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REACTIVE INTERMEDIATES DR. R.M. PATON 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. 5 LECTURES

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.

INTRODUCTIONMany 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 C+ NuR3C Nu

H E+ E - H+

E

etcThis course concentrates on neutral reactive intermediates Table Relationship between reactive intermediates C -onium ion neutral molecule anion radical R5C+ carbonium ion R4C hydrocarbon R3Ccarbanion R3C.

[M&W p2] N R4N+ O R3O+ oxonium ion R2O ether ROalkoxide RO.

ammonium ion R3N Amine R2Namide anion R2N.

carbon radical -enium ion -ene R3C+ carbenium ion R2C: carbene

aminyl radical R2N+ nitrenium ion RN: nitrene

oxyl radical RO+ oxenium ion :O: oxene

Various other neutral reactive intermediates; egH H H

H

C6H4

cyclooctyne( strained )

(Z)- cycloheptene (E)- cycloheptene( unstrained ) ( strained )

benzyne

1,3-Dipoles are class of neutral reactive intermediates with considerable synthetic potential. A=B+C- A+BC- AB+C- A+=BC- Eg RCN+O- nitrile oxides etc etc RCN+S- nitrile sulfides

Some other examples are more stable Eg O=O+O- ozone NN+O- nitrous oxide NN+N-R azides

Evidence for short-lived intermediates Kinetics & isotopic labelling Matrix isolation experiments Spectroscopy eg in N2 or Ar at ~20 K IR, UV Flash photolysis / UV EPR ( ESR) for paramagnetic species (radicals)

RADICALS Methods of Generation1. Thermal cleavage of covalent bonds Require bond dissociation energy < 160 kJ mol-1 Peroxideseg

see table below

ROORO Ph O O O dibenzoyl peroxide Ph heat or h 80 C O

2

Ph

O

eg

Me3C

O

O

heat CMe3 100 C

2 Me3C O

di-t-butyl peroxide

Azo compoundseg Me NC Me N N CN Me Me heat 80 C Me CN Me

N2

+

2

azobisisobutyronitrile "AIBN"

2. Photochemical cleavage of covalent bondsHalogens X X h 2X where X = Cl, Br, I

Ketones

eg Me

O Me

h Me

O + Me

3. Electron transfer reactionseg eg RO-OH + RCO2 Fe2+ -e RCO2 RO + OH+ Fe3+

Radical ion formation eg C10H8 radical cation e removed from HOMO EPR evidence for both radical ions -e +e C10H8 radical anion e added to LUMO

naphthalene C10H8

Table Bond dissociation energies CH bonds HCCH CH3H H2C=CHCH2H HOCH2H 522 435 364 401

energy (kJ mol-1) to break bond homolytically

PhH MeCH2H PhCH2H MeCOH

468 410 355 364

H2C=CHH Me2CHH MeCOCH2H

451 397 410

CC & CX bonds HCCH MeCH2CH3 MeCH2Cl Cl3CCl 836 355 339 284 H2C=CH2 Me3CCH3 MeCH2Br Cl3CBr 635 339 284 226 H3CCH3 PhCH2CH3 MeCH2I MeCH2OH 368 301 222 380

XX & XY bonds ClCl HOOH Me3SnBr 242 213 226 BrBr ButOOBut 192 155 lI AcOOAc 150 125

HH & HX bonds HH BrH HOOH Me3SnH 435 368 376 310 FH IH H2NH 568 297 431 ClH HOH MeOH 431 497 426

Types of Radical Reaction1. Radical-radical reactions (a) Combination (or coupling)R + R' R R'

(b) DisproportinationH3C CH2 H2C H3C CH3 CH2 + H3C H2 C

CH H

H2 C

C H

CH3

2. Radical-molecule reactions (a) Abstractioneg Cl +

(or transfer)H CH3 Cl H + CH3

ease of H-abstraction:

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

likewise for halogen abstraction

(b) Addition to multiple bondseg RO + H2C CH2 H2 C

RO

CH2

3. Unimolecular radical reactions (a) FragmentationO eg Ph Me Me Me O O

(or -scission)heat Ph + CO2

eg

heat

Me O Me + Me

(c) Rearrangementeg Ph3C CH2 Ph2C CH2Ph

4. Electron transfer reactions (a) OxidationR -e R+

(d) ReductionR +e R

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

Reactivity, Stability & Lifetimes of RadicalsMost 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 ExamplesMethyl CH3 H H H a -radical e localised, therefore reactive and short-lived

Phenyl

Ph or C6H5

sp2

a -radical

e localised, therefore reactive and short-lived

CH2 Benzyl PhCH2 a -radical likewise forBut more stable than Ph But.

CH2 etc

H H Ph O and Ph NR

for steric reasons

In summary, alkyl radicals are usually short-lived:

Me3C > Me2CH > MeCH2 > CH3

.

.

.

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

Persistent Carbon RadicalsHistorical perspective: 1900 GombergO2 2 Ph3CCl + 2 Ag 2 AgCl + Ph3C-CPh3.

eg

triphenylmethyl Ph3C

.

Ph3COOCPh3 NO Ph3CNO

2 Ph3C

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

C

C

etc

steric factors inhibit dimerisation to (Ph3C)2 Non-symmetrical dimer isolated+ H H CPh2 Ph3C CPh2 structure proved by NMR

H

1968Ph3C

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

.

.

eg Kolsch's radical 1932-1957

Persistent Oxygen & Nitrogen RadicalsOxidation of phenolsPhOH [O] PhO various dimers C12H10O2

O

O H

O etc H

Mechanism for dimer formation

OH

OH + OPh

PhOH

[O] HO

OH

+

OH

+

OH tautomerism

+ o-isomer OH

PhO

O

H

H

O

etc

etc

etc likewise for phenol itself OH H O H H

PhOOPh

(weak O-O bond)

hindered phenoxyls are more persistent dimerisation impeded

OH But But [O] But

O But But But

O But etc

But

But

Oxidation of amineseg Ph2NH [O] Ph2N Ph2N NPh2

etc

delocalisation of e over 2 aryl rings weak NN bond in dimer

Stabilisation by adjacent heteroatomsAr eg hydrazyls Ar N : NHAr Ar : Ar : : N NAr

delocalisation of e over 3 Ar rings

R : eg nitroxyls R N O: :

R : : N R O:

Radical Chain Reactions3 phases Examples initiation propagation termination

from previous courses [ McMurry V p 361 VI p 320 ]h HCl + CH3Cl etc

Halogenation of alkaneseg CH4 + Cl2

Peroxide-induced addition of HX to alkeneseg RCH CH2 + 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-]-

Initiationeg PhCO2O-OCOPh heat or h heat or h PhCO2 Ph + CO2

eg

NCCMe2-N=N-CMe2CN AIBN Initiator R +

NCCMe2

+ N2

in general then

R CH2=CHX RCH2CHX

PropagationRCH2CHX CH2=CHX RCH2CHXCH2CHX n CH2=CHX R(CH2CHX)nCH2CHX

NB "head-to tail" addition

Terminationcoupling 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: