuMgBr or ROMgBr

XBr-2

+

+

O

C7H15

OBn

MgX

Br

+Bu

-2

Donor Effects on C=O Reactivity

■ Donation slows addition of nucleophiles

Guthrie, J. P. JACS 1978, 100, 5892

■ Rates of HO— addition to C=O

■ Evidence for Donation = Rotational Barriers

Carey & Sundberg "8.4 Reactivity of Carbonyl Compounds Toward Addition"Advanced Organic Chemistry. Part A: Structure and Mechanism, 4th Ed.

O

X

.. -

+

O

X

O

X

.. -

+..

: : : : : :

EMO

nO

πC=O*

π

π*

O

R

RO..

new π*

old π*

recall:

O

H

O

CH3

O

OR

O

NR2

> > >

krel (OH-) 1011

O

H H> O

O->

109 107 104 1 <1

O

Me OMe

O -

Me OMe

+

OO

Me

120 °

Costs ~12 kcal/mol

to twist

pO π*O

Me NMe

pN is more nucleophilic than pO

O -

Me NMe

+H H

Costs ~20 kcal/mol

to twist

O

Cl

O

OR

O

NR2

>>> > O

O->

1011 100 10-2 ??

Overall Hydrolysis Rates:

Effects of Ring Size on C=O Reactivity

■ Electronic and strain effects

C&S A, 5th Ed. Table 7.4

■ Relative rates for carbonyl addition

Proposed model: pyramidalization relieves eclipsing

NaBH4 in i-PrOHO

krel

O OO

20 10 1 0.5

Ph H

O

12,400

H

H

HH

H

H H

H

O

H

H

HH

HO

H

OH

H H

H

OH

H

many confs.always ≥1 eclipse

best conf.= 2 eclipse

many confs.always ≥1 eclipse

no eclipse

H2OR

O-

R+e- deficient

+H H

OHOH

O

H H

Keq 2300

O

CH3 H

1

O

H3C CH3

0.008

σC-H = donor

O

F3C CF2

1,200,000

O

CH3O

Me

0.6

F

OR

OHHO

ROFF FF

lubiprostone

HO OH

cyclopropanonehydrate

cyclopropanone

Owants 120°instead of 60° OEtHO

commerciallyavailable

Effects of Charge and Electronegativity

■ Formal charge is more important than electronegativity

Borch, R. F.; Hassid, A. I. "New Method for Methylation of Amines" JOC 1972, 37, 1673.

■ Borch reductive amination

ONON

BCN

HHH

Si

H

EtEtEt

X

<+

< <+

--reacts w/

BH

HHH -

E π*C=N+

π*C=N< +

RNH2

NaCNBH3

H2O

O+ aq. MeOH

pH 5

NHR

HNR+

5 fastelementary steps

HB

CN

H H-

+

HNR

HB

NC

HH-

+

fast

O

HB

CN

H H-

slow

Substitution through Addition-Elimination

■ Stable TIM with Weinreb's amide

■ Easier to add to π* than σ*

■ Unstable Tetrahedral Intermediate (TIM)

L.p. on O-Li pushes out the L.G.

Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.

O

ClNu.. -

never

O

XNu +..

X

O -Nu....

.. O

Nu+ ..-

σ*c-x

π*c=oTIM

X

PhLi PhLi

OMe

O

Ph

O

Ph

OLi

Phevenfaster

OMe

O

Ph

Li: Li+

N

O

N

O

Me

OMe OMeLi

Me

PhPh

O

stable

PhLi H2O

workup

Why Are Acid Chlorides Reactive?

■ Relative reactivity toward Nu:

■ The order is not because of electronegativity: Br (3.0) < Cl (3.2) < F (4.0)

p

s

HF/STO-3G■ C-X bond lengths:

Conclusion: acid chlorides are reactive b/c of poor l.p donation

■ Long bonds = poor overlap nX -> π*

O

Br

O

Cl> >> O

F

O

Br

O

Cl> >> O

F

1.88 Å 1.73 Å 1.34 Å

O

F..

O

F

-

+O

Cl..

important not

H

H F>..+

H

H H+

cationstability: >>

H

H CF3+

F

H F>..+

:

a 3rd fluorinedoesn't stabilize

Nucleophilic Acyl Transfer Catalysis

■ Rebek “three-phase test” distinguishes nucleophilic catalysis from base catalysis.

■ 4-DMAP catalyzes acyl transfer G. Hoefle, W. Steglich, Vorbrueggen, H Angew. Chem., Int. Ed. Engl. 1978, 17, 569.

Rebek, J., Jr. "Mechanistic Studies Using Solid Supports: The Three Phase Test" Tetrahedron1979, 35, 723.

"…grinding the polymer-bound acylating agent and polymer-bound amine in a mortar, with or without solvent, failed to induce direct reaction between the solid phases."

10 mol% DMAP leads to 104 rate acceleration in the acylation of 3° alcohols.

Used in conjunction w/ stoichiometric bases.

■ The key residue in the ribosome looks like DMAP, but is just a base.

NN

HO

O

O

O+

O

O

10 mol% DMAPEt3N

CH2Cl2

O

N+

Nvia

O

NHProtein

proteintranslation

NNH2N

NN ribosome

:

A2486

H2NProtein

O

O-tRNA+

role?

O -

O-tRNANH

HProtein+

NN NH2

N Nribosome

:via

R

O

O

NO2

N NH

R NH2

H2O / dioxane

R

OHNO2

R NH

O

O

N+

via

NHR

O

O -

NR H

H+ N si:

NOTsimply a base

mech?

LUMO Lowering Catalysis

Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4232.

■ Organocatalytic D-A(rapid equilibrium for iminium ion formation)

■ Knoevenagel Condensation – It looks like addition of an enolate to a C=O, but not the use of a 2° amine.

Jones Org. React. (1967), 204Crowell & Peck JACS (1953),1075

OEt

O OO

R H+

NH

OEt

O O

CHR

OEt

OH O

NR

H OEt

O O

N

H

AcOH

R+

PhO

PhN*R

R*+

fast D-A Ph

CHO

Ph

+rapid

up to 93% e.e.

NH

NOMe

Me

Me

Bn

R*2NH =

5 mol% R*2NH

*R2Nrapid

Conjugate Addition Reactions

■ LUMO coefficients predict 1,4

■ Effects of conjugation and E.N. on LUMO Read: Fleming 1.1C&S A 1.6

■ Charge predicts 1,2 Best for 1,2 C=O additionWorst Nu for 1,4 addition

F- or Cs+ -OR

0.62 -0.42 -0.53LUMO coeff. 0.60 0.38 0.17 0.28c2 ∝ e- pop. 0.36

High, localized charge

Best Nu for 1,4 addition

HOMO

EMO

LUMOconjugation

2000Nobelprize

O

π*

π

EMO

R-LUMO

calculate,predict,

or memorize

O

MO

+.62 -.43-.53 +.60

Nu.

HF/STO-3G coeff.

:

.

O - O -+ +

6x higher+0.21+1.25

O O- NR2R3PRS

..- ..