Topic 18: Nucleophilic Sigma Bonds

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

R CE+

R LiE+

R HE+

References:Literature cited

Recall the Six Types of Canonical Frontier Orbitals

■ We’ve already discussed the interactions of 3 types of filled orbitals and 3 types of unfilled orbitals. If all things are equal then C-C and C-H sigma bonds should be the least reactive type of nucleophiles but if we replace C with Li to make a C-Li bond then the bonds became exquisitely reactive.

p

EMO

σ

π

π*σ*

n

H

-O

E+

Li E+

HB

E+

HH

H-

■ We need to discuss the nucleophilicity of sigma bonds more broadly.

rapid atom transfer

pi characterweaker, more nucleophilic bonds

electropositive

electronegative

Periodic Trends - Electronegativity

http://www.green-planet-solar-energy.com/electronegativity-values.html

■ Here are some periodic trends you should know…

Frontier Molecular Orbital Energies Predict Reactivity

■ What happens when you replace carbon with an electropositive atom? Bonds to electropositive atoms can be highly nucleophilic.

■ For bonds to O and N, the non-bonding FMO (i.e., the lone pair) is still more reactive than the sigma bond FMO.

EMOσC-Li

σC-C

σC-NH3C CH3

H3C LiE+

E+

faster

σC-B

σC-Be

EMO

σO-Li

nO(C)

nO(B)

nO(Be)

nO(Li)faster

O Li..

slowerO CH3..

O LiE+

E+

E+

Alkyllithiums: Frontside vs. Backside Attack

Verner, E. J.; Cohen, T. JACS 1992, 114, 375.

Still, W. C.; Sreekumar, C.JACS 1980, 102, 1201.

■ Backside attack of the R—Li bond is important for [2,3]-Wittig rearrangement

■ Frontside attack is most common for R-Li.

Ashweek, N. et. al.JACS 2005, 127, 449With Et2O, krac ∝ [RLi] not [RLi]2

However, electrons in the HOMO of R-Li also spend time on the back side of the carbon-lithium bond.

Et O

CH3

H OBn

CH3OSO O

H3CO

Et O

Li

H

OBn

Li

CXRR

Li

Li

CX R

RCX R

R

Li

+

Li+

Li+

OHR Li

.. [2,3] OLi

HR

Nucleophilic Hydrides

■ Nucleophilic hydrides are generally attached to “-ate” complexes with electropositive elements. Bonds to anionic atoms are more nucleophilic than comparable bonds to neutral atoms.

■ NaBH4 and LiAlH4 change with each hydride addition

■ Cheap, “simple” reagents rarely involve simple reaction mechanisms.

HB

HHH

-H

AlH

HH

- > >> SiEt EtEt

H

OAc

-N

LiN

CH3

+ +

-2

betterNu

lithiate

N

Li

N

CH3

TMEDA

.. ..

HAl

HH

H- O O

H

LiLi HAl

HH

O

H

AlH

HH

-+ OLi+

etc.:

HAl

ROOR

OR- less reactive

than AlH4-

Nucleophilic Hydrides and Selectivity

■ Ketone reduction is fast (SN2 on R-Br isn't fast)

Brown, H. C.; Krishnamurthy, S. JACS 1973, 95.

Jean-Claude, B. J.; Just, G.Syn. Comm. 1994, 24, 1565.

■ Alkyl groups increase reactivity of anionic “ates” versus hydrogen. Et3BH- is 104 more nucleophlic than BH4-. LiEt3BH = "Super Hydride"

■ H atoms generally move faster than C atoms. Hydridogroups undergo [1,2] migrations faster than R.Bases attack H faster than R.

H2O: H Cl

H2O: H3C Cl

faster

slower

RBH

RR- O

Li+

O

Br

NaBH4

MeOHrt, 1 h

OH

Br 100%

H3B H-

Na+

Br

THF25 °C, 3 h

HH BEt3-

Li+

Selectivity of Hydride Donor Reagents

■ Selectivity of hydride reagents toward π*

Borch, R.F., et. al. JACS 1971, 93, 2897.

H

SiHH HOR

O

RR

HRN

RR

HO

HR

O

RR

O

ORR

O

NR2R

O

OLiR

++

-

LiAlH4/THF

NaBH4/MeOHHBH

H CN- or

react fastest react slowest

HCl(slow addn, pH 3)

O

PhCH3OH

23 °C, 1 h

OH

Ph

CNBH

H H-

Na+

O

Ph

H+

H

■ Sodium cyanoborohydride doesn’t react with carbonyls unless they are protonated.

Hydridostannates and Hydridosiliconates

■ NaCNBH3 reduces enamines, indoles, and pyrroles via iminium ions. This reduction works with hydridosiliconates.

Lanzilotti, A. E., et. al. JOC 1979, 44, 4809.Usually with NaCNBH3 /CF3CO2H

■ R3SnH and R3SiH form nucleophilic hydride reagents in situ

Shibata, I.; Yoshida, T.; Baba, A.; Matsuda, H.Chem. Lett. 1991, 307.H

SnBuBu Bu

F

-O

OMePh

Bu4N+ F-+

n-Bu3SnH

0 °C, 5 h

OH

OMePh

81%

HO

NH

Et3SiH

CF3CO2H

NH

NH+

HH

SiEtEt Et

O2CCF3

-

..

HO

CF3O O CF3

O

SiHEt

EtEt -:

NH+

H

SiEtEt Et

O2CCF3

Electrophilic Hydride Reagents

■ BH3 and i-Bu2AlH reduce ketones. They are not nucleophilic UNTIL after they coordinate to the carbonyl

■ LiAlH4 reduces esters to alcohols via electrophilic alane (AlH3).

■ DIBAL-H reduces esters to aldehydes because it only delivers one hydride

R2Al-, R2B-, and R3Si- groups reduce the nucleophilicity of oxygen l.p.

O

OEt

Li+O

OEt

LiAlH4 O

OEt

LiH

H3Al H-

O

OEt

LiH

H3Al AlH3-

O

H

LiOEtAl -

+

++

THF ..

:

HH

H

OB+H

H

H-

OB

H

H

H OBH

HH

.. AlH

DIBAL-H

O

OEt

Al+H

R

R-

O

OEt

:O

OEt

AlR

RHtoluene

i-Bu2AlH workup

H2O

O

H HOEt

C-H Weakening by Lone Pair Donation

■ Bohlmann bands occur ~ 2700 - 2850 cm-1 in the IR spectrum.

■ An extreme example of nitrogen lone pair donation affecting spectroscopy and chemical reactivity

Wuest, J. JACS 1980, 6365.Watkins, T. JACS 1980, 6363..

Ferdinand Bohlmann Chem. Ber. 1958, 2157.Vapor phase IR spectrum

Daly, J. W., et.al. JOC 2000, 65, 8908.

Bohlmann bands are due to donation of nitrogen lone pairs into σ*C-H

N

H H

..

NN N

H H

H

2690-2800 cm-1

2450 cm-1

~2900 cm-1 aliphatic C-H

Bohlmann bands

....

..

NN N

H

HX

......

X-X-

N

N NH

+ N

NN+

23 h

110 °C+

H

H HnN donate into σ*C-H

Hydride Transfer from Carbon

■ Aldehydes without α-hydrogens can’t undergo aldol reactions. Instead, they disproportionate via hydride transfer (Cannizzaro reaction).

■ Formaldehyde and formate are particularly good hydride donors

Eschweiler, W. Chem. Ber. 1905, 38, 880. Clarke, H. T., et. al. JACS 1933, 55, 4571.Moore, Org. React. 1949, 5, 301.

Geissman, T.Org. React. 1944, 2, 94.

■ Eschweiler-Clark methylation

Dai-Ho, G., Mariano, P. S.JOC 1988, 53, 5113.Awachie, P.I.; Vagwanda, V.C.Tetrahedron 1990, 46, 1899

O

Ph H

O

Ph ONa

OH

Ph H2

HH

Na-O PhOH....

O PhOH

+NaOH

O

O

NH2O

O

N

O

O

NR

CH2OH2CO2H

+

H

O O -..

N+

Oppenauer and Meerwein-Pondorff-Verley Reactions

■ Oppenauer oxidation: (i-PrO)3Al catalyzes hydride transfer to acetone solvent

■ The reaction is reversible and is driven by the use of solvent as a reagent

Wilds, A. L.Org. React. 1944, 2, 178.

Djerassi, C.Org. React. 1951, 26, 207

■ Meerwein-Pondorff-Verley Reduction (M-P-V): Run the reaction in i-PrOH

OH

acetone

cat. Al(Oi-Pr)3

O

= oxidation !

OAlOH

OROR

+

-OAl

OR

OR

OAlOH

OROR

-+

..

OH

isopropanol

cat. Al(Oi-Pr)3

O