reactive intermediates_lectures

24
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.

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Page 1: reactive intermediates_lectures

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.

Page 2: reactive intermediates_lectures

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

Page 3: reactive intermediates_lectures

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

Page 4: reactive intermediates_lectures

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

Page 5: reactive intermediates_lectures

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

Page 6: reactive intermediates_lectures

(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

Page 7: reactive intermediates_lectures

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

Page 8: reactive intermediates_lectures

(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

Page 9: reactive intermediates_lectures

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

Page 10: reactive intermediates_lectures

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

Page 11: reactive intermediates_lectures

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 ]

Page 12: reactive intermediates_lectures

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

Page 13: reactive intermediates_lectures

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

Page 14: reactive intermediates_lectures

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

Page 15: reactive intermediates_lectures

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:

Page 16: reactive intermediates_lectures

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-

Page 17: reactive intermediates_lectures

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

Page 18: reactive intermediates_lectures

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

Page 19: reactive intermediates_lectures

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:

Page 20: reactive intermediates_lectures

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

Page 21: reactive intermediates_lectures

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

Page 22: reactive intermediates_lectures

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

O

O

O

heat

- CO - CO2

NN

N

N::

- 2 N2

[O]

NN

N

NH2

1 aminobenzotriazole

Page 23: reactive intermediates_lectures

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

Page 24: reactive intermediates_lectures

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