REACTIVE INTERMEDIATES

DR. R.M. PATON 5 LECTURES

AIMS
1. To demonstrate the concept of reactive intermediates in organic chemistry by a general
overview of evidence for their structure and their reactivity.
2. 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. A general knowledge of the generation, detection and structure of important classes of
neutral reactive intermediates, eg radicals, carbenes, nitrenes and arynes.
2. An understanding of the reactivity of radicals, carbenes, nitrenes and arynes.
3. 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. General Text
Clayden, Greeves, Warren & Wothers “Organic Chemistry”, Oxford 2000.
2. 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.

k1 k2
starting material intermediate 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:

- Br- Nu-
R3C Br R3 C+ R3C Nu

H
E
E+ - H+
E

etc

This course concentrates on neutral reactive intermediates

Table Relationship between reactive intermediates [M&W p2]

C N O
-onium ion R5C+ R4N+ R3O+
carbonium ion ammonium ion oxonium ion
neutral molecule R4C R3N R2O
hydrocarbon Amine ether
anion R3C- R2N- RO-
carbanion amide anion alkoxide
radical . . .
R3C R2N RO
carbon radical aminyl radical oxyl radical

-enium ion R3C+ R2N+ RO+

carbenium ion nitrenium ion oxenium ion
-ene R2C: RN: :O:
carbene nitrene oxene
Various other neutral reactive intermediates; eg

H
H
H C6H4
H

cyclooctyne (Z)- cycloheptene (E)- cycloheptene benzyne

( strained ) ( unstrained ) ( 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

Eg RC≡N+−O- nitrile oxides RC≡N+−S- nitrile sulfides

Some other examples are more stable

Eg O=O+−O- ozone 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 see table below

Peroxides RO−OR

O O
eg O Ph heat or hν
Ph O 2 Ph O
O 80 °C

dibenzoyl peroxide
 eg Me3C O heat
O CMe3 2 Me3C O
100°C
di-t-butyl peroxide

Azo compounds
Me
Me heat Me CN
eg N CN
NC N N2 + 2
Me 80 °C Me
Me

azobisisobutyronitrile "AIBN"

2. Photochemical cleavage of covalent bonds

hν
Halogens X X 2X where X = Cl, Br, I

O hν O
Ketones eg + Me
Me Me Me

3. Electron transfer reactions

eg RO-OH + Fe2+ RO + OH- + Fe3+

-e
eg RCO2 RCO2

Radical ion formation

-e +e
eg C10H8 C10H8

radical naphthalene radical

cation C10H8 anion

e removed e added
from HOMO to LUMO

EPR evidence for both radical ions

Table Bond dissociation energies energy (kJ mol-1) to break bond homolytically

C−H bonds
HC≡C−H 522 Ph−H 468 H2C=CH−H 451
CH3−H 435 MeCH2−H 410 Me2CH−H 397
H2C=CHCH2−H 364 PhCH2−H 355 MeCOCH2−H 410
HOCH2−H 401 MeCO−H 364

C−C & C−X bonds

HC≡CH 836 H2C=CH2 635 H3C−CH3 368
MeCH2−CH3 355 Me3C−CH3 339 PhCH2−CH3 301
MeCH2−Cl 339 MeCH2−Br 284 MeCH2−I 222
Cl3C−Cl 284 Cl3C−Br 226 MeCH2−OH 380

X−X & X−Y bonds

Cl−Cl 242 Br−Br 192 l−I 150
HO−OH 213 ButO−OBut 155 AcO−OAc 125
Me3Sn−Br 226

H−H & H−X bonds

H−H 435 F−H 568 Cl−H 431
Br−H 368 I−H 297 HO−H 497
HOO−H 376 H2N−H 431 MeO−H 426
Me3Sn−H 310

Types of Radical Reaction

1. Radical-radical reactions

(a) Combination (or coupling)

R + R' R R'

(b) Disproportination

H3C CH2 H3C CH2

CH H2 C H2
H + C
H C H3C CH3
H2C CH3

2. Radical-molecule reactions

(a) Abstraction (or transfer)

eg Cl + H CH3 Cl H + CH3

ease of H-abstraction: benzylic/allylic/aldehydic > aliphatic > alkynic/alkenic/aromatic

likewise for halogen abstraction
 (b) Addition to multiple bonds

H2
eg RO + H2C CH2 C
RO CH2

3. Unimolecular radical reactions

(a) Fragmentation (or β-scission)

O
heat
eg Ph + CO2
Ph O

Me Me
heat
eg Me O O + Me
Me Me

(c) Rearrangement

eg Ph3C CH2 Ph2C CH2Ph

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

H H a π-radical e localised, therefore reactive and short-lived

Methyl CH3
H
Phenyl Ph sp2 a σ-radical
or C6H5
e localised, therefore reactive and short-lived

CH2 CH2
Benzyl PhCH2 H
etc
a π-radical H

likewise for Ph O and Ph NR

But

more stable than Ph for steric reasons

But

. . . .
In summary, alkyl radicals are usually short-lived: Me3C > Me2CH > MeCH2 > CH3

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
O2 Ph3COOCPh3

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 Non-symmetrical dimer isolated

H H
CPh2 structure proved
Ph3C + CPh2 by NMR
Ph3C
 . .
(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

[O]
PhOH PhO various dimers C12H10O2

O O O

H etc

Mechanism for dimer formation

OH
OH

[O] OH
PhOH OH + + +
HO
OPh

+ o-isomer
OH
OH

tautomerism

H O etc etc etc

PhO O H

likewise for phenol itself

OH O
H
H
H
PhOOPh (weak O-O bond)

hindered phenoxyls are more persistent – dimerisation impeded

 OH O O
But But But But But But
[O]
etc

But
But But

Oxidation of amines

[O]
eg Ph2NH Ph2N Ph2N NPh2

etc

• delocalisation of e over 2 aryl rings

• weak N−N bond in dimer

Stabilisation by adjacent heteroatoms

Ar Ar
eg hydrazyls
:

: :

N NHAr N NAr
:

Ar Ar

delocalisation of e over 3 Ar rings

R R
:

: :

eg nitroxyls N O: N O:
:

R R

Radical Chain Reactions

3 phases initiation propagation termination

Examples from previous courses

Halogenation of alkanes [ McMurry V p 361 VI p 320 ]

hν
eg CH4 + Cl2 HCl + CH3Cl etc
Peroxide-induced addition of HX to alkenes [ March p 571 ]

peroxide
eg RCH CH2 + HBr 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
heat
eg PhCO2O-OCOPh PhCO2 Ph + CO2
or hν

heat
eg NCCMe2-N=N-CMe2CN NCCMe2 + N2
AIBN or hν

in general Initiator R
then R + CH2=CHX RCH2CHX

Propagation
CH2=CHX n CH2=CHX
RCH2CHX RCH2CHXCH2CHX R(CH2CHX)nCH2CHX

NB "head-to tail" addition

Termination
coupling product

CH2CHX CH2-CHX-CHX-CH2

CH2CHX
CH2CH2X + CH=CHX

disproportination products
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

. .
i) Termination: eg R + R → R-R
. .
R + ROO → ROOR
.
2 x ROO → ROOR + O2

Examples:

a) Alkylarenes

H Me CH2OOH
Me2C-OOH CHMe2 CH
Me C Me
O2
+ +

CH3 CH2OOH CH3

CH3

statistically expect 10% 30 % 60 %

observe 80% 20 % 0%

O2 OOH
b) Ethers Et2O polymeric products
CH
EtO Me
:
: :

via EtO CHMe EtO CHMe

:

O2
c) Alkenes eg OOH via

c) Unsaturated lipids [ Perkins p 71 ]

RO
eg linoleate esters
O
Antioxidants eg hindered phenols

OH
O
.
Me3C CMe3
+ R
. RH +
Me3C CMe3

Me
Me

Me3C
O
CMe3 ROO
. Me3C
O
CMe3

.
Me OOR Me

.
• ArO Detected by EPR spectroscopy

• Both R and ROO radicals removed

Functional Group Transformations

1) Reduction of alkyl halides (RBr & RI)

AIBN
RBr + Bu3SnH RH + Bu3SnBr
heat

Mechanism a radical chain process

Initiation
heat
NCCMe2-N=N-CMe2CN NCCMe2 + N2
AIBN or hν

abstraction
NCCMe2 + Bu3SnH NCCHMe2 + Bu3Sn

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

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

Bu3Sn + RBr Bu3Sn-Br + R

R + Bu3Sn-H RH + Bu3Sn
 . .
Termination radical couplings involving R and / or Bu3Sn etc

RX Bu3SnX

initiation
Bu3SnH + AIBN Bu3Sn R

RH Bu3Sn

2) Carbon-carbon bond formation

AIBN
eg R X + + Bu3SnH R + Bu3SnX
W W
heat

[ W e-withdrawing ]

RX Bu3SnX

R + W

initiation
Bu3SnH + AIBN Bu3Sn

R
W

RH Bu3Sn

Br Bu3SnH CN
eg + CN
AIBN

3) Intramolecular reactions for ring synthesis [ M & W p 18 ]

Br AIBN
eg + +
+ Bu3SnH

12:1 reactant ratio 17% 81% 2%

use low [BuSn3H] to

minimise hexene formation kinetic product
eg macrocyle synthesis

O O O
Bu3SnH
O O O
+
AIBN (CH2)14
(CH2)12I (CH2)12CH3

4) Homolytic aromatic substitution

eg PhCO2OCOPh + PhH → Ph-Ph + CO2

Mechanism:

heat
PhCO-O-O-COPh PhCO2 Ph + CO2

H
Ph
. H . "-H"
Ph
Ph

H
Ph etc
.
H

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

Ph N N
+e
Ph N N
.
Ph + N2
PhNH2
NaNO2
HCl Cuo 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)

Cuo HONO
eg
N2+ 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

:
Carbenes C: Nitrenes R N:
R

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 R

sp2 singlet (bent) sp2 triplet (bent) 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 : Cl
C: C:
:

Cl 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
N: N
C: C: etc
:

N: N:
R R
:

also carbon monoxide :O C: :O C:

:

and isonitriles RN 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 R 100 °C R
C N N C N N C: + N2
R R or hν R
[M]
- N2
M = eg Rh, Cr R
eg Rh2(OAc)2 C [M] carbene products
R
metallocarbene
alkylidene complex

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

heat [O]
R2C O + H2NNH2 R2C N NH2 R2C N N
- H2O

Bamford-Stevens method via tosylhydrazones

- H2O H base
R2C O + H2NNHTos R2C N N Tos R2C N N Tos

- Tos
products R2C N N R2C N N Tos

2) From ketenes

heat
R2C C O R2C: + CO
or hν

3) By α-elimination reactions

R X - XY
C R2C:
R Y

Ph H base Ph - Br-
:

eg C C PhCBr
Br Br Br Br

PhHg Cl heat
eg C PhHgBr + Cl2C:
Br Cl
4) By ring cleavage reactions

O
Ph hν

:
eg epoxides Ph PhCH + PhCH=O
H H

R N hν
eg diazirenes R2C: + N2
R N

[O]

R2C=O + NH3 R N

+ ClNH2 R N

For other methods – see M & W p 28

Reactions

1) With nucleophiles R2C: + Nu-H → R2CHNu

H
- HCl
RNH2 + :CCl2 R N CCl2 R N C
H

2) Insertion into C-H bonds R2C: + H-CR3 → R2CH-CR3

2 mechanisms are possible, depending whether a singlet or triplet carbene is involved

Singlet mechanism

X X X
one-step H
R2C: + H R2CH via
concerted R2C
ZY ZY ZY

Triplet mechanism

X X X
..
R2C + H R2CH + R2CH
ZY ZY YZ

H abstraction
racemic
coupling mixture
. . Y
R2CH + X
Z
3) Cycloaddition to alkenes

Again, 2 mechanisms are possible, depending whether a singlet or triplet carbene is involved

R R

R2C: + X2C CX2

X X

X X

Singlet mechanism

H
Me one step R Me
R2C: +
concerted R
Me Me
H

Triplet mechanism

Me Me Me
.. R R
R2C + +
Me R Me R Me
( + enantiomer )
radical couple
addition
couple

H . Me
Me . H
. .
R2C H R2C H
Me
Me

Synthetic applications of carbene cycloaddition reactions; eg

via CH: from CH=N-NH-Tos

N N N

4) Cycloaddition to arenes

H H
eg :CHCO2Et
CO2Et CO2Et

norcaradiene
By-products from carbene reactions eg “dimer” formation

- N2 Ph2CH
eg Ph2CN2 + + Ph2C=CPh2

- N2

:CPh2 CPh2
R
C N N Ph N N
R Ph

NITRENES RN: [ M & W ch 4 ]

Structure & Reactivity

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

sp2 singlet R N sp triplet

: :

R N
:

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

N N: N N:
:

Generation
1) From azides

heat
:

R N N N R N N N R N: + N2
or hν

2) From isocyanates

heat
RN C O RN: + CO
or hν
3) By α-elimination reactions

H base

:
eg R N R N X R N:
X

H base

:
eg EtO2C N OSO2Ar EtO2C N:

O O O

eg [O]
:

:
N NH2 N N: N N:
:

:
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: + H CR3 R N CR3

heat NHR
eg + RN3
or hν

Singlet mechanism
X X
:

R N: + H C RHN C
YZ YZ

Triplet mechanism
X X
Z
:

R N: + H C RNH + X RNH C
Y
:
:

YZ YZ

racemic mixture

2) Cycloaddition to alkenes very similar to corresponding reaction of carbenes

X
X
:

R N: + X2C CX2 R N aziridines

X
X
 Mechanisms: singlet 1-step & stereospecific
triplet 2-steps & non-stereospecific

H Me H
heat Me
eg EtO2C N3 + EtO2C
H Me - N2 Me
H

Me

Me Me
heat
eg Ar N3 R N EtO2C
- N2
:
2 steps
Me
Me
heat
Me Ar
Me - N2
N
N
N Me

ARYNES [ M & W ch 5 ]

Benzyne C6H4 (didehydrobenzene)

Structure

ortho-benzyne

(1,2-didehydrobenzene)

singlet singlet diradical triplet diradical

meta- & para-benzynes (1,3- & 1,4-didehydrobenzenes)

or or
Generation

1) via aryl anions

X -X

- Br

Br Br
KNH2
eg
H

2) via zwitterions

X -X

Y -Y

- N2 - CO2

NH2 N2
HONO
eg
CO2H CO2

3) Fragmentation of cyclic systems

X heat or hν
Y
Z - XYZ
- CO
hν heat - CO2
O - 2 CO2
O
O
eg
O O
- 2 N2
O O

N [O] N
N N
N N
NH2 N:
:

1 aminobenzotriazole
Evidence
13
C and 14C isotopic labelling experiments

Cl NH2
KNH2 NH3
+
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 H2O Nu
Nu

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.

75%
eg + (a 1-step concerted process)

dienophile diene

eg + ie

3) (2 + 2) Cycloaddition to alkenes

+ (not concerted)

OEt
eg +
O Et
OEt
3) Ene additions to alkenes

H R H R
[ see M & W pp 83 ]

(concerted)

4) 1,3-Dipolar cycloaddition reactions [ see Heterocyclic Chemistry course – 2nd semester ]

O
N O
N [ see M & W pp 84 ]
C
R (concerted) 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