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 \u201cOrganic Chemistry\u201d, 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
k2
intermediate
product(s)
In general, reactive intermediates correspond to a shallow dip on the reaction profile. ie k2 > E2k1 In most cases \u2206E2 < \u2206 [ for diagram \u2013 see M & W p1 ] Examples from earlier courses include: R3C
- Br
Br
-
-
Nu
+
R3C
R3C
Nu
H +
E
+
E
E
-H
etc
This course concentrates on neutral reactive intermediates Table
Relationship between reactive intermediates
-onium ion
C
N
O
R5C+
R4N+
R3O+
ammonium ion
oxonium ion
R4C
R3N
R2O
hydrocarbon
Amine
ether
R3C-
R2N-
RO-
carbanion
amide anion
alkoxide
carbonium ion
neutral molecule anion radical
R3C
.
carbon radical
-enium ion
R3C+ carbenium ion
-ene
[M&W p2]
R2N
.
aminyl radical
R2N+ nitrenium ion
RO
.
oxyl radical
RO+ oxenium ion
R2C:
RN:
:O:
carbene
nitrene
oxene
Various other neutral reactive intermediates; eg H H
H
C6H4
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+\u2212C-
\ u 2 1 9 4
A\u2261B+\u2212C-
A+etc \u2212B\u2212C
etc A+=B\u2212C-
\ u 2 1 9 4
\u2194 \u2194
RC\u2261N+\u2212O- nitrile oxides RC\u2261N+\u2212S- nitrile sulfides
Eg
Some other examples are more stable O=O+\u2212O- ozone
Eg
+ N\u2261N+\u2212O- nitrousN oxide \u2261N \u2212N R azides
Evidence for short-lived intermediates \
u
2
0
2
2
Kinetics & isotopic labelling
\
u
2
0
2
2
Matrix isolation eg experiments in N2 or Ar at ~20 K
\
u
2
0
2
2
SpectroscopyIR, 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 RO\u2212OR
Peroxides
O eg
see table below
Ph
O
Ph
O O
dibenzoyl peroxide
heat or h\u03bd 80\u00b0 C
O 2
Ph
O
eg
Me3C
O
O
heat CMe3
2
100° C
di-t-butyl peroxide
Me3C O
Azo compounds Me
eg
Me
NC
N
heat
CN
N
Me Me
N2
80°C
+
2
azobisisobutyronitrile "AIBN"
2. Photochemical cleavage of covalent bonds Halogens
hν
X X
2X O
Ketones
eg
Me
where X = Cl, Br, I O
hν Me
+
Me
3. Electron transfer reactions eg
RO-OH
eg
RCO2
+
2+
Fe
-e
RO
+
-
OH
+
3+
Fe
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
CH2
H
H3C
H2 H2C
C
C H
CH2 +
CH3
H2 H3C
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 H2 +
RO
eg
H2C CH2
RO
C
CH2
3. Unimolecular radical reactions (a) Fragmentation O eg
heat
Ph
Ph
O
Me eg
(or β-scission)
Me
CO2
Me
heat
O
+
O
+
Me
Me
Me
(c) Rearrangement Ph2C CH2Ph
Ph3C CH2
eg
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 or
a σ-radical
sp2
Ph C6H5
e localised, therefore reactive and short-lived
CH2 Benzyl
PhCH2
CH2
H H
a π-radical likewise for
etc
Ph O
and
Ph NR
t
Bu
more stable than
Ph
for steric reasons
t
Bu
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 eg
Historical perspective:
triphenylmethyl Ph3C
.
1900 Gomberg 2 Ph3CCl + 2 Ag
Ph3COOCPh3
O2 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
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
H
etc
H
Mechanism for dimer formation
PhOH
[O]
OH HO
OH
OH
+
OH +
+
OPh OH
OH
+ o-isomer
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
But
[O]
But
But
But etc
But
But
t
Bu
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 eg
Ar
hydrazyls
Ar :
N
NHAr
:
N
:
Ar
NAr :
Ar
delocalisation of e over 3 Ar rings
R eg
nitroxyls
R
:
N
O:
:
N
:
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 RCH CH2
eg
+
HBr
peroxide
[ March p 571 ] 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
eg
NCCMe2-N=N-CMe2CN AIBN
Initiator
in general then
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
ii) Propagation:
R + O2
.
.
→
InH + R R-O-O
→
.
R-O-O + R-H eg R + R .
.
→
R + ROO .
R-O-O-H + R
→
.
i) Termination:
.
R-R
.
2 x ROO
→
.
ROOR
ROOR + O2
.
→
Examples: a) Alkylarenes H
Me2C-OOH
Me C Me
O2 CH3
statistically expect observe
b) Ethers
Et2O
via
CH3
10%
30 %
60 %
80%
20 %
0%
O2
OOH EtO
CH
EtO CHMe
O2
eg
eg
linoleate esters
[ Perkins p 71 ] RO O
polymeric products
Me
:
c) Unsaturated lipids
CH2OOH
CH2OOH
:
c) Alkenes
CH
+
+
CH3
Me
CHMe2
:
EtO CHMe :
OOH
via
eg hindered phenols
Antioxidants OH Me3C
O
CMe3
.
+
R
RH
.
Me3C
+
Me
CMe3
Me
O Me3C
O .
CMe3
Me3C
ROO
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
Mechanism
RH
heat
+
Bu3SnBr
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
+
+
RBr Bu3Sn-H
Bu3Sn-Br RH
+
+
R
Bu3Sn
Termination
radical couplings involving R and / or Bu3Sn etc .
.
RX
Bu3SnH
+
initiation
AIBN
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
CN
3) Intramolecular reactions Br
eg
+
W
Bu3Sn
CN
Bu3SnH +
eg
W
Bu3Sn
R
Br
+
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 Bu3SnH
O
O
AIBN
(CH2)12I
O
O O
+
(CH2)14
(CH2)12CH3
4) Homolytic aromatic substitution eg
PhCO2OCOPh
+ PhH
Ph-Ph + CO2
→
Mechanism: heat
PhCO-O-O-COPh
PhCO2 H
H
.
Ph
Ph
+
"-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
Ph
N N
HCl
.
Ph
Ph N N o
Cu
+
N2
+
Cu
thus providing a route to unsymmetrical biaryls eg
ArCO2OCOAr + PhH
→
[ no Ar-Ar formed ]
Ar-Ph
eg polycyclic aromatic hydrocarbons via intramolecular homolytic aromatic substitution (the Pschorr reaction)
o
eg
Cu
HONO 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)[see - Clayden p 1328 ] 2
CARBENES & NITRENES R
Carbenes
R
Nitrenes
C:
:
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 :
Cl
:
Cl
C:
:
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
N:
N
C:
:
N:
N:
R also carbon monoxide
R :
:O :
and isonitriles
etc
C:
C:
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
R C N N
R
[M] - N2
M = eg Rh, Cr eg
R
C N N
R
Rh2(OAc)2
100 °C
R
or hν
R
C: + N2
carbene products
C [M]
R 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 N N
via tosylhydrazones
- H2O
R2C O + H2NNHTos
[O]
R2C N NH2
products
base
H R2C N N Tos
R2C N N
R2C N N Tos
- Tos
R2C N N Tos
2) From ketenes heat R2C C O
R2 C:
or hν
+
CO
3) By α-elimination reactions R R
eg
eg
Ph Br PhHg Br
C
X
- XY
Y
C
H
C
Cl
base
Br
Cl
R2C:
Ph Br
heat
C
- BrBr
PhHgBr
+
Cl2C:
:
PhCBr
4) By ring cleavage reactions O
Ph
eg
epoxide s
eg
diazire nes
hν
Ph H
H
R
N
R
N
:
PhCH
hν
+
PhCH=O
R2C: + N2
[O] R2C=O + NH3
R
N
+ ClNH2
R
N
For other methods – see M & W p 28
Reactions 1) With nucleophiles
R2C: + Nu-H H
RNH2
+
R
:CCl2
N
R2CHNu
→
- HCl
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 R2C:
+
X
one-step
H
via
R2CH
concerted
ZY
H R2C
ZY
Triplet mechanism X
.
R2C
.
+
X
H
R2CH ZY
+
R2CH
ZY
H abstraction
coupling .
.
R2CH
X
+
X
Y Z
YZ
racemic mixture
X ZY
3) Cycloaddition to alkenes Again, 2 mechanisms are possible, depending whether a singlet or triplet carbene is involved R X2C CX2
+
R2C:
R
X
X X
X
Singlet mechanism Me R2C:
one step
+
R
concerted
Me
H
R
H
Me Me
Triplet mechanism Me .
R2C
.
Me
R
+
Me
R +
Me
R
R
Me Me ( + enantiomer )
couple
radical addition
couple H
.
Me
Me
.
H
.
R2C
.
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
H
CO2Et
CO2Et
norcaradiene
eg “dimer” formation
By-products from carbene reactions
+
Ph2CN2
eg
-
Ph2CH
N2
+
Ph2C=CPh2
-
:CPh2
R
CPh2 Ph
C N N
RN:
N
N
Ph
R
NITRENES
N2
[ 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 R
R
N N N
heat
N N N
or hν
2) From isocyanates heat RN C O
or hν
RN:
+
CO
:
R
N:
+
N2
3) By α-elimination reactions R N
eg
base
H
:
X base
H EtO2C N OSO2Ar
eg
R N:
R N X
:
EtO2C N:
O
O [O]
:
eg
N NH2
O :
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
:
R N:
+
R
H CR3
RN3
+
eg
Singlet mechanism +
H
or hν
X
X
Y
R N: :
+
H
:
RHN
C
Triplet mechanism
NHR
heat
:
R N:
H N CR3
C
Z
Y
Z
X
X RNH
C Y
:
+
:
Z Y
X
Z
RNH
C Y
Z
racemic mixture
2) Cycloaddition to alkenes
very similar to corresponding reaction of carbenes X X
:
R N:
+
X2C CX2
R
aziridines
N X X
Mechanisms:
singlet
1-step & stereospecific
triplet
2-steps & non-stereospecific
H eg
Me
heat
+
EtO2C N3
H
H Me EtO2C
- N2
Me
Me H
Me
Ar
eg
heat
N3
- N2
R N :
ARYNES
Ar N N N
EtO2C
2 steps
Me Me
Me
Me
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 eg
- CO2 N2
HONO
CO2
CO2H
3) Fragmentation of cyclic systems X Z
heat or hν
Y
- XYZ hν
O
heat
- 2 CO2
- CO - CO2 O
O
eg
O
O
- 2 N2
O
O
N
N
N NH2 1 aminobenzotriazole
[O]
N
N
N N: :
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
O
N C R
[ see Heterocyclic Chemistry course – 2nd semester ]
(concerted)
N
[ 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
