Topic 14: Alkali Organometallics

Read:F. A. Carey & R. J. Sundberg Advanced Organic Chemistry, Part A: Structure and Mechanisms. 5th Ed. Ch. 6M. Schlosser, Ed. Organometallics in Synthesis: A Manual Wiley, 1994. "Chapter 1. Organoalkali Reagents"

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

LiX

X OR2

E+

Misconception

■ Avoid ionizing R-M bonds; just use the bond as the base/nucleophile.

■ Electronegativity determines ionic character & basicity

R-MgBr R-Li R-Na R-K R-Cs< < < <

Li Na K Rb CsMg > > > >>

1.3 0.98 0.93 0.82 0.82 0.79

R-M Covalent character:

Electronegativity:

H >

2.2

(Ionic character) Basicity:

R MgBr R Li R Na R K R Cs

■ Consider these two resonance forms:

R3C M R3C M+

..

covalent ionic

-

H3C Li H3C Li+

..-

O

like this not this

They want 8 valence electrons! Here’s what H3CLi does in hexane.

■ COMPLETE FICTION: Li, Na, K, Mg, Ca, etc. want no electrons

CH3Li

H3C Li H3C Li

CLiH H

H+

- C Li

CLiH H

H+

-H

HH

+

-H3C Li Lewis structure

Formal charges: Li2-, C2+

3 bonds to each Li6 bonds to each C

CLi CH3

Li

LiC Li

C

HHH

HH H

HHH

+2

+2

+2

+2

-2

-2

-2

Aggregation of Alkali Organometallics

■ Metal alkoxides also aggregate

■ Alkyllithiums aggegrate to form tetramers, hexamers, etc. to help lithium satisfy the octet. Sterics often prevents Li from achieving an octet. Bulkier alkyl groups lead to less aggregation. Using dative bond representations reduces the complexity of these structures.

CLi CH3

Li

LiC Li

C

HHH

HH H

HHH

Lewis structure

CLi CH3

Li

LiC Li

C

HHH

HH H

HHH

+2

+2

+2

+2

-2

-2

-2

dative bonds

OKO

K

KOK

O

+2

+2

+2

+2

-2

-2

-2

t-Bu

t-But-Bu

t-Bu

t-BuOK

OLi=

■ You don’t have to draw these aggregrates; but never be afraid to form additional bonds to alkali metals.

crystal structures of (MeLi)n

Dos and Don’ts for Drawing Mechanisms with Organoalkali Species in Chem 201

■ Draw arrow-pushing mechanisms that avoid ionizing anions and cationic metals

H3C MgBr H3C+MgBr..

-

H3C MgBr MgBr

O

H3CO-

+

Don't do this:

Do this:

O

t-BuO K t-BuO+K..

-Don't do this:

RH

t-BuO KDon't do this:

RH

t-BuO HR:-

+K

t-BuO KDo this:

RH

.. t-BuOH

K+ R:- t-BuO

H

K+ -R

t-BuO HK R

I'll accept.. t-BuO K

RH

.. t-BuOH

K+ R:- t-BuO H

K Rt-BuO

HR:-

+K

Metal Hydrides

■ Example: metal hydride basicity

■ Basicity (vs nucleophilicity) increases from RMg to RK.

Grovenstein, E. JACS 1959, 4842

(Arrow pushers: pretend M—H is a monomer)

Na-H K-H

Dyck, W.; Jex, H. J. of Physics C 1981, 14, 4193

■ Na—H = cubic lattice

more negative charge= more basic

Na–H

O

R

H–OR Na–OR

OM

H2C Ph H H

H H

KH

Li-HMH

NaH+ +

krel1

1,0001,000,000

+ +

M H

Ph-MO

PhH

H H

OM

CH3 Ph

OM

CH2 PhPh

0977514604670

Ph M

π∗ σ∗M

Ph MgBrPh LiPh NaPh K

Synthesis of Organometallics

■ Rates depend on R-X: RI > RBr > RCl

■ Kronos behaviour (children swallowed by creator)

■ Always make R–Li from R––Cl but not R –– I. Here’s why…

Formation of R-Na requires special conditions:(finely dispersed Na, high speed stirrer, vortical fluid motion, special glass, -10 °C)

Why don’t we make n-BuNa?

σ*C——I

σ*C—Br

σ*C-Cl

Step 1 =e- into σ* orb

Why rel. order?

E

■ We don’t have arrow pushing representations for electron transfers, nor good Lewis representations for the radical anion intermediates.

NaCl + +

e-R Cl

•–

2Na NaCl

Na+

R•-NaCl

MNa+

σC-Cl

σ*C-Cl

EMOR Cl•– =

ClE2 +

Wurtz coupling

n-BuM

SN2

n-BuX n-BuLi

X

ClBrI

Et2Ot1/2

40 h30 min< 5 min

t1/2

>100 h40 h3 h

in C6H6...

+ E2 + SN2

Preparation of Alkyllithiums by Reductive Lithiation

■ Reductive lithiation of thiophenyl ethers. Li + naphthalene = LiNp, but it is a pain to remove one equivalent of naphthalene after the reaction is over. Dimethylaminonaphthylamine is readily removed with an acid wash.

Cohen, T. J. Am. Chem. Soc. 1984, 106, 1130.

O SPh

NMe2

.. .-

-78 °C O Li

Li+

"LDMAN"

SPh SPhR

SPh

rate of reductive lithiation:

many, manyres. structs.

S .. -. .

Li+

Li+e-

Li+e-

radical

■ LiNp efficiently adds an electron to the pi* antibonding orbital of PhS groups. Rates of reductive lithiation correlate with the ease of radical formation.

Preparation of Alkyllithiums by Exchange Reactions

Rates depend on R-X: RI > RBr > RCl

Sn: MacDonald, T. J. Am. Chem. Soc. 1988, 110, 842.I: Farnham, W. B. J. Am. Chem. Soc, 1986, 108, 2449.

■ Sn-Li exchange proceeds with retention at carbon Reich, H J. Am. Chem. Soc. 1992, 114, 6577-9.

Kanda, T J. Phys. Org. Chem. 1996, 9, 29.

Mechanism = stann"ate"

With R-I, instantaneous at -80 °C

Mechanisms: Newcomb, M. TL, 1989, 26, 1183R-I, low temp - iodate; R-Br, high temp = e- transfer

■ Metal/halogen exchange

■ Sn-Li exchange (same with lithium-iodide exchange)

+ X—Phn-Bu—Li + Li—Phn-Bu—X

Rates: I >> Me3Sn > Me3Sn

-70 °C

80 : 1

R

MeO

SnMe3n-BuLi

Et2OR

MeO

SnMe

MeMeBu

Li+

R

MeO

Li Bu—SnMe3–

stann-ate

Metal-Halogen Exchange Driven by Thermodynamics

■ Metal-halogen exchange is faster than SN2 (at low temp.)

Applequist, D.E.; O'Brien, D. F. “Equilibria in Halogen-Lithium Interconversions” J. Am. Chem. Soc., 1963, 85, 743-748.

R Li Ph I+ R I Ph Li+

Li

Li

Li

Li

0.004

Keq

1

10

7,500

Compound

Li 10,000,000

-70 °C

R Li R'I

R'IR- Li+

R Li R' I

way faster than SN2

R I Li R'

Li >10,000,000

n-BuLi ~

s-BuLi ~

Formation of Organometallics by Metalation

■ Recall:

■ Alkynes can be directly metalated ...also with BuLi

■ Direct metalation (deprotonation) of benzene is too slow to be useful

■ Recall: deprotonation of alkyne C-H is relatively fast

Shiner, V. J.; Humphrey, J. S., Jr. J. Am. Chem. Soc. 1967, 89, 622.See also… Sonogashira couplings

H3C CH2Li H2C CHLi HC CLi R2NLi> >> <

109 1017 1012Basicity:

pKa' 50 41 24 36

+ +Lislow!

Li H

Et-MgBr Et-HR C C H + R C C MgBr +fast

H

Cl

H

OEtNaOEt

EtOH

CC -

Cl

CC

EtO -

....

CC

Ph

Ph

(w/ t-BuOK)

Directed Ortho Metalation

■ Chelation of R-Li speeds up metalation and stabilizes Ar-Li

■ Relative directing power; (you keep the chelate in the aryllithium)

V. Snieckus“Directed ortho metalation. Tertiary amide and O-carbamate directors in synthetic strategies for polysubstituted aromatics”Chem. Rev. 1990, 90, 879.

OH OHMe?

O

NEt2

O

THF -78 °C,1 h

O

NEt2

O

HLiH

O

NEt2

OLi

+ C4H10

‡

OCONEt2Me

n-BuLi

CH3I

NaOH

+-

+-

O

NEt2

OLi

S O

Li

t-Bu O

Li

NO

> > Li

N

Li

LiO NMe

O OMeLi

Metalation of Strained Rings

■ Lithium amide bases convert epoxides to allylic alcohols. The base removes the proton syn to the epoxide.

Cope, A. C.; Lee, H.-H.; Petree, H. E. JACS 1958, 80, 2849.Hodgson, D.M.; Bray, C.D.; Humphreys, P.G. Synlett 2006,1.

■ Very aggressive bases deprotonate epoxides and generate lithium carbenoids.

■ Epoxides undergo two competing reactions with bases

Thummel, R.P.; Rickborn, B. J. Am. Chem. Soc., 1970, 92, 2064

LiNR2OHLiNR2..

OOLi

OR-LiH

OLi

O -carbenoid

Li+

O

H

H

Li NEt2

OLiOLiH

70%16%

H

H

filled σC-Li

empty p

Li

it's anelectrophile

it's anucleophile

Aggregation of R-Li

■ Ether solvents coordinate to alkali metals. n-BuLi forms a tetramer in THF + some dimer

■ Li enolates = 99% dimer in THF, but reacts via monomer.

■ C=O Addition: Me—Li / n-Bu—Li add as dimer! Arrow Pushers: Pretend RM is monomer

StreitwieserJOC 1995, 4688

Kaufmann, E.; Schleyer, P. v. R.; Houk, K. N.; Wu, Y. D. JACS 1985, 107, 5560.Nakamura, M.; Nakamura, E.; Koga, N; Morokuma, K. JACS 1993, 115, 110167.

But never forget aggregation

IMPORTANT RULE:

CLi

CLi

O

OTHF

CLi

LiC

LiC

CLi O

C = n-Bu

.

Li wants octet MgPh

Br

OEt2OEt2

MgPh

Br

OEt2

OEt2+–....

wrong!

dative bonds to metalsdon't draw chargesdon't use for arrow pushing

Li = Li•THF

i-Pr2N–LiO

ArH

O

Ar

PhTHF, -78 °C 25 °C

OLi

Ar

" "

LiO

LiO

Ar

Ar

~1%

99%

25 °C

Bn-Br

SLOW

LiOC R

LiR+ -

OC

+

R LiR

Li-

O M

R+M = Li, MgBr O

R

M

Organocuprates

■ Cuprates, R2CuLi are ARE nucleophilic.They do all the things you wished RLi could do: substn with R-X, opening epoxides, 1,4-addn., etc.Require exquisite technique and involve complex mechanisms.

■ Cuprates favor SN2'

■ Organocopper, R-Cu is not very nucleophilic or basic

■ Cross-coupling

The true structures are complex

2 MeLi + "Me2CuLi" + LiICu-I

HB

HH

H-

HAl

HH

H-

HSiEt

EtEt-

ORCuMe

Me-

cuprate borate aluminate silicate

1. nucleophilic C2. low charge on C other "-ate" complexes

not soft

actually, aggregated

" "

i.e., SOFT

Li+LiI

(Me2CuLi = Gilman reagent)

Br Ph

Et2O0 °C, 5 h

Ph2CuLi

X

Me

Bu

X = Cl, OAc

Bu2CuLi

CuCu

CuCu

SMe2Me2S =

PhCu • 1/2Me2S

LiCu

LiCu

OEt2Et2O =

Ph2CuLi•Et2O

X-ray struct.

1,4 - Addition by Organocuprates

■ TMS-Cl accelerates 1,4 addn.

Nakamura, E.-I.; Kuwajima, I. JACS 1984, 3368

■ Cuprates add 1,4- to α,β-unsaturated aldehydes. All other organometallics would add to C=O.

■ 1,4-Addition

Canisius, J.; Gerold, A.; Krause, N. Angew. Chem. Int. Ed. 1999, 38, 1644.

O

MeLiO

O

Me

CuMe-

MeLi

Me2CuLi

Li+Cu–R

OLi

CuR

R

OLi

R

O

CuR

Li

R

OBu2CuLi

•LiI

O

Me

SiMe3

Me -70 °C< 1 sec no rxn at -70 °C

w/o TMSClBu

99%added last

+ Me3SiCl silyl enol ether

H

O

H

O

Me

SiMe3

Me

+ Me3SiCl

Bu

R2CuLi

Zinc Homoenolates

■ Nucleophilic cyclopropane bonds

Nakamura, E.-I.; Kuwajima, I. JACS 1986, 27,83

OSiMe3EtO ZnCl2

Et2OZnO O OEtEtO

OSiMe3EtO..

ZnCl2ZnCl2

OEtOSiMe3+

–