Organomagnesium (Grignard) and organolithium … reagents • Methyllithium CH 3-Li (MeLi) • a strong base and a strong nucleophile • n-Butyllithium n-C 4H 9-Li (n-BuLi) • a

Organomagnesium (Grignard) and organolithium reagents

Different polarization of non-metallic andorganometallic reagents

CH3 - IHO HO - CH3 + I

H3C

H3COH3N

H3C

H3C

OH3N+

H3C

OHH2N

H3C

I - CH3 CH3 - M CH3 - CH3 + M + I

CH3

CH3O CH3 - M O

CH3

CH3

CH3 + M

Organometallic reagents (R-M) are not fully ionic

Metal K Na Li Mg

% Ionic Character 51 47 43 35

reactivity of organometallic reagents

Ethers are the only solvents fororganomagnesium (Grignard) reagents

R - X + Mg RMgX MgX

R

OEt2

OEt2

MgR

X

XMg

R

OEt2

Et2O

X = I, Br, Cl

R = alkyl, aryl, alkenyl

Et2O

Generation of Grignard reagents bymetallation (hydrogen – metal exchange)

RH + R1MgX RMgX + R1H

R-C C-H + C2H5MgBrR-C C-MgBr + C2H6

H H

+ C2H5MgBr

H

+ C2H6

MgBr

Reactivity: magnesium atom is transferred to a more electronegative atom, as in metallation

• ROH + R1MgX → RO-MgX + R1H• R2NH + R1MgX → R2N-MgX + R1H• R2C═O + R1MgX → R2R1C-O-MgX

O

then H+

n-C6H13OH+ n-BuMgBr

SN2-type (coupling) reactions

EtMgBr + Br + MgBr

MgCl+EtO

SOEt

O O+ MgCl(OSO2OEt

MgCl + n-Bu-O-SO2- MeC5H11-n

+ MgCl(OTs)

BrMeMe

Me

Me

Me

MeMe

+ MgBr(OSO2OMe)

1) Mg

2) (MeO)2SO2

Transition metal ion (e.g. CuBr) mediated 1,4-addition to unsaturated carbonyl compounds

O EtMgBr then H+OH

Et+

O1) EtMgBr2) H+ O

Et+

Et

OH1,4-addition 1,2-addition

OEt MgBr 1) Me-I

2) H+ O

intermediate enolate

EtMgBrH+

Et

(from pure Mg)

Organolithium reagents

• Methyllithium CH3-Li (MeLi) • a strong base and a strong nucleophile

• n-Butyllithium n-C4H9-Li (n-BuLi) • a strong base and a strong nucleophile

• t-Butyllithium Me3C-Li (t-BuLi) • a strong base and a strong nucleophile

• basicity increases in the following order:

• MeLi < n-BuLi < t-BuLi

Basicity vs. nucleophilicity• A basic reagent has a strong

affinity for proton (e.g. removal of proton from a C-H moiety

• A nucleophilic reagent has a strong affinity for carbon in the molecule (e.g. SN2 reaction at the carbon atom)

Phenyllithium C6H5-Li (PhLi) a strong base and a strong nucleophile

Lithium diisopropylamide iPr2N-Li (LDA) a strong base and a relatively weak nucleophile

LDA: lithium diisopropylamide Li N

Alkyllithium and aryllithium reagents are strongly basic and strongly nucleophilic, while lithium amide reagents are

strongly basic and relatively non-nuleophilic

N

R-Li(any temperature)

NH

RLi

LDA- 78 oC

N Li N Me

LDA: lithium diisopropylamide Li N

addition

lithiation

MeI

Generation of organolithium reagents

• RCl + 2Li RLi + LiClthe reaction of alkyl halides with lithium metal

• RLi + R1X R1Li + RX lithium – halogen exchange in the reaction of an alkyllithium reagent and an alkyl halide, X = I or Br

• RLi + R1H RH + R1Lilithium – hydrogen exchange in the reaction of an organolithiumreagent with a relatively acidic hydrocarbon portion of a molecule (lithiation)

Lithium – halogen exchange

S

Brn-BuLi (1.0 equiv)

Et2O, -70 oC S

Li

+ n-BuLiN Br

n-BuLi (1.0 equiv)Et2O, -70 oC

N Li

+ n-BuLi

Lithiation and complex – induced proximity effect (CIPE)

S

n-BuLi

S Li S D

SO

N n-BuLi

SO

N

Li

complex-induced proximity effect

D2O

Lithiation and CIPE (contd.)

N

2) Me3SiCl1) LDA

N SiMe3

N OMe

N OMeMe3Si

N OMe

SiMe3complex-inducedproximity effect

CIPE (contd.)

N Cl N Cl N Cl

OH

MeMeCHOLDA Li

complex-induced proximity effect

CIPE and transmetallation

NH

t-BuOCOCOBu-t

N

Ot-Bu O(BOC group)

n-BuLi

Low yield,many byproducts

(n-Bu)3SnCl

NBOC

Sn(n-Bu)3

n-BuLi

NBOC

Li

NBOC

LiHigh yield,high purity

Synthesis of ketones

R-Li O=C=O RO-

O

R Li

Li+ RR OLi

OLi

RR

O + 2 LiOH

H3O+

Reaction with unsaturated carbonyl compounds

Ph PhO

Ph PhOPh

Ph PhPh

OH

1) PhMgBr

2) H+

1) PhLi

2) H+

1,4-addition

1,2-addition

Addition reaction to the formal C=N bond ofheteroaromatic compounds

N

N

N

S Li

N

S Br

n-BuLi

Cl NH

N

ClN

Sthen H2O

N

N

ClN

S

O

OCN

CNCl

Cl

OH

OHCN

CNCl

Cl

(DDQ)

H

Addition to heteroaromatic compounds (contd.)

N

N

Cl NN

The addition reaction of organometallic reagents

Organocopper (RCu) and lithiumorganocuprates (R2CuLi)

• MeLi + CuI → MeCu + LiIcolorless yellow

• MeLi + MeCu → Me2CuLi colorless

1,4-addition reaction of R2CuLi(not reactive enough for a 1,2-addition)

RCu-

RO

RCuR O-

-RCu

O-ROR H+

R2CuLi: reactions with acid chlorides andepoxides

O Cl O Me

Me1) (Me2C=CH)2CuLi

2) H+

Me 1) Et2CuLi

2) H+Et

Me

OHO

R2CuLi: coupling reactions

C10H21Br C14H30Bu2CuLi

1-bromodecane tetradecane

Br Bu2CuLi

Drying of diethyl ether (ether or Et2O) andtetrahydrofuran (THF) for organolithium reactions

EtOEtdiethyl ether O

terahydrofuran

Ph Ph

O Na

(metal) Ph Ph

O Na H2OO2 Brown mixture

benzophenone (colorless)

sodium benzophenone ketyl radical (intensively violet)

The use of THF

THF must be used below 0 oC. The following reaction occurs if the temperature is above oC:

O

n-Bu-Li

OLiOLi

enolate ethylene

Titration of organolithium reagents

CH COOH

diphenylacetic acid

RLiCH COO_ Li+

RLi

colorless

C COO_ Li+Li

yellow

Synthesis of 2-chloro-4-(2-thienyl)pyrimidine

N N

Cl

S Li

S

n-Bu-Li

then H2O SHN N

H

Cl

SN N

Cl

O

O

CN

CN

Cl

Cl

DDQ

OH

OH

CN

CN

Cl

Cl

12

3

Synthesis of 3-butylcyclohexanone

OO

Bu

n-Bu-Li CuI Bu2CuLi

H2O O

Bu4

Graduate Studies in ChemistryMS and PhD Programs offered in:

• Analytical• Biological / Biochemical• Biophysical / Computational• Organic / Medicinal

For more information:[email protected]

• Competitive stipends and fellowships; waived tuition; and assisted health insurance (PhD’s supported: 82)

• Ranked top 10 of 178 by National Research Council in “Student support and Outcomes” and “Faculty Diversity”http://www.nap.edu/rdp/

• Masters program ranked number 9 in the United States (number one in the Southeast) by the American Chemical Society for MS degrees conferred in 2008-2009http://pubs.acs.org/cen/email/html/8834acsnews1.html

32

Center for Diagnostics and Therapeutics

33

34

35