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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.
starting material intermediate product(s)k1 k2
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 R3C NuR3C+- Br- Nu-
E+H
E- H+ E
etc This course concentrates on neutral reactive intermediates Table Relationship between reactive intermediates [ M & W p 2 ] C N O
-onium ion R5C+
carbonium ion
R4N+
ammonium ion
R3O+
oxonium ion
neutral molecule R4C
hydrocarbon
R3N
Amine
R2O
ether
anion R3C-
carbanion
R2N-
amide anion
RO-
alkoxide
radical R3C.
carbon radical
R2N.
aminyl radical
RO.
oxyl radical
-enium ion R3C+
carbenium ion
R2N+
nitrenium ion
RO+
oxenium ion
-ene R2C:
carbene
RN:
nitrene
:O:
oxene
Various other neutral reactive intermediates; eg
cyclooctyne
C6H4
benzyne
H
HH
H
(Z)- cycloheptene (E)- cycloheptene
( strained ) ( strained )( unstrained ) 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
egPh
O
OO
O
Ph
dibenzoyl peroxide
heat or hνPh
O
O80 C°
2
eg Me3CO
OCMe3
di-t-butyl peroxide
heat
100 C°2 Me3C O
Azo compounds
egNC
Me
NN
Me
CN
azobisisobutyronitrile "AIBN"
heat
80 C°Me
MeN2 +
CN
Me
Me2
2. Photochemical cleavage of covalent bonds
X XHalogenshν
2 X where X = Cl, Br, I
Me
O
MeKetones hνeg
Me
O+ Me
3. Electron transfer reactions
eg RO-OH + Fe2+ RO + OH- + Fe3+
eg- e
RCO2RCO2
eg+ e
Radical ion formation
- eC10H8C10H8
radicalcation
radicalanion
naphthalene C10H8
e removedfrom HOMO
e addedto 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
+CH
CH2H3C
H2C
H2C
CH3
CH
CH2H3C
H3C
H2C
CH3H
2. Radical-molecule reactions
(a) Abstraction (or transfer) eg Cl H + CH3H CH3+Cl ease of H-abstraction: benzylic/allylic/aldehydic > aliphatic > alkynic/alkenic/aromatic
likewise for halogen abstraction
(b) Addition to multiple bonds
eg H2C CH2+RO RO
H2C
CH2 3. Unimolecular radical reactions
(a) Fragmentation (or β-scission)
eg +
+
Ph O
OPh CO2
eg OMeMe
Me
heat
heatO
Me
MeMe
(c) Rearrangement
eg Ph3C CH2 Ph2C CH2Ph 4. Electron transfer reactions
(a) Oxidation
R+R- e
(d) Reduction
RR+ e -
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
HHH e localised, therefore reactive and short-liveda π-radicalCH3Methyl
Ph
e localised, therefore reactive and short-lived
Phenylor C6H5
sp2 a σ-radical
HH
a π-radical
Benzyl
CH2 CH2
etc
likewise for Ph O and Ph NR
PhCH2
Ph
But
But
more stable than for steric reasons
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
2 Ph3CCl + 2 Ag 2 AgCl + Ph3C-CPh3 2 Ph3C
O2Ph3COOCPh3
Ph3CNONO
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
Ph3C CPh2H
+ CPh2H
Ph3Cstructure provedby 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]
PhO various dimers C12H10O2
etc
O O
H
O
H Mechanism for dimer formation
PhOH[O] OH
HOOH
OH OH
OH
+ + +
OH
OPh
+ o-isomer
PhO HOH O
tautomerism
etc etc etc
PhOOPh (weak O-O bond)
OH O
HH
H
likewise for phenol itself
hindered phenoxyls are more persistent – dimerisation impeded
etc
OH
But
ButBut[O]
O
But
ButButO
ButBut
But
Oxidation of amines
etc
[O]eg Ph2NH Ph2N Ph2N NPh2
• delocalisation of e over 2 aryl rings
• weak N−N bond in dimer
Stabilisation by adjacent heteroatoms
eg hydrazyls N NHArAr
Ar
:: N NAr
Ar
Ar
::
delocalisation of e over 3 Ar rings
eg nitroxyls N O:R
R
:: 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 ] eg CH4 + Cl2
hνHCl + CH3Cl etc
Peroxide-induced addition of HX to alkenes [ March p 571 ] eg + HBrRCH CH2
peroxideRCH2CH2Br
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-]-
eg
Initiation
PhCO2O-OCOPhheat
or hνPhCO2 Ph + CO2
egheat
or hν+ N2NCCMe2-N=N-CMe2CN
in general Initiator R
then R + CH2=CHX RCH2CHX
NCCMe2AIBN
CH2=CHXRCH2CHX
Propagation
RCH2CHXCH2CHXn CH2=CHX
R(CH2CHX)nCH2CHX
NB "head-to tail" addition Termination
CH2CHX
CH2CHX
CH2-CHX-CHX-CH2
coupling product
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
C
CH3
O2
CH3
CHMe2
CH2OOH
CH
CH3
++
Me CH2OOH
observe 80% 20 % 0 %
statistically expect 10% 30 % 60 %
MeMe
H Me2C-OOH
b) Ethers Et2OO2
CHEtO
OOH
Mepolymeric products
via EtO CHMe
:: EtO CHMe
::
c) AlkenesO2 viaeg OOH
c) Unsaturated lipids
eg linoleate esters RO
O
[ Perkins p 71 ]
Antioxidants eg hindered phenols
OHCMe3Me3C
Me
OCMe3Me3C
Me
OCMe3Me3C
Me
+ R.
RH +
.
.ROO
.OCMe3Me3C
Me OOR • ArO. Detected by EPR spectroscopy
• Both R and ROO radicals removed
Functional Group Transformations 1) Reduction of alkyl halides (RBr & RI)
RBr + Bu3SnH
AIBN
heatRH + Bu3SnBr
Mechanism a radical chain process Initiation
heat
or hν+ N2NCCMe2-N=N-CMe2CN NCCMe2
AIBN
NCCMe2 + Bu3SnHabstraction
NCCHMe2+ Bu3Sn
[ NB weak Sn-H bond (~310 kJ mol-1) ] Propagation
+
Bu3Sn-H
Bu3Sn
[ strong Sn-Br bond (~550 kJ mol-1) ]
RBr + R
+ +RHR Bu3Sn
Bu3Sn-Br
Termination radical couplings involving R. and / or Bu3Sn
. etc
AIBN+initiation
Bu3SnH
RX Bu3SnX
Bu3Sn
RH Bu3Sn
R
2) Carbon-carbon bond formation eg R X W+ + Bu3SnH
AIBN
heatR
W + Bu3SnX
[ W e-withdrawing ]
W
RW
AIBN+initiation
Bu3SnH
RX Bu3SnX
Bu3Sn
RH Bu3Sn
R +
AIBN
Bu3SnHeg
Br
CN+CN
3) Intramolecular reactions for ring synthesis [ M & W p 18 ]
AIBN
+ Bu3SnH+eg
Br+
12:1 reactant ratio 17% 81% 2%
kinetic productuse low [BuSn3H] tominimise hexene formation
eg macrocyle synthesis
AIBN
Bu3SnH+
O
O
O
O
(CH2)14(CH2)12I
O
O
(CH2)12CH3 4) Homolytic aromatic substitution eg PhCO2OCOPh + PhH → Ph-Ph + CO2
Mechanism:
Ph.
PhCO-O-O-COPhheat
PhCO2 Ph + CO2
HPh
H. " - H " Ph
HPh
H. etc
similarly for Ph radical generated from other sources, eg thermolysis of Ph-N=N-CPh3 and
Ph. + N2PhNH2 NaNO2
HCl
N NPh+ e
Cuo Cu+
Ph N N
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
N2+ NH2
HONOeg
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
RC:
RRCarbenes Nitrenes 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
RR 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
ClC:
Cl
:::
ClC:
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
:
N:C:
N:R
RN:
C:NR
R
etc
:O C:
:
also carbon monoxide
and isonitriles
:O C:
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
C N NR
RC N N
R
R
100 °C
or hνC: + N2
R
R
C [M]R
Rcarbene products
[M]- N2
M = eg Rh, Cr
eg Rh2(OAc)2
metallocarbenealkylidene complex
Diazo compounds are good source of carbenes because they can be prepared readily or generated in situ.
R2C N N[O]
R2C N NH2heat
- H2OR2C O + H2NNH2
Bamford-Stevens method via tosylhydrazones
R2C N N
baseR2C N
HN
- H2OR2C O + H2NNHTos Tos R2C N N Tos
R2C N N Tos- Tos
products
2) From ketenes
R2C C Oheat
or hνR2C: + CO
3) By α-elimination reactions
- XYC
XRYR
R2C:
baseC
HPhBrBr
eg CPh
BrBrPhCBr
:
heatC
ClPhHgClBr
eg PhHgBr + Cl2C:
- Br-
4) By ring cleavage reactions
OPhPhHH
hνPhCH + PhCH=O
:
eg epoxides
N
N hνR2C: + N2eg diazirenes
R
R
N
NR
R
[O]
R2C=O + NH3
+ ClNH2 For other methods – see M & W p 28 Reactions 1) With nucleophiles R2C: + Nu-H → R2CHNu
N CRCCl2NR
H
H
- HClRNH2 + :CCl2
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
+R2C: HX
YZ
one-stepR2CH
X
YZ
viaX
YZ
H
R2Cconcerted
Triplet mechanism
+R2C HX
YZ
R2CHX
YZ
.. R2CHX
ZY
+
R2CH.
+ XZY.
H abstractioncoupling
racemicmixture
3) Cycloaddition to alkenes
Again, 2 mechanisms are possible, depending whether a singlet or triplet carbene is involved
+R2C:
R R
X
X
X
X
X2C CX2
Singlet mechanism
+R2C:Me
Me
R
R
Me
Me
H
H
one step
concerted
Triplet mechanism
+R2C..
Me
Me
R
R
Me
Me
R
R
Me
Me+
( + enantiomer )
Me
R2C
MeH
H ..
radical addition
couple
H
R2C
MeH
Me ..
couple
Synthetic applications of carbene cycloaddition reactions; eg
N NCH:
NCH=N-NH-Tosfromvia
4) Cycloaddition to arenes
:CHCO2EtH
CO2Et
norcaradiene
HCO2Et
eg
By-products from carbene reactions eg “dimer” formation
eg Ph2CN2 +- N2
Ph2CH+ Ph2C=CPh2
C N NR
R:CPh2
PhPh
CPh2
N N
- N2
NITRENES RN: [ M & W ch 4 ] Structure & Reactivity Nitrogen atom has 6 e, including 4 non-bonded; therefore singlet and triplet states possible
NR
::sp2 singlet R N :sp triplet
As for carbenes π-donor groups stabilise the singlet, and influence reactivity
N N:::
N N::
Generation 1) From azides
N N NN N Nheat
or hνR R R N:
:
+ N2
2) From isocyanates
RN C Oheat
or hν+ CORN:
3) By α-elimination reactions
:baseN
eg
eg
RH
Xeg NR X
:
R N:
EtO2CHN OSO2Ar
:
EtO2C N:base
N
O
O
NH2[O]
N
O
O
N::
:: N
O
O
N::
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
eg
:
R N: + H CR3HN CR3R
+ RN3heat
or hν
NHR
Singlet mechanism
::
R N: +X
CH
Y Z
XCRHN
Y Z
Triplet mechanism
:
:R N: +X
CH
Y Z
XCRNH
Y Z
: + XYZRNH
racemic mixture 2) Cycloaddition to alkenes very similar to corresponding reaction of carbenes
:
R N: N
XX
XX
X2C CX2+ R aziridines
Mechanisms: singlet 1-step & stereospecific
triplet 2-steps & non-stereospecific
eg +EtO2C N3
Me
MeEtO2C
heat
- N2
Me
Me
H
H
H
H
:eg R NAr N3 EtO2Cheat
- N2 2 steps
Me
Me
NN
NAr
Me
Me
Me
Me
heat- N2
Me
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
egBr
H
KNH2Br
- Br
2) via zwitterions
X - X
NH2
CO2H
N2
- CO2
Y - Y
CO2
- N2
HONOeg
3) Fragmentation of cyclic systems
- 2 CO2
- XYZ
eg
ZY
X heat or hν
OO
O
O
hν
O
O
O
heat
- CO - CO2
NN
N
N::
- 2 N2
[O]
NN
N
NH2
1 aminobenzotriazole
Evidence 13C and 14C isotopic labelling experiments
Cl
H
KNH2 NH3NH2
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.
75%+
dienophile diene
+eg
eg
ie
(a 1-step concerted process)
3) (2 + 2) Cycloaddition to alkenes
+
+egO
(not concerted)
Et
OEt
OEt
3) Ene additions to alkenes
(concerted)
[ see M & W pp 83 ]H R H R
4) 1,3-Dipolar cycloaddition reactions [ see Heterocyclic Chemistry course – 2nd semester ]
(concerted)
[ see M & W pp 84 ]
ONCR
NO
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