OC 2 (FS 2013) Lecture 4 Prof. Bode

1

Carbenes and Nitrenes

1 Introduction

1.1 Review of carbon valencies and hybridization

Methane Methyl anion Methyl radical Methyl cation

CH4 CH3− CH3

CH3+

sp3 sp3 sp2 sp2

Rule of thumb: electron deficiency normally goes in p orbitals, negative charge in s orbitals.

2 Carbenes

2.1 Definition

“Carbenes are neutral, highly reactive species containing a divalent carbon atom with an electron sextet”

2.2 Possible hybridizations of methyl carbene

Structure

Hybridization sp2 sp2 sp

Geometry Bent Bent Linear (not observed)

State Singlet Triplet Triplet

2.3 Comparison between triplet and singlet carbenes

2.3.1 Spin state

2.3.2 Geometry

From X-ray structures (see also subchapter 5.6.1) we know that both singlet and triplet states are bent.

Triplet carbene Singlet carbene

Bond angle 130-150° 100-110°

H

HH H HH H HH

HH

H

H

H

H

H

HH H

triplet carbene singlet carbene

sp2

p

σ

In most cases lowerin energy (Hund's rule)

sp2

p

σ

These two spin systemscan be distinguished by EPR

OC 2 (FS 2013) Lecture 4 Prof. Bode

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2.4 Reactivity differences of singlet vs triplet carbenes

3 Generation of Carbenes

3.1 1,1 elimination

3.2 Diazo compounds

4 Carbenoids (metal stabilized carbenes) 4.1 Generation

4.2 Properties

Improved thermodynamic and kinetic stability with respect to the non-stabilized carbenes.

H2C N N

CHBr3

hνH2C

singlet

H2Crelaxation

triplet

KOtBu

-N2

-KBr-tBuOH

Br2C

singlet

hν

Generation of triplet carbenes

Generation of singlet carbenes

Different reactivities

H2CN2

Me

Me+ hν

cis-olefin

Me

Me

Me

Me

+

trans cis

Me

Me+

cis-olefin

CHBr3KOtBu

Me

Meonly cis, stereospecific reaction

triplet carbenes react like biradicals(stepwise)

singlet carbenes react in concerted way

H

X

baseX R RR

RR

R

R2C N NR2C N N

a) Δb) h νc) metal catalyst

R R + N2

CMCC

CC C

O

O

O

O

O

OR1 Li

(OC)5MOLi

R1 R2X-LiCl (OC)5M

OR2

R1

M = Cr, Mo, W

Fischer route

stable complex

From diazocompounds

Rh2(OAc)4

EtO

O

N2

H+ -N2 EtO

O

Rh

H

Rh Rh

O

OO

O

O

O

O

O

MeMe

MeMe

Rh2(OAc)4

Rh

Fischer carbenes

- low oxidation state metals;- middle and late transition metals Fe(0), Mo(0), Cr(0), W(0);- π-acceptor metal ligands;- π-donor substituents on methylene group (-OR or -NR2).

Shrock carbenes

- high oxidation states metals;- early transition metals Ti(IV), Ta(V);- non π-acceptor ligands non π-donor substituents.

singlet

HH

M d-orbitals

triplet

HH

M d-orbitals

OC 2 (FS 2013) Lecture 4 Prof. Bode

3

4.3 Examples

5 Reactions of Carbenes and Carbenoids

5.1 Cyclopropanation

5.1.1 Intermolecular

5.1.2 Intramolecular

5.1.3 Simmons-Smith

5.2 C–H insertion

PCy3

RuPCy3

PhClCl

Grubbs' complex

Me

W(CO)5

OMe Ph

Fe(CO)4

NEt2

Fischer carbenes Shrock carbenes

TaMe

CH2Ti

Cl

H2C Al

Me

MeTi CH2 AlMe2Cl+

+ CR2C

R R

CH2N2+Pd(OAc)2 (1 mol%)

Et2OCO2Me

N N

CO2Me96%

Me Me

S

O

N2 S

ORh2(OAc)4

CH2Cl2rt, 15 h

91%

OTMS Et2Zn (1.5 equiv)CH2I2 (1.5 equiv)

Et2O0 °C to reflux, 4 h

OTMS

ZnEt2 + CH2I2

+

R3

R1 R2

R4

C4H10

H2C

R1 R2

R3 R4

IZn I

R1 R2

R3 R4+ ZnI2

Mechanism

IZnCH2I(carbenoid)

C+R1

R3R2 H

R1

R3R2

HM

R1

R3R2 C

H

M

R5

R4

O ON2

Rh2(OAc)4

CHCl3rt, 1 h

O O

MechanismR4R5

R5

R4

OC 2 (FS 2013) Lecture 4 Prof. Bode

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5.3 Dimerization

5.4 O–H & N-H insertion

5.5 Ylide Formation

5.6 Wolff Rearrangement

Cr(CO)5

MeO

Ph

Pd(PPh3)4 (10 mol%)Et3N (1.1 equiv)

THFrt, 1.5 h

MeO

Ph OMe

Ph

53% (E/Z = 2/1)

(OC)5CrR1

R2Pd

PdR1

R2

Cr(CO)5

R1

R2

PdR1

R2

R1

R2

R1

R2

R1

R2

Mechanism

O

PhN2

+ H OCH3

(solvent)

O

PhOCH3

Cu bronze

50 °C55%

O–H insertion

O

PhN2

+ H NO

PhN

Cu bronze

EtOH45 °C

80%

N–H insertion

(excess)

MeO2C

N2

CO2Me+

(solvent)

SMeO2C

S

CO2Me

Ylide, 95%

Rh2(OAc)4

rt, 24 h

reflux, 2 h

SCO2Me

CO2Me

70%

MeOOC COOMe

S

MeOOC

S

COOMe

SCOOMe

COOMeH

SCOOMe

COOMe

Mechanism

H

PhO

PhN2

benzene

refluxC

O

Ph Ph

Mechanism

R1O

R2

N

N

R1O

R2

N

N–N2

O

R2

R1

C

O

R1 R2

α-diazoketones ketenes

Reminder:

C

O

R R

NuO

NuR

RNucleophiles: amines, alcohols...

OC 2 (FS 2013) Lecture 4 Prof. Bode

5

5.6.1 Arndt-Eistert β-amino acid synthesis

5.7 Alkyne synthesis

5.7.1 Corey-Fuchs reaction

Little is known about the reaction mechanism from the dibromoolefin to the alkyne, one of the accepted mechanisms proceeds via a carbene intermediate.

O

OHHN

BocR

1. iBuOCOCl Et3N/Et2O, –15 °C

2. CH2N2 0 °C

OHN

BocR

N2

1. PhCO2Ag Et3N/MeOH, rt

2. Base MeOH/H2O, rt

HN

BocR O

OH

α-amino acids β-amino acids

Mechanism

–N2

OHN

R'R

NN O

HN

R'R

NN

OHN

R'R

C

O

R

HN

R'

OMe H

R

HN

R'

O OH

Me

R

HN

R'

HO OMe

R

HN

R'O

OMe

R

HN

R'O

OH

H+ transfer

OH-

O

H H

Br BrH

MeO

PPh3 (3.0 equiv)CBr4 (1.5 equiv)

CH2Cl20 °C, 30 min

MeOMeO

90% from aldehyde

1. nBuLi (4 equiv) THF, –78 °C, 30 min

2. aq. NH4Cl

Mechanism

Ph3P C+ Ph3P CBr2

Br PPh3 Ph3P CBr2

Ph3P CBr2

R

O

H O

CBr2

PPh3

R

O

CBr2

PPh3

R

R

Br

Br

O PPh3

nBuLi

R

Li

BrRRH

Aldehyde Alkyne

ylide

H

carbene

R

Br

Br

H

nBuLi

R Li R BrnBuLi

R HH3O+

Br

Br BrBr

OC 2 (FS 2013) Lecture 4 Prof. Bode

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5.7.2 Seyferth-Gilbert Homologation

6 N-heterocyclic carbenes

6.1 History

The first applications of thiazolydenes in umpolung organocatalysis were reported as early as 1943 (J.

Pharm. Soc. Jpn. 1943, 63, 296) and metal complexes of NHCs were already reported in the late 60’s.

However, it is only in the last two decades (milestone: 1991, Arduengo, first X-ray structure of a carbene)

that NHCs have become ubiquitous both as ligands in organometallic chemistry and as organocatalysts.

6.2 NHCs are singlet carbenes

For NHCs the singlet state is lower in energy than the triplet state, the reason being π-donation into the p-

orbital of carbon from the heteroatoms adjacent to the carbene.

6.3 Examples of the most frequent NHCs and their nomenclature

Imidazolynidene Imidazolydene Benzimidazolydene Tetrahydropyrimidiylidene

Pyrrolidinylidene Triazolydene Thiazolidene

R can be modified to fine-tune the chemical behavior of the NHC (R = alkyl or aryl).

6.4 Properties

NHC are electron rich and particularly stable carbenes. The stability arises both from:

- shielding effect by sterically demanding substituents (minor effect);

O

H

H

ClCl

97%

+

N2

P(OMe)2

O K2CO3 (2 equiv)

MeOHrt, 8 h

Mechanism

Me

O

N2

P(OMe)2

O

Me

O

MeO

N2

P(OMe)2

O R1

O

R2

N2

P(OMe)2

OO

R1R2

N2

R1

R2

OP(OMe)2

C NR1

R2N C N

R1

R2N

–N2C

R1

R2

R1

R2

O

Ohira-Bestmann reagent

N N

H

Cl

N NNaH

THF

stable carbene(Arduengo 1991)

N NR R N NR RN NR R

N NR R

NR RR N N

N

R RN SR

OC 2 (FS 2013) Lecture 4 Prof. Bode

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- electronic stabilization (mesomeric interaction of the lone pairs of electrons on the nitrogen atoms

with the empty p orbital of the sp2 hybridized carbene).

Acidic proton: the pKa value of the 2-position of imidazolium salts ranges from 16 to 23 (in DMSO).

6.5 Synthesis (generation)

6.6 Use as ligands

NHC-complexes are known for almost every transition metal, but the most important for organic chemist are:

Metal Class Example Catalyst

Ru Metathesis

reactions

Pd Cross-coupling

reactions

NHC behave like phosphines when they are coordinated to metals (electron donating properties) but they

have more influence on the coordination sphere of the metal (sterics).

N NR R

H

X

azolium salt

N NR Rbase

ylide

N NR R

carbene

N NR R

Free NHC

N NR R

H

X

N NR R

Cl

XN NR R

S K0

base

N NR R

H Y

N NR R

O O

ΔΔ

mostcommonroute

Y= C6H5, CF3, CCl3 ...

- HY -CO2

- KS

Hg(TMS)2

- Hg- TMSCl- TMSX

COOEtEtOOCEtOOC COOEt

Grubbs II catalyst

CH2Cl2, 40 °C

RuPCy3

NN MesMes

PhClCl

Grubbs II

ClNH2MeMeiPr iPr

+Pd-PEPPSI

KOtBu, DME, 24 h, rt

HN

Me

Me iPr

iPr

Buchwald-Hartwig coupling with hindered substrates

90 %

PdN

NN

Cl Cl

R

R

R

R

ClPd-PEPPSI

M

NNRR P

M

RR

RNHC-Pd

Cross-coupling reactions

Suzuki-MiyauraNegishi

Kumada

Stille Sonogashira

Buchwald-Hartwig

Heck

R groups pointing atthe metal "coordinationsphere"

R groups pointing away fromthe "coordination sphere"

OC 2 (FS 2013) Lecture 4 Prof. Bode

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6.7 Use as catalysts

See redox neutral chapter.

7 Nitrenes

7.1 Structure & hybridization

Nitrenes are nitrogen analogues of carbenes. The nitrogen atom possesses only six valence electrons; in

nitrenes the triplet state is lower in energy than the singlet state.

7.2 Generation

7.2.1 From 1,1-elemination

7.2.2 From azides

7.3 Hoffman-type rearrangements

7.3.1 Hoffman rearrangement

7.3.2 Curtius rearrangement

R NR N

RNX

base NR X

HN

Rnitrene

N N NN N Na) heatb) light

+ N2R R

N

R

Mechanism

R

O

NH

HBase

R NH

O Br Br

R

O

NH

Br

Base

R

O

N

Br

R

O

N

RN

CO

H2O or

ROHR

HN

O

OH

BaseR

NH2–CO2

nitrene

isocyanate

NF

NH2

O

NF

NH2NaOH, Br2

THF, 70 °C

Mechanism

R

O

NN

N

R

O

NN

N

–N2 R

O

N RN

CO

NH

O

O

N3

O

NH

NO

O

CO

Toluene

65 °C, 10 min

Acyl azide Isocyanate

OC 2 (FS 2013) Lecture 4 Prof. Bode

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7.3.3 Lossen rearrangement

7.4 Beckmann rearrangement

7.4.1 Mechanistic analogy to Baeyer-Villiger reaction

7.4.2 Industrial nylon synthesis

7.4.3 Metal catalyzed C–H insertion

Mechanism

R

OR

NC

ONO

O

R'

H

O

NH

O

O

NC

OΔ

R

O

N

–R'OOH

NOH

Mechanism

R1 R2

NOH

R1 R2

NOH2

aq. H2SO4

rt, 4 d

H H2O N

R1 OH

R2

NH

R1 O

R2

O

NH

63%

- H2O

NR1 R2

C NR1 R2

tautom.

R1 R2

O m-CPBA

R1R2

OO O

O

HAr

R1

O

OR2

NOH

NH

Oaq. H2SO4, Δ

BeckmannRearrangement

base (cat.)

Ring-OpeningPolymerization

HN (CH2)5

O

nNylon 6

N3

Ph [(cod)Ir(OMe)]2(2 mol%)

benzenert, 15 h

F3C F3C NH

Ph

93%

Mechanism

NN

N–N2

Ph

NN

N

Ph

F3C F3C

[Ir] Ph

F3C N

[Ir]

H

Ph

F3C N H

[Ir]

F3C NH

Ph–[Ir]

OC 2 (FS 2013) Lecture 4 Prof. Bode

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8 Biological counterparts

Carbenes play a central role in a number of biological processes. One of the most important examples is

Vitamin B1 (Thiamine pyrophosphate), a coenzyme involved in many metabolic pathways. For instance, the

enzyme pyruvate decarboxylase is assisted by TPP in catalyzing the transformation of pyruvate into

acetaldehyde: a key step in the anaerobic fermentation… Think about it next time you’ll have a drink!

O

O

OMe

Glucose

OH

HO

H

HO

H

OHOHH H

OHGlycolysis

Pyruvate

Me H

OEtOH

Acetaldehyde

N

N

NH2

Me

N

S OP O

O

OH

P OH

O

OH

Me

alcohol dehydrogenasepyruvate decarboxylase

NADH + H+ NAD+TPP, Mg2+

CO2

TPP = thiamine pyrophosphate