Reactive Intermediates_lectures

REACTIVE INTERMEDIATES DR. R.M. PATON

5 LECTURES

AIMS 1. 2.

To demonstrate the concept of reactive intermediates in organic chemistry by a general overview of evidence for their structure and their reactivity. To provide detailed coverage of the structure, reactivity and synthetic utility of important classes of neutral reactive intermediates including radicals, carbenes, nitrenes and arynes.

LEARNING OUTCOMES 1. 2. 3.

A general knowledge of the generation, detection and structure of important classes of neutral reactive intermediates, eg radicals, carbenes, nitrenes and arynes. An understanding of the reactivity of radicals, carbenes, nitrenes and arynes. Knowledge of how such reactive intermediates can be used in organic synthesis.

SYNOPSIS As the chemistry of carbocations and carbanions has been covered in earlier years this course deals mainly with monodentate and bidentate neutral reactive intermediates (eg radicals, carbenes, nitrenes, arynes). Emphasis is on (i) the molecular and electronic structures of these reactive intermediates and how these are related to reactivity and reaction mechanism, and (ii) the use of such reactive intermediates in synthesis. Radicals: History - generation - detection and characterisation - structure and stability - reactivity use in synthesis - autoxidation and antioxidants. Carbenes: Generation - molecular and electronic structure of singlet and triplet species carbenoids - reactions - use in synthesis. Nitrenes: Similarity to carbenes - generation, structure and reactions. Arynes: History - generation - detection and characterisation - molecular and electronic structure reactions - use in synthesis. RECOMMENDED TEXTBOOKS 1. 2.

General Text Clayden, Greeves, Warren & Wothers “Organic Chemistry”, Oxford 2000. Specialised Texts Moody and Whitham, "Reactive Intermediates", Oxford Science Publications, 1992. Perkins, "Radical Chemistry", Oxford Chemistry Primers, 2000 "Comprehensive Organic Chemistry", Vol. 1, p. 455. "Comprehensive Organic Chemistry", Vol. 2, p. 287.

INTRODUCTION Many reactions in Organic Chemistry proceed in more than one step via one or more short-lived reactive intermediates.

starting material

k1

intermediate

k2

product(s)

In general, reactive intermediates correspond to a shallow dip on the reaction profile. In most cases ∆E2 < ∆E2 ie k2 > k1 [ for diagram – see M & W p1 ] Examples from earlier courses include: R3C Br

- BrR3

Nu-

C+

R3C Nu

H E+

E

E

- H+

etc This course concentrates on neutral reactive intermediates Table

Relationship between reactive intermediates

-onium ion neutral molecule anion radical

-enium ion -ene

[M&W p2]

C

N

O

R5C+

R4N+

R3O+

carbonium ion

ammonium ion

oxonium ion

R4C

R3N

R2O

hydrocarbon

Amine

ether

R3C-

R2N-

RO-

carbanion

amide anion

alkoxide

.

.

.

R3C

R2N

RO

carbon radical

aminyl radical

oxyl radical

R3C+

R2N+

RO+

carbenium ion

nitrenium ion

oxenium ion

R2C:

RN:

:O:

carbene

nitrene

oxene

Various other neutral reactive intermediates; eg H

H

C6H4

H H

cyclooctyne

(Z)- cycloheptene (E)- cycloheptene

( strained )

( unstrained )

benzyne

( strained )

1,3-Dipoles are class of neutral reactive intermediates with considerable synthetic potential. A=B+−C- ↔ A+−B−C- ↔

etc

A≡B+−C- ↔ A+=B−C- ↔

etc

RC≡N+−O- nitrile oxides

Eg

RC≡N+−S- nitrile sulfides

Some other examples are more stable O=O+−O- ozone

Eg

N≡N+−O- nitrous oxide

N≡N+−N-R azides

Evidence for short-lived intermediates •

Kinetics & isotopic labelling

•

Matrix isolation experiments

eg in N2 or Ar at ~20 K

•

Spectroscopy

IR, UV Flash photolysis / UV EPR ( ESR) for paramagnetic species (radicals)

RADICALS Methods of Generation 1. Thermal cleavage of covalent bonds Require bond dissociation energy < 160 kJ mol-1 Peroxides

RO−OR O

eg

see table below

Ph

O

O

Ph O

dibenzoyl peroxide

heat or hν 80 °C

O

2

Ph

O

eg

Me3C

O

O

heat CMe3

2 Me3C O

100°C

di-t-butyl peroxide

Azo compounds Me NC

eg

Me N

N

heat

CN Me Me

N2

80 °C

+

2

azobisisobutyronitrile "AIBN"

2. Photochemical cleavage of covalent bonds Halogens

X X

Ketones

hν

2X

O

eg Me

where X = Cl, Br, I

O

hν Me

Me

+

3. Electron transfer reactions eg

RO-OH +

eg

RCO2

Fe2+ -e

RO

+

OH-

+ Fe3+

RCO2

Radical ion formation eg

C10H8 radical cation

+e

-e

naphthalene C10H8

e removed from HOMO EPR evidence for both radical ions

C10H8 radical anion e added to LUMO

Me

Me

CN Me

Table Bond dissociation energies

energy (kJ mol-1) to break bond homolytically

C−H bonds HC≡C−H CH3−H H2C=CHCH2−H HOCH2−H

522 435 364 401

Ph−H MeCH2−H PhCH2−H MeCO−H

468 410 355 364

H2C=CH−H Me2CH−H MeCOCH2−H

451 397 410

H2C=CH2 Me3C−CH3 MeCH2−Br Cl3C−Br

635 339 284 226

H3C−CH3 PhCH2−CH3 MeCH2−I MeCH2−OH

368 301 222 380

Br−Br ButO−OBut

192 155

l−I AcO−OAc

150 125

F−H I−H H2N−H

568 297 431

Cl−H HO−H MeO−H

431 497 426

C−C & C−X bonds HC≡CH MeCH2−CH3 MeCH2−Cl Cl3C−Cl

836 355 339 284

X−X & X−Y bonds Cl−Cl HO−OH Me3Sn−Br

242 213 226

H−H & H−X bonds H−H Br−H HOO−H Me3Sn−H

435 368 376 310

Types of Radical Reaction 1. Radical-radical reactions (a) Combination (or coupling) R

+

R'

R R'

(b) Disproportination H3C

CH H

CH2 H2C

H2 C

H3C CH3

C H

CH2 +

H3C

H2 C

CH3

2. Radical-molecule reactions (a) Abstraction eg

Cl

+

(or transfer) H CH3

ease of H-abstraction:

Cl H

+

CH3

benzylic/allylic/aldehydic > aliphatic > alkynic/alkenic/aromatic

likewise for halogen abstraction

(b) Addition to multiple bonds eg

+

RO

H2C CH2

RO

H2 C

CH2

3. Unimolecular radical reactions (a) Fragmentation O eg

heat

Ph

Ph

O Me

eg

(or β-scission) CO2

Me

heat

O

Me

+

O Me

Me

+

Me

(c) Rearrangement eg

Ph2C CH2Ph

Ph3C CH2

4. Electron transfer reactions (a) Oxidation -e

R

R+

(d) Reduction +e

R

R

Reactions (1) & (4) destroy radical centre, whereas for reactions (2) & (3) it is retained.

Reactivity, Stability & Lifetimes of Radicals Most radicals exist only as transient intermediates during a reaction, But others are long-lived or persistent Need to consider bond strengths and the availability of the unpaired electron Delocalisation of the electron increases stability and lifetime Steric effects: bulky groups impede reaction and increase lifetime Examples Methyl

CH3

H H

H

a π-radical

e localised, therefore reactive and short-lived

Phenyl

a σ-radical

sp2

Ph or C6H5

e localised, therefore reactive and short-lived

CH2 Benzyl

PhCH2

CH2

H H

a π-radical likewise for

Ph O

etc and

Ph NR

But more stable than Ph

for steric reasons

But .

In summary, alkyl radicals are usually short-lived:

.

.

Ie reverse of order of C−H bond strengths In summary, lifetime increased by delocalisation and by steric effects

Persistent Carbon Radicals Historical perspective:

.

eg

triphenylmethyl Ph3C

1900 Gomberg

Ph3COOCPh3

O2 2 Ph3CCl + 2 Ag

2 AgCl + Ph3C-CPh3

2 Ph3C

NO Ph3CNO

.

EPR spectroscopy provides for persistence of Ph3C Long lifetime attributed to: •

extensive delocalisation

C

•

C

etc

H

steric factors inhibit dimerisation to (Ph3C)2

1968 Ph3C

Non-symmetrical dimer isolated +

H

H CPh2

Ph3C

.

Me3C > Me2CH > MeCH2 > CH3

CPh2

structure proved by NMR

.

.

(Cl5C6)3C and (4-O2NC6H5)3C are more persistent and can be isolated

eg Kolsch's radical 1932-1957

Persistent Oxygen & Nitrogen Radicals Oxidation of phenols PhOH

[O]

various dimers C12H10O2

PhO

O

O

O

etc

H H

Mechanism for dimer formation

PhOH

[O]

OH HO

OH

OH

+

OH +

+

OPh + o-isomer

OH

OH

tautomerism

PhO

O

H

H

O

etc

etc

etc likewise for phenol itself O

OH H PhOOPh

(weak O-O bond)

hindered phenoxyls are more persistent – dimerisation impeded

H H

O

OH But

But

[O]

O

But

But

But

But etc

But

But

But

Oxidation of amines Ph2NH

eg

[O]

Ph2N NPh2

Ph2N

etc

•

delocalisation of e over 2 aryl rings

•

weak N−N bond in dimer

Stabilisation by adjacent heteroatoms Ar

Ar NHAr

N

:

N Ar

: :

hydrazyls

:

eg

NAr

Ar

delocalisation of e over 3 Ar rings

R nitroxyls

O:

N

:

N R

: :

:

eg

R O:

R

Radical Chain Reactions 3 phases

initiation

Examples

from previous courses

Halogenation of alkanes eg

CH4

+

Cl2

propagation

termination

[ McMurry V p 361 VI p 320 ] hν

HCl

+

CH3Cl

etc

Peroxide-induced addition of HX to alkenes eg

RCH CH2 +

HBr

[ March p 571 ]

peroxide

RCH2CH2Br

Radical Polymerisation Involving monomers of the form CH2=CHX where X = Ph, Cl, CN, CO2Et etc also CH2=CXY eg CH2=CMeCO2Me ( “methyl methacrylate” ) but rarely symmetrical monomers XCH=CHX repeating unit of product:

-[-CH2CHX-]-

Initiation eg

PhCO2O-OCOPh

eg

heat

NCCMe2-N=N-CMe2CN AIBN

in general then

Initiator R

+

Ph

PhCO2

or hν heat

NCCMe2

or hν

+

CO2

+ N2

R RCH2CHX

CH2=CHX

Propagation RCH2CHX

CH2=CHX

RCH2CHXCH2CHX

n CH2=CHX

R(CH2CHX)nCH2CHX

NB "head-to tail" addition

Termination coupling product CH2CHX CH2CHX

CH2-CHX-CHX-CH2 CH2CH2X + disproportination products

CH=CHX

Autoxidation of hydrocarbons Overall R3C-H + O2 → R3C-O-O-H → alcohols, ketones and carboxylic acids a hydroperoxide Mechanism: .

.

i) Initiation:

In + R-H → InH + R

ii) Propagation:

R + O2 → R-O-O

.

.

.

.

R-O-O + R-H → R-O-O-H + R .

.

eg R + R → R-R . . R + ROO → ROOR . 2 x ROO → ROOR + O2

i) Termination:

Examples: a) Alkylarenes H

Me2C-OOH

Me C Me O2

CH3

CH2OOH

CH2OOH

CH3

statistically expect

10%

30 %

60 %

observe

80%

20 %

0%

b) Ethers

Et2O

OOH CH EtO Me :

EtO CHMe

O2

eg

[ Perkins p 71 ]

c) Unsaturated lipids

linoleate esters

polymeric products

RO O

EtO CHMe :

c) Alkenes

O2

: :

via

eg

CH

+

+

CH3

Me

CHMe2

OOH

via

Antioxidants

eg hindered phenols

.

OH Me3C

O

.

CMe3 +

R

RH

Me3C

+

Me

CMe3

Me

.

O Me3C

CMe3

Me

O Me3C

ROO

.

OOR

Me

.

•

ArO Detected by EPR spectroscopy

•

Both R and ROO radicals removed

Functional Group Transformations 1) Reduction of alkyl halides

Mechanism

(RBr & RI)

AIBN

RBr + Bu3SnH

RH + Bu3SnBr

heat

a radical chain process

Initiation NCCMe2-N=N-CMe2CN AIBN NCCMe2 +

Bu3SnH

heat

NCCMe2

or hν abstraction

+ N2

NCCHMe2 +

Bu3Sn

[ NB weak Sn-H bond (~310 kJ mol-1) ]

Propagation

[ strong Sn-Br bond (~550 kJ mol-1) ]

Bu3Sn R

+

+

CMe3

RBr Bu3Sn-H

Bu3Sn-Br RH

+

+

R

Bu3Sn

. . radical couplings involving R and / or Bu3Sn etc

Termination

Bu3SnH

+

initiation

AIBN

RX

Bu3SnX

Bu3Sn

R

RH

Bu3Sn

2) Carbon-carbon bond formation eg

R X

+

+

W

Bu3SnH

AIBN

R

heat

W

+

[ W e-withdrawing ] RX

Bu3SnX R

Bu3SnH

+

initiation

AIBN

RH

Br CN

3) Intramolecular reactions Br +

W

Bu3Sn

CN

Bu3SnH +

eg

W

Bu3Sn R

eg

+

AIBN

for ring synthesis AIBN

use low [BuSn3H] to minimise hexene formation

+

+

Bu3SnH

12:1 reactant ratio

[ M & W p 18 ]

17%

81%

kinetic product

2%

Bu3SnX

eg macrocyle synthesis O O

O

O

Bu3SnH

O

(CH2)12I

O

+

AIBN

(CH2)14

(CH2)12CH3

4) Homolytic aromatic substitution eg

PhCO2OCOPh

+ PhH → Ph-Ph + CO2

Mechanism:

PhCO-O-O-COPh

. Ph

heat

Ph

PhCO2 H

.

H

+

"-H"

CO2

Ph

Ph

H Ph

etc

. H

similarly for Ph radical generated from other sources, eg thermolysis of Ph-N=N-CPh3 and

.

+e PhNH2

NaNO2 HCl

Ph N N

Ph

Ph N N Cuo

+

N2

Cu+

thus providing a route to unsymmetrical biaryls eg

ArCO2OCOAr + PhH → Ar-Ph

[ no Ar-Ar formed ]

eg polycyclic aromatic hydrocarbons via intramolecular homolytic aromatic substitution (the Pschorr reaction)

eg

Cuo N2+

HONO NH2

NB This approach to biaryls has now largely been superseded by the Suzuki coupling reaction involving aryl halides and arylboronic acis ArB(OH)2 [see - Clayden p 1328 ]

CARBENES & NITRENES

R

Nitrenes

C:

:

R

Carbenes

R N:

Carbenes and nitrenes are neutral, e-deficient (6e) and highly reactive intermediates

CARBENES

R2C:

[ M & W ch 3 ] [ Clayden ch 40 ]

Structure & Reactivity Carbon atom has 6 e, including 2 non-bonded; therefore singlet and triplet states possible. R

:

R R

R

R

sp2 singlet (bent)

sp2 triplet (bent)

R

sp triplet (linear)

Most carbenes have triplet ground states, but if there is a lone pair on an adjacent atom then the ground state may be singlet. eg

CH2 triplet, but CCl2 singlet

:

Cl

C:

:

Cl

: Cl

C:

:

:

: Cl

Substituents can also affect reactivity. As carbenes are e-deficient, the carbon having only 6e, they are electrophilic, particularly when e-donating groups are attached. In contrast, e-donating groups reduce the reactivity; eg Cl2C is less reactive towards Nu than CH2 Diaminocarbenes are even less reactive, and can sometimes be isolated if the substituents are bulky; eg R

R C: N:

R

R :O C:

:

and isonitriles

etc

:

also carbon monoxide

N :

N: C: N:

RN C:

:O C: RN C:

Generation Carbenes are transient species and must be generated in situ in the presence of the co-reactant 1) From diazo compounds R C N N R

R C N N R

[M]

100 °C

R

or hν

R

C: + N2

- N2

M = eg Rh, Cr

R C [M] R

eg Rh2(OAc)2

carbene products

metallocarbene alkylidene complex

Diazo compounds are good source of carbenes because they can be prepared readily or generated in situ. heat

R2C O + H2NNH2

- H2O

Bamford-Stevens method R2C O + H2NNHTos

[O]

R2C N NH2

R2C N N

via tosylhydrazones

- H2O

products

H R2C N N Tos

R2C N N

base

- Tos

R2C N N Tos

R2C N N Tos

2) From ketenes heat R2C C O

R2C:

or hν

+

CO

3) By α-elimination reactions - XY

eg

Ph H C Br Br

base

eg

PhHg Cl C Br Cl

heat

R2C:

Ph C Br Br

PhHgBr +

- Br-

Cl2C:

:

X R C R Y

PhCBr

4) By ring cleavage reactions O eg epoxides

hν

Ph H

eg diazirenes

R

N

R

N

:

Ph H

PhCH

hν

+

PhCH=O

R2C: + N2

[O] R2C=O + NH3

R

N

+ ClNH2

R

N

For other methods – see M & W p 28

Reactions R2C: + Nu-H → R2CHNu

1) With nucleophiles

H RNH2

+

:CCl2

- HCl

R N CCl2

R N C

H

R2C: + H-CR3 → R2CH-CR3

2) Insertion into C-H bonds

2 mechanisms are possible, depending whether a singlet or triplet carbene is involved Singlet mechanism X R2C: +

X

one-step

H

R2CH

concerted

ZY

H

via

R2C

ZY

Triplet mechanism

..

R2C

X

X

+ H

R2CH

ZY

+ ZY

H abstraction coupling

.

R2CH

+

X

.

Y Z

X R2CH

racemic mixture

YZ

X ZY

3) Cycloaddition to alkenes Again, 2 mechanisms are possible, depending whether a singlet or triplet carbene is involved R R2C: +

X2C CX2

R

X

X X

X

Singlet mechanism Me R2C: +

H

one step

R

concerted

Me

R

H

Me Me

Triplet mechanism

..

R2C

Me

Me

R

+

+

R

Me

R R

Me

Me Me ( + enantiomer )

couple

radical addition

couple H

.

Me

Me

.

R2C

.

H

.

H Me

R2C

H Me

Synthetic applications of carbene cycloaddition reactions; eg

N

via

CH: N

from

CH=N-NH-Tos N

4) Cycloaddition to arenes eg

:CHCO2Et

H CO2Et norcaradiene

H CO2Et

By-products from carbene reactions

Ph2CN2

eg

eg “dimer” formation Ph2CH

- N2

+

+

Ph2C=CPh2

- N2 :CPh2

R

CPh2 Ph

C N N R

NITRENES

RN:

N N Ph

[ M & W ch 4 ]

Structure & Reactivity Nitrogen atom has 6 e, including 4 non-bonded; therefore singlet and triplet states possible sp triplet

R

N

:

R N

: :

sp2 singlet

As for carbenes π-donor groups stabilise the singlet, and influence reactivity

:

N N:

:

:

N N:

Generation 1) From azides

or hν

2) From isocyanates heat RN C O

or hν

RN:

+

CO

:

heat

R N N N

R N N N

R N: + N2

3) By α-elimination reactions

eg

H EtO2C N OSO2Ar

R N:

R N X

X

base

:

R N

:

base

H

eg

EtO2C N:

O [O]

N N:

N N:

O

:

:

:

N NH2

O

:

:

eg

O

O

O

For other methods – see M & W p 52

Reactions Nitrenes are transient species and must be generated in situ in the presence of the co-reactant Their reactions are similar to those of carbenes 1) Insertion into C-H bonds

very similar to corresponding reaction of carbenes H R N CR3

:

R N:

+

H CR3

RN3

+

eg

Singlet mechanism

NHR

heat or hν

X

X :

:

R N:

+

H

RHN

C

C YZ

YZ

Triplet mechanism

X

X H

C

RNH

+

X

YZ

:

+

:

:

R N:

Z Y

RNH

C YZ

racemic mixture

2) Cycloaddition to alkenes

very similar to corresponding reaction of carbenes X X

:

R N: +

X2C CX2

aziridines

R N X X

Mechanisms:

singlet

1-step & stereospecific

triplet

2-steps & non-stereospecific

H eg

EtO2C N3

Me

heat

+ H

EtO2C

- N2

Me

H Me Me H

Me

eg

heat - N2

R N

EtO2C

:

Ar N3

2 steps

Me Me

ARYNES

Me

Me

Ar N N N

Me

heat - N2

Me Me

[ M & W ch 5 ]

Benzyne

C6H4 (didehydrobenzene)

Structure ortho-benzyne (1,2-didehydrobenzene)

singlet

singlet diradical

meta- & para-benzynes

or

triplet diradical

(1,3- & 1,4-didehydrobenzenes)

or

Generation 1) via aryl anions X

-X

- Br Br

Br

KNH2

eg H

2) via zwitterions X

-X

Y

-Y - N2

NH2

- CO2 N2

HONO

eg CO2

CO2H

3) Fragmentation of cyclic systems X

heat or hν

Y Z

- XYZ hν

O

heat - 2 CO2

O O

eg

- CO - CO2 O O

- 2 N2

O

O

N N

1 aminobenzotriazole

N N N N: :

N NH2

[O]

Evidence 13

C and 14C isotopic labelling experiments Cl

NH2

NH3

KNH2

+

H

NH2

Trapping experiments – see Reaction 2 below Detection by spectroscopic methods (matrix isolated)

Reactions 1) Nucleophilic addition reactions Arynes are electrophilic and react with readily with nucleophiles. Nu

Nu

H2O

Nu H

where Nu = OH, OR, SR, RNH, RCO2

2) (2 + 4) Cycloadditions to 1,3-dienes An example of a Diels-Alder reaction; for an introduction to Diels-Alder reactions, see McMurry p 536 and Clayden ch 35. eg dienophile

eg

75%

+

(a 1-step concerted process) diene

+

ie

3) (2 + 2) Cycloaddition to alkenes +

eg

(not concerted)

OEt

+ O Et

OEt

3) Ene additions to alkenes H

H

R

R [ see M & W pp 83 ]

(concerted)

4) 1,3-Dipolar cycloaddition reactions O N C R

[ see Heterocyclic Chemistry course – 2nd semester ] O N

(concerted)

[ see M & W pp 84 ]

R

Synthetic Applications For examples of arynes in the synthesis of natural products and analogues, see M & W p 85 and Comprehensive Organic Synthesis Vol IV ch 2.3