1

Cyanide: C Nucleophile

• The reaction with an alkyl halide with cyanide is an SN2 process and the best yields of nitrile are obtained with primary and secondary substrates, whereas tertiary halides such as 2-chloro-2methylbutane sometimes react via elimination to give the alkene. • The use of polar, aprotic solvents such as DMSO, DMF or THF give the best yields of nitriles.

R—X

+

NaCN

DMSO

R—C!N

X = Br, Cl, I, OSO2R

+

NaX

2

Sulfonate Esters

• Sulfonate ester leaving groups can also be used, as in the conversion of alcohol 1 to the mesylate group and then to nitrile 2 with NaCN in DMSO. • Another common reagent that generates a nitrile is tosylmethylisocyanide (TsCH2N≡C, also called TosMIC), which reacts with ketones or aldehydes to generate a nitrile (R2C=O → R2CH-C≡N). N)

BocHN 1

OH Ph

MeSO2Cl , NEt3

BocHN

NaCN , DMSO 90°C OSO2Me Ph

BocHN 2

CN Ph

3

Isonitriles

• An isomeric product is often observed (an isonitrile, also called an isocyanide, 4) when the reaction is done in a refluxing alcohol solvent, or when certain metal cyanides are used. • If M+ in MCN is sodium or potassium, which favor formation of ionic compounds, cyanide reacts primarily at carbon. • If M+ is Cu or Ag that forms relatively covalent bonds, nucleophilic strength at carbon is diminished and cyanide reacts primarily at nitrogen. • The reaction of 1-bromopentane with potassium cyanide (KCN) generates hexanenitrile (3), whereas reaction with silver cyanide (AgCN) gives the isomeric isonitrile 4. C5H11 C!N 3 R X

SN2 "C" M=K

M :CN:

AgCN

+

C5H11 Br

Ag C N X 5

R

SN2 "N" M = Ag

C5H11 N!C: 4 R N!C: 6

4

Isomerization of Isonitriles

• Isocyanides can also be converted to the nitrile by thermal rearrangement, but the reaction requires temperatures of between 140°-240°C. • Isonitriles are also formed by formylation of a primary amine followed by dehydration, as in the conversion of 9 to 10. Me n-C8H17 Me H C!N

270°C

H

Me

H

H

H H

N!C

7

n-C8H17

Me

NH2

H

8 H

NC

1. AcOCHO HO

H NH2 9

O

2. TsCl , Py HO C!N

H 10

O

5

Passarini Reaction

• The Passerini reaction is a convenient route to amide esters and is considered to be a three-component coupling reaction. • When propionic acid was heated with acetone and tertbutylisonitrile, the product was α-propanoyloxy amide 11. A 11 useful modification of the Passerini reaction used trifluoroacetic acid. • Hydrolysis of the trifluoroacetyl ester with aqueous sodium carbonate led to isolation of the α-hydroxyamide (14) in 69% yield. O

O

Me

O

Me

Me

O

OH

11

t-Bu N!C

Me

H N

t-Bu

O

O PhO 12

CHO

t-Bu N!C CF3CO2H , –50°C CHCl3

OH aq Na2CO3

O

F3C PhO

PhO

NHt-Bu

NHt-Bu 13

O

14

O

6

Alkyne Anions

• 3 fundamental reaction types RC!C:–

R H C

R H C

Br

H

H O

RC!C:–

R1

–O

R2

R1

C!C-R

R2

OR2

acyl addition

R1 –O

O RC!C:–

SN2 (alkylation)

C!C-R

R2 O

C!C-R

acyl substitution

R1

Plus acid/base; carbon dioxide; epoxides

7

Alkyne Anions

• Acetylene and other terminal alkynes have an acidic hydrogen atom (C≡C-H), and they are weak acids, pKa about 25-26. • The conjugate base of an alkyne is an alkyne anion (a carbanion. older literature, acetylide), and it is generated by reaction with a strong base. • A carbon nucleophile that reacts with alkyl halides or sulfonate esters via an SN2 sequence to give disubstituted alkynes such as 36. BASE

R C C H

TBSO

R C C: M 35 O

TfO O

O 37

R1—X

OPMB

R C C R1 36

, BuLi , THF

OTBS

PMBO

O

DMPU , –65°C

Tf = triflate = SO2SO2CF3

O 38

O

8

Acidity of Alkynes

Acid RC!CH R2C=CH2 O

H3C

Conjugate Base

pKa

RC!C: R2CH=CH:

25 36

O

CH3

H3C

ROH

19

CH2

17

RO

NEt3 , DMF

R–C!C–H

D2O R

PhHn-BuCl(CH2)4HC!C(CH2)4MeO-

R–C!C–D

39 Relative Acidity 1.0 0.73 0.058 0.033 0.076 2.0

9

Acyl Addition: Alkynyl Alcohols

O

1. CH3C!C:–Na + , DMF 2. aq. H+

• Do not see much acyl substitution with alkyne anions

OH

10

Grignard Reagents

• 3 fundamental reaction types R RMgX H C H

Br

R1

–O

R2

R1

R

R2

OR2

acyl addition

R1 –O

O RMgX

SN2 (alkylation)

R

H

O RMgX

R H C

R2 O

R

acyl substitution

R1

Plus acid/base; carbon dioxide; epoxides

11

Preparation of Grignard Reagents

• The so-called Grignard reagent (RMgX) is formed by the reaction of magnesium (Mg(0)) with an alkyl or aryl halide, usually in an ether solvent. • A simple example is the reaction of bromoethane with magnesium in ether to give 51. • The C-Mg bond in the Grignard reagent generates a negative dipole on carbon, so it is a nucleophilic carbon.

!+C—Br!"

CH3CH2Br

+

Mg°

ether

CH3CH2MgBr 51

!"C—Mg!+—Br

12

Barbier Reaction

• The reaction was first discovered in 1899 by Barbier, who was Grignard's mentor, although its nature was not well understood at the time. A ketone, Mg and halide were all mixed together in what is now known as the Barbier reaction or Barbier coupling. • In subsequent work, Grignard took the reaction much further. He premixed magnesium metal and the halide, characterized the resulting product as RMgX, and showed how RMgX reacted with many functional groups (particularly with ketones and aldehydes).

Me

1. Mg° , ether , MeI 2. H2O

52

O

53

Me Me OH

13

Schlenk Equilibrium • In solution, a Grignard reagent (see 56) is not the monomeric RMgX. • The RMgX structure (56) usually drawn for a Grignard reagent is in equilibrium with dimethylmagnesium (57) and MgBr2 as well as 58, in what is called the Schlenk equilibrium. • The Grignard reagent equilibrium is more complex in ether than it is in THF. • The equilibrium favored RMgBr in ether, although there is a mixture.

X R Mg Mg R X 59

2 RMgX

R2Mg

56

57

R2Mg2X2 58

+

MgX2

R X Mg Mg R X 60

14

Aggregation State

• In ether, the monomeric species is largely of RMgX with lesser amounts of R2Mg and MgX2. • In other work, it was concluded that the Grignard reagent exists primarily as the RMgX species in ether, THF or triethylamine but the composition varies in each solvent. • Ether solutions of Grignard reagents are stable if protected from moisture and air. A 2 N solution of CH3MgI in ether was stored in a sealed tube for 20 years, and shown to have virtually the same concentration of Grignard reagent as when originally sealed.

X R Mg Mg R X 59 R Mg OEt2

R X Mg Mg R X 60

R X

Mg

61

OEt2

R X

Mg OEt2

X

15

Solvent Stabilization

• To form a Grignard reagent, an ether solvent stabilizes the Grignard reagent by forming a Lewis acid-Lewis base chargetransfer complex such as 62. • Coordination with ether assists in the initial magnesium insertion reaction, and minimizes decomposition of the Grignard reagent via disproportionation. • For vinyl and aryl halides stronger Lewis base is required, both to assist the insertion and to stabilize the organometallic and, the more basic solvent THF is used when aryl or vinyl Grignard reagents must be prepared. O

O

C Mg X

C Mg X O

O

62

63

16

Grignards are BASES

• Grignard reagents are strong bases - the conjugate acid is an alkane RMgX → RH • Grignard reagents react with weak acids such as water, alcohols, amines, terminal alkynes. • Grignard reagents react with oxygen.

RMgX RMgX

+

+ O2

HOH

R—H ROOMgX 64

RMgX

+

HOMgX 2 ROMgX 65

2 ROH

17

Grignards with Alkyl Halides

• For Grignard reagents derived from simple aliphatic, aryl, or vinyl halides that react with aliphatic alkyl halides, the yield of coupling product (R-R1) is usually poor. • Only reactive Grignard reagents such as allylmagnesium halides react with alkyl halides that are also highly reactive (iodomethane, allyl bromide, benzyl bromide) to give good yields of a coupling product. MgCl

Cl

THF-HMPA

66

67

Disproportionation is common. MgBr

71

EtMgBr ether 5% MnCl2

CH2 CH2

+ 52%

CH3 CH3

+

+ 48%

44%

+ 31%

72

10%

18

Kharasch Reaction

• Kharasch showed the effectiveness of several transition metals that promoted the coupling reaction of phenylmagnesium bromide and chlorodiphenylmethane (68). • Transition metal catalyzed coupling reaction is known as the Kharasch reaction. • Ferric chloride is a very effective catalyst for the cross coupling of alkyl halides with aryl Grignard reagents, when tetramethylethylenediamine (TMEDA) is used as a stoichiometric additive. PhMgBr

+

Ph2CH–Cl

M

Ph2CH–Ph

68

M No catalyst CoCl2 FeCl3 Cu2Cl2 MnCl2

+

69

Ph2CH–CHPh2

70

% 69

% 70

0 82 63 30 0

90 6 17 47 82

[Reprinted with permission from Sayles, D.C.; Kharasch, M.S. J. Org. Chem. 1961, 26, 4210. Copyright © 1961 American Chemical Society

19

Grignard Reagents + Cuprous Salts

• Cuprous [ Cu(I) ] salts are readily available, and when mixed with Grignard reagents give excellent yields of cross-coupled products with very little disproportionation.

RMgBr RCu

+ +

CuIBr slow

R1Br

Me Me

MgBr

(Z/E = 90:10)

RCu R-R1

97%

+

MgBr2 CuIBr Me

I , THF , CuI –30°C

+

Me (Z/E = 88:12)

20

Grignard Cuprates

• Li2CuCl4 is prepared by reaction of LiCl and CuCl2 in THF) to catalyze the coupling of Grignard reagents and alkyl halides. • Note that the coupling occurred with the unprotected hydroxyl group in 75. OH

Li2CuCl4 , THF

+ Br

75

MgBr 76 OH 77

(CH2)9

95%