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CHAPTER 3

Radical Reactions: Part 1

A. J. CLARK, J. V. GEDEN, and N. P. MURPHY

Department of Chemistry, University of Warwick

Introduction

Rearrangements

Group Migration

β-Scission (Ring Opening)

Ring Expansion

Intramolecular Addition

Cyclization

Tandem Reactions

Radical Annulation

Fragmentation, Recombination, and Homolysis

Atom Abstraction Reactions

Hydrogen abstraction by Carbon-centred Radicals

Hydrogen Abstraction by Heteroatom-centred Radicals

Halogen Abstraction

Halogenation

Addition Reactions

Addition to Carbon-Carbon Multiple Bonds

Addition to -containing Multiple Bonds

Addition to -containing Multiple Bonds

1 Homolytic Substitution

Aromatic Substitution

SH2 and Related Reactions

Reactivity Effects

Polarity and Philicity

Stability of Radicals

Stereoselectivity in Radical Reactions

Stereoselectivity in Cyclization

Stereoselectivity in Addition Reactions

Stereoselectivity in Atom Transfer

Redox Reactions

Radical Ions

Anion Radicals

Cation Radicals

Peroxides, Peroxyl, and Hydroxyl Radicals

Peroxides

Peroxyl Radicals

Hydroxyl Radical

References

2

Introduction

Free radical chemistry continues to be a focus for research with a number of reviews being published in

2000. Green aspects of chemistry have attracted a lot of attention with most work conducted investigating , however on a review the use of supercritical fluids in radical reactions dealing solvent effects on chemical reactivity has appeared.1A The kinetics and thermochemistry of a range of free radical reactions has been reviewed. The review includes descriptions of the kinetics of a variety of unimolecular decomposition and isomerisation reactions as well as bimolecular hydrogen atom abstraction, additions, combinations and disproportionations. 204.

In synthetic applications a review on the hydroxylation of to phenol using Fenton’s reagent has appeared 254 as well as reviews on the synthesis of heterocycles using SRN1 mechansims279, and radical reactions controlled by Lewis Acids, 265. This latter review deals with effects of diastereoselectivity of reactions based upon size and chelation effects of the Lewis acids. The effect on radical cascade and rearrangement (Surzur-Tanner rearrangement) is also reported.

A range of symposia have appeared including the theoretical study of hydrogen atom substitution in aromatics, 245, kinetic and mechanistic studies on the reaction between hydroxyl radicals with trichloroethylene, 246, the kinetics of radical radical combination reactions of ethyl radicals, 247and a kinetic study on vinyl radical addition to chloroethene 248.

Two general reviews on the use of free radicals in have appeared with particular emphasis on inter- and intra-molecular addition reactions as well as stereoselectivity of reactions.

101,102. Continuing the theme of stereoselectivity the electronic factors governing the diastereofacial selectivity of the reactions of 5-substituted -2-adamantyl radicals has been reviewed. 103. Other reviews exploring the use of radicals in synthesis have included a review of the chemistry of acyl radicals (highlighting the properties, structure, decarbonylation, decarboxylation and synthetic utility of

3 acyl radicals) 104 and a comprehensive account of the use of radicals to prepare medium sized rings

(including cyclisation and ring expansion approaches). 105 The use of radical addition-cyclisation strategies towards the synthesis of ring systems has also been reviewed, with 106, 107 particular attention on the rearrangement and cyclisation of vinyl radicals promoted by radical addition to .107. The radical chemistry of sulphur has attracted more attention this year with reviews on the chemistry of aromatic thiyl radicals 108 and sulphur-centered reactive intermediates appearing 109.

Accounts of empirical correlational solvent effects 110 in radical reactions as well as radical reactions in supercritical fluids have appeared. 111, The important contempory areas of copper mediated atom transfer polymerisation 112 and polarity reversal catalysis 113 have been reviewed by Matyjaszewski and Roberts respectively.

Other reviews that have appeared this year include those on combination and disproportionation reactions, 114, theoretical models for addition and abstraction reactions, 115, homolytic addition reactions of dialkylaminyl radicals 116 and the chemistry of nitroarene and aromatic N-oxide radicals 117.

Rearrangements

Group Migration

The rearrangement of a range of β-(phosphatoxy) and β-(acyloxy)alkyl radicals (generated by laser flash photolysis) have been studies and the rate constants and kinetic parameters determined in a range of solvents. Migrations were found to be accelerated in polar solvents. Migrations were also accelerated when electron donating groups were substituted in the alkyl group and electron withdrawing groups substituted in the migrating group. 118 The first example of a conformationally contstrained β-(acyloxy)alkyl radical undergoing rearrangement by a pure 1,2-shift mechanism has

17 -3 been reported. Reaction of the the O labelled esters (1a-c) with Bu3SnH in the presence of 10 M

PhSeH led to an inseparable mixture of the reduced (2a-c) and the ring contracted (3a-c) products

(Scheme 1). No scrambling of the O17 label was detected indicating that the rearrangement occurs via a

1,2-shift process.119.

The study of intramolecular aromatic 1,5-hydrogen transfer reactions in range of systems has been reported. The activation energy and the rate of H-abstraction between the ortho position of ortho- benzophenone has been calculated using molecular orbital theory and transition-state theory.

4 Stabilisation of the transition state appears to be the result of a C-H…O, H-bond between the oxygen atom and the ortho- that are not involved in the H-transfer. 120. In other work products derived from the photolysis of iodobenzophenone (4) indicarted that the initially formed radical is in equilibrium with that derived from a 1,5-hydrogen transfer to the other aromatic ring (Scheme 2). 121.

The rates of 1,5-hydrogen abstraction is a range of fluorinated radicals containing differing substituents at the site of C-H abstraction (X) have been measured. For 1,1,2,2-tetrafluoro-n-pentyl radicals

(XCH2CH2CH2CF2CF2·) and 1,1,2,2,3,3-hexafluoro-n-pentyl radicals (XCH2CH2CF2CF2CF2·), where

X = MeO, MeS, Me, Ph there was little observed difference in rates for differing X groups. 122

The energy barrier for the 1,2-shift of a H-atom in a range of aryl radicals has been calculated to be in the order of 60 kcalmol-1 precluding these type of rearrangements from occurring under normal laboratory conditions. However, rearrangements such as these may become important in or flash vacuum pyrolysis. 123

Two new radical clocks have been calibrated, (notably the rearrangement of (5a → 6a) and

(5b → 6b)). Rates were found to be 6.4 x 103 and 1.4 x 104 M-1s-1 respectively. These two new clocks are intermediate between those of the neophyl and 1-hexenyl clocks and thus should be valuable new additions as tools to investigate reactions with intermediate rates, (Scheme 3). 124.

ΙΝSERT SCHEME 1-3

β-Scission and Ring Opening

The accurate kinetic measurement of both 3-exo cyclisations and the reverse ring openings continue to attract much research. The kinetics of ring opening of a series of (trans-2-arylcyclopropyl)methyl radicals (where a range of substituents located at the m- and the p-postions of the aryl group) have been measured by indirect methods. The radicals were generated from PTOC esters and trapping with

PhSeH was used as a competition reaction. Rate constants at 25 °C ranged from 1.0 x 1011 s-1 (for p-

11 -1 Me) to 4.1 x 10 s (for p-CF3). These new radical rearrangements have potential to be used as ultra fast mechanistic probes. 125. PTOC esters have also been used to prepare Eand Zisomers of the 4-(2,2- diphenylcyclopropyl)-3-butenyl radical (7) by laser flash photolysis. These radicals cyclise in a 3-exo fashion to give the intermediate radical (8) which undergoes rapid ring opening, (Scheme 4). The initial rate constants for the 3-exo cyclisations were determined and it was found that Z-(7) cyclised

5 faster than the E-(7) isomer as a result of a more favourable entropy of activation. 126. The ring opening of fluorinated cyclopropylcarbinyl radicals has been investigated using DFT calculations and the remarkable impact of the fluorine atoms on the structure and reactivity of these radicals was proposed with the stereoelectroinc influences thought to be largely responsible for the predicted reactivity and regiospecificity of ring opening. 127 A range of 3-arylaziridinylcarbinyl radicals (9) have been prepared from the Bu3SnH mediated reduction of thiocarbamates and the products arising from their ring opening reactions determine, (Scheme 6). Only products arising from specific C-N bond cleavage were detected which is in contrast to the mode of ring opening in the related oxygen analogues (oxiranylcarbinyl radical). 128. The approximate transition structures for the ring opening of a range of cyclopropylcarbinyl radicals have been determined using a specific mathematical model of the Bell-Evans-Polanyi principal. 129. The factors effecting the ring cleavage of the alkoxy radical

(10) have been explored computationally in order to understand why cleavage occurs to give the less thermodynamically stable ring expanded product (11) instead of the allylic radical (12) (Scheme 6).

Two factors influencing the kinetic preference were observed and the activation energies of cleavage for a range of cyclic and acyclic radicals were determined. 131

The decarboxylation reaction of alkoxyacyl radicals and the related (methoxy)thioacyl,

(methylthio)acyl and (methylthio)thioacyl radicals have been investigated by ab initio methods.

Transition states for the decarboxylations have been calculated and for alkoxyacyl radicals the decarboxylations were found to be significantly exothermic. Calculations indicated that (alkoxy)thio acyl radicals should also provided synthetically useful β−fragmentation reactions. 22

A radical mechanism involving ring opening has been invoked for the production of 4- methylcyclohexan-1-ol from the LiAlH4 mediated reduction of norbornan-1-ol in THF at reflux. 130

SCHEME 4-6

Ring Expansion

The ring opening of the cyclopropylcarbinyl radical has been used in a number of ring expansion protocols. Thus ring expansion via endocycliccleavage of the cycloalkyl carbonyl radical (13) has been studied in the ring expansion to give seven-membered rings. Reaction of suitably functionalised

6 thiocarbamamtes with Bu3SnH furnishes the desired radicals which undergo the observed ring expansion, (Scheme 7).132 A synthesis of bicyclo[2,2,2] also makes use of the facile ring opening of the cyclopropylcarbinyl radical. Thus treatment of the vinyl bromide (14) with Bu3SnH furnishes the vinyl radical which after 5-exo cyclisation followed by reversible 3-exo cyclisation gives rise to the radical (15) which ring opens to give the observed bicyclic system (16), (Scheme 8). 133.

INSERT SCHEMES 6-8

A dramatic temperature effect upon the regiochemical outcome of cyclisation of the aryl bromide (17) has been observed. At 60 ºC a 6:1 ratio of the formal 5-exo (18) to 6-endo (19) products are formed but at 169 C this ratio is reversed to 1:5. The reversal in selectivity was due to the ring expansion reaction via the cyclohexadienyl radical (20), the activation energy of which is sufficiently high that this rearrangement only competes at relatively high temperatures, (Scheme 9). 134. A similar mechanism has been invoked to explain the formation of the formal 6-endo cyclisation product (25) in the cyclisation of the iodopyrrole (21). Cyclisation with Bu3SnH leads to the 5-exo product (23) in 65% yield, while reaction with TTMSS furnishes a 1:1 mixture of the 5-exo (23) and 6-endo (25) products.

This was explained due to the longer lifetime of the intermediate cyclised radical (22) under the

TTMSS conditions which has sufficient lifetime to rearrange to the ring expanded product via the radical (24), (Scheme 10). 137..

INSERT SCHEMES 9-10

A two carbon ring expansion of 2-bromomethyl-1-oxaspiro[2,n] to give cyclic ketones has been investigated using EPR and intermediate radicals detected. Generation of the radical (26) by room temperature reaction with Bu3SnH underwent two β-scission reactions which furnished the acyclic radical (27). Cyclisation of (27) in an endo mode furnished the ring expanded product. Although the endo mode of cyclisation predominated at low temperatures the cyclisation was not regioselective enough to make this a synthetically viable 2-carbon ring expansion reaction,

(Scheme 11). 135. A one carbon ring expansion of cyclopropanols mediated by manganese (III)

7 tris(pyridine-2-carboxylate) generates cyclic β-keto radicals which when followed by a cyclisation lead to bicyclic intermediates. 136.

SCHEME 11

Intramolecular Addition

Cyclization

Radical cyclisation continues to be one of the most popular synthetic classes of radical reaction. By far the majority of cyclisation reactions are 5-exo in nature and this year is no exception in the number of papers that describe such processes. The rates of 5-exo cylcisation reactions continue to be measured.

For example the rate constants for the 5-exo cyclisations of the 6,6-diphenyl-5-hexenyl, 1-methyl-6,6- diphenyl-5-hexenyl and the 1,1,-dimethyl-6,6-diphenyl-5-hexenyl radicals have been measured by laser flash photolysis studies and Arrhenius parameters determined. The relative rate constants for cyclisation and the reaction with PhSeH were determined at 20 ºC. At 20 ºC the rates of the three 1º,

2º, and 3º radicals with PhSeH were approximately (1.2 ± 0.1) x 109 M-1 s-1. The rate consants for alkyl radicals calibrated by competition reactions with PhSeH and PhSH were found to be 30-40% smaller than previously reported and thus it was concluded that derived rate constants for some fast radical reactions may have to be adjusted accordingly. 138. The rate constants for the 5-exo cyclistion of secondary radicals onto hydrazones and oxime ethers have been determined. The fastest rate constants were observed for the N-benzoylhydrazone acceptor. The rate constants were found to be approximately 800 times faster than the corresponding 5-exo cyclisation onto . 139 Other work has measured the rate constants of cyclisation of a range of fluorinated 5-hexenyl, 6-heptenyl, 7- octenyl and 8-nonenyl radicals. Not only were the rate constants measured but the regioselectivity of cyclisation was compared to the all carbon homologues. 140 Six-exo cyclisation of the 1,1,2,2- tetrafluoro and the 1,1,2,2,3,3,4,4-octafluoro-6-heptenyl radicals were found to be approximately 103 times faster than the parent . In contrast fluorinated hexenyl and heptenyl radicals exhibited lower reactivity with the 7-octenyl fluorinated analogues cyclising in an endo mode.

Transition state polar effects were rationalised to explain these observations.140.

Tributyltin hydride mediate 5-exo cyclisation of a range of secondary haloamides has been investigated. 141. Yields were better when the reactions were carried out at 110 ºC in toluene at reflux

8 rather than in benzene as solvent at 80 ºC. The predominant formation of trans isomers was consistent with a reversible reaction under thermodynamic control, (Scheme 12). 141. Cyclisation of tertiary iodoamides have been reported to occur in in an atom transfer manner when the water soluble initiator (28) was utilised at 75 ºC. 142. The cyclisation of structurally related α-halo sulfonamides has also been reported to proceed in a 5-exo manner at 80 ºC. Interestingly, in larger systems the 7-endo mode of cyclisation predoiminated over the 6- exo mode. 143. Cyclisation of a--5-hexenyl and hexynyl radicals proceeds in the expected 5-exo manner. Under the reaction conditions the reaction of the phenylselenyl (29) furnished the cyclic nitrogen heterocycle (30) exclusively with no reduction before cyclisation being detected, (Scheme 13). 144.

Nitrogen centered radicals (specifically iminyl radicals) have been produced from o-2,4- dinitrophenyl oximes with NaH in the presence of phenols via a radical anion intermediate. Radicals produced in this way cyclised as expected in a 5-exo manner and could be trapped reductively (with added 1,4-cyclohexadiene) or by a halogen (with added CCl4), (Scheme 14) 145

INSERT SCHEMES 12-14 and STRUCTURE 28

Cyclisation onto aromatic rings has been investigated by a number of workers. The use of reductive conditions (Bu3SnH/AIBN) facilitiates an intramolecular homolytic substitution onto imidazoles and benzimadazoles, (Scheme 15). 146 This chemistry allowed for a range of ring sizes to be produced. Another oxidative cyclisation, this time mediated by the addition of the p- toluenesulfinate radical to an , has been reported. Oxidative addition occurs in the presence of

Cu(II)(OAc)2 which oxidises any intermediate cyclohexadienyl radicals back to the aromatic ring

(Scheme 16). 147.

Polarity reversal catalysis has been used to mediate a cyclisation reaction that otherwise could not be accomplished. Reaction of (31) with the (32) failed to produce any of the desired cyclic material (33). However when the reaction was repeated in the presence of tri-tert-butoxysilathiol (5 mol%) as a polarity reversal catalyst the cyclic compound (33) was furnished in 92% yield (Scheme

17). 148.

INSERT SCHEMES 15-17

9

Theoretical treatments which investigate the outcome of cyclisation reactions continue to be popular. The effect of geminal substituents in the chain upon the rate of 4-exo cyclisation of alkyl radicals has been investigated using computational methods (PM3), UHF/3-21G and UHF/6-31G*.

149. The effect of steric interactions on the cyclisation of a range of acyclic sugar derivatives has been investigated using MM2-transition state methodology (MM3 force field) 150. The effect of pressure on the hypothetical cyclisation of 1-alkenes to has been discussed as has the effect of pressure upon homolytic bond cleavage. 151.

Ring synthesis by radical-radical coupling as well as intramolecular radical substitution is an alternative method for producing rings which do not rely on the addition of a radical to an unsaturated bond. Cyclopropanes have been prepared from di-iodides by the reaction of a catalytic amount of a fluorinated tin hydride with NaCNBH3 in a fluorinated/organic solvent mixture. The rate constant for

5 -1 the reaction was determined using Ph3SiH as a chain carrier and found to be 5 x 10 s at 80 ºC,

(Scheme 18). 152 The cyclisation of the 2,2-diethyl-1,3-propanethiol and 4,4,-diethyl-1,2-dithiolane in the presence of 2,5-dmethyl-2,4,hexadiene and AIBN has been shown to proceed via a radical chain mechanism, (Scheme 19). 153.

Cyclisation of alkyl lithium onto alkenes has been reported previously to potentially be a one electron process. Recent results have indicated that PhLi initiated cycloisomerisation of primary alkyl iodides involves a radical mediated atom transfer process similar to that previously reported for secondary and tertiary substrates. This is a revision of earlier postulates about the proposed mechanism of the reaction of primary alkyl iodides. 154.

Trapping of reactions after a successful cyclisation is an important part of any synthetic sequence. The ability to trap intermediate radicals with a phosphorous group has been reported.

Cyclisation of the radical (34) in the presence of P(OMe)3 furnishes initially a vinyl radical from 5-exo dig cyclisation followed by the phosphorous radical (35) formed by trapping of this vinyl radical. Loss of a occurs to give the observed phosphonate (36), (Scheme 20). 155.

INSERT SCHEME 18-20

10 Cyclisation onto unsaturated C=N bonds has been reported by a number of workers to proceed in the unusual 6-endo fashion prpeferentially. Generation of the initial radical by addition of either a tin centered or a sulphur centered radical onto an alkyne or allene has been demonstrated. Thus cyclisation of vinyl radicals (produced by the Bu3SnH mediated addition to alkynes) onto imines proceeds in a 6-endo manner to give functionalised piperidines (Scheme 21). 156. In a similar manner allyl radicals (generated by Ts· addition to allenes) add in a 6-endo manner onto hydroxylamine derivatives. Elimination of the RO· leads to the formation of dihydropyridines, (Scheme 22). 157

Functionalised bicyclic β-lactams have been produced by an unusual 7-endo cyclisation triggered by a similar addition of a tin centered or sulphur centered radical onto substituted N-propargyl β-lactams.

158.

INSERT SCHEME 21-22

Cascade Reactions

Tandem or ‘cascade’ reactions continue to be arguably the most efficient way of preparing complex synthetic . In radical chemistry this has been remarkably demonstrated by a Bu3SnH mediated stereoselective cascade of SEVEN 6-endocyclisations. Thus reaction of (37) with Bu3SnH and AIBN furnishes a 20% yield of the all-trans-anti heptacycle (38) as a single diastereomer (Scheme

23). 159. Tandem cyclisation of nitrogen centered radicals has also been accomplished. Thus heating either N-chloroderivatives 160 or O-acyl hydroxamic acid derivatives 161 with Bu3SnH furnishes aminyl and amidyl radicals respectively which can undergo cascade processes.

Cascade reactions often involve a number of cyclisations interdispersed by other radical processes such as fragmentations, eliminations or hydrogen transfers. Two examples which illustrate the sequencing of cyclisations and hydrogen transfers have been reported. An efficient radical sequence involving a 5-exo-dig cyclisation followed by a diastereoselective 1,5-hydrogen transfer and then an unusual 5-endocyclsation gives rise to a highly functionalised cyclopently derivatives bearing four stereogenic centers, (Scheme 24). 162. An even more unusual sequence has been reported to give rise to bicycle[3,1,1] via a 5-exo-dig cyclisation followed by an unusual sequence of 1,6- hydrogen transfer, 6-endo cyclisation, 4-exo cyclisation and another 1,6-hydrogen transfer. 163.

11 INSERT SCHEMES 23-25

Fragmentation, Recombination, and Homolysis

Substituent effects on the disproportionation/recombination reactions of ( CF3 and CF3CH2CF2 ) and

CF3CH2CF2 and CF3CH2CF2 ) have been studied at 295 K. The results were compared to the reactions of the analogous CF3CH2CH2, CF3CH2CHCl, CF3CH2CHCF2). 13

Atom Abstraction Reactions

Hydrogen abstraction by Carbon-centred Radicals

Phenyl radicals have an important role in the combustion of fossil fuels and in the formation of polycyclic aromatic . The absolute rate constant for the reaction of C6H5 with 2- methylpropane, 2,3-dimethylbutane, and 2,3,4-trimethylpentane has been measured using cavity ring- down spectrometry between 290 and 500 K. The reactions were found to be dominated by the extraction of the tertiary C-H bonds. 17.

Hydrogen Abstraction by Heteroatom-centred Radicals

Reactions of Halogen-centered Radicals, Halogen Abstraction and Halogenation

While the is thought to play a major role in the destruction of a range of organic materials in the atmosphere the reactions of chlorine atoms are also important, particularly in the marine boundary layer and on the Arctic. The reactions of a range of biogenic organic compounds including , α-pinene (R and S), β-pinene, (R)-limonene, myrcene and 3-carene with Cl· has been studied at 298 K and 1 atmosphere using the relative rate technique. Conclusions drawn suggest that loss of biogenics by atomic Cl· must be taken into account in addition to their reactions with HO·,

O3, and NO3. 12…H abstraction by Cl in has also been investigated. 48. In addition the temperature dependence of the rate coefficients for the reaction of Cl· with chloromethanes has been undertaken over the temperature range 222-298 K. 2…..Relative rate techniques have been used to

15 3 -1 -1 investigate the reactions of Cl· CF2ClCFClH (an HCFC) at 298 K (5.1 x 10- cm s ) and Cl

12 with CH3ONO2 and CH3ONO at 700 torr using N2 as a diluent. While the reaction with CH3ONO2 was found to be in good agreement with previous data the results for CH3ONO were 4.5 times lower than previously reported..15…11…The hydrogen abstraction reaction of Cl from CH3CHO has been studied using flash photolysis / tunable laser absorption spectroscopy to measure the production of HCl. 16

The abstraction of iodine from substituted iodobenzenes by the cyclohexyl radical has been reported. The reaction was found to be highly efficient in some systems (e.g. 2-iodocumyl alcohols) despite the unfavourable C-I bond dissociation energies. This was attributed to H-bonding between the

OH group and the iodine atom. 54.

Radical halognation of hydrocarbons continues to be an area of interesting research. The mechanisms and selectivity of free radical halogenation reactions has been reviewed. The review includes discussions of energetic (thermodynamic) and polar (kinetic) factors and mechanisms of chain propagation. 53. The selectivity of the reactions of alkanes with molecular chlorine was found to increase in halogenated hydrocarbons and this was postulated to arise due to the formation of a chlorine radical-haloalkane complex. 51. Chlorination of alkanes with N-halosulfonamides has also been investigated. The selectivity was found to be intermediate between radical chlorination and radical bromination with molecular halogens. 52.

Addition Reactions

Addition to Carbon-Carbon Multiple Bonds

Addition to Oxygen-containing Multiple Bonds

Addition to Nitrogen-containing Multiple Bonds

Homolytic Substitution

Aromatic Substitution

SH2 and Related Reactions

13 Reactivity Effects

Polarity and Philicity

Stability of Radicals

Many enzymatic systems have been discovered that produce reactive intermediates in proteins. The properties and stability of radicals is thus an important area of study. The 2-glycyl radical (A),

2-glycyl methyl ester (B) and 2-glycyl N-methylacetamide radical (C) have been generated in the gas phase by collisional neutralization of the corresponding cations and studies by mass spectrometry and the results analysed using ab initio and density functional theory calculations. The major unimolecular dissociations observed were cleavages of the CO-X bond (X = OH, OMe, NHMe) and of the C-CO bond. In addition an unusual methyl migration occurred in (C). Stable fractions were found for (A-C) which did not dissociate on the 4μs timescale of the experiment. 20. The performance of a number of different theoretical methods for computing stabilization energies of a range of radicals has been examined (including CH2F, CH2CN, and CH2CH=CH2.) The influence of both electron correlation and basis set size was investigated. The results indicated that generally reliable estimates could be achieved using RMP2/6-311+ G(2df,p)//RMP2/6-31G(d) energies. 21. Stabilization energies for the

1-cyanomethyl radical (a highly spin contaminated species) have been calculated using ab initio, density functional theory and compound methods. Good agreement with benchmark values was found for RMP2, RMP4, QCISD (T) and CCSD (T) techniques. 50. The addition of phosphoryl r adicals to

[76] fullerene has been studied by EPR and seven out of the nineteen possible RC76 isomers were obtained, six of which were stable. Semi-empirical MNDO/PM3 calculation of all the possible isomers were undertaken to aid assignment of the different isomers. 18 The formation and reactions of the stable 1,2,3-dithiazole radical (A) has been discussed in a review of 1,2,3-dithiazole chemistry…41.

Stereoselectivity in Radical Reactions

Stereoselectivity in Cyclization

Stereoselectivity in Addition Reactions

14 Stereoselectivity in Atom Transfer

Redox Reactions

Radical Ions

Anion Radicals

Cation Radicals

Peroxides, Peroxyl, and Hydroxyl Radicals

Peroxides

The rate constants for the co-oxidation of acenaphthene and d-10 acenaphthene with cumylperoxide have been determined. The isotope effects were explained by a considerable contribution of the tunneling effect of the H atom.36…..The thermolysis of a range of peroxides has been reported. Thus heating tert-butyl-(2-phenyl-prop-2-yl) peroxide at 110-155 C in cumene led acetophenone as the major thermolysis product. 46….The rate constants for the decomposition of a range of diacyl peroxides has been reported. At 80 C and 1500 bar the rates of decomposition followed the order (3,5,5-trimethyl-hexanoyl)>dioctanoyl>dibenzoyl reflecting the β-branching of the chain.45….

The reaction of TEMPO with (in particular Ph2C=C=O) proceed to yield unstable species that upon reaction with O2 forms a stable peroxide (A). Heating (A) at 100 C in toluene woth added TEMPO leads to benzophenone, PhCH2OTEMPO and tetramethylpiperidine, indicating that the peroxide is a source of aminyl radicals (B).31…Kinetic studies of the reaction of TEMPO with ketenes in hydrocarbon solvents have also been reported. 49.

The reaction of various alkyl radicals with peroxides has attracted some interest. Thus the reactions of both the methyl radical and the hydroxy methyl radical with .29…19 and the methyl radical with t-butyl hydroperoxide 37…. have been reported and the rate constants for the processes determined. In related work it was reported that alkanes are iodinated by perfluoroalkyl iodides under free radical conditions (using t-BuOOH in AcOH) to give iodoalkanes. However, in the presence of excess t-BuOOH the iodo alkanes were reduced back to the starting alkanes.34….

15 The mechanism of the O-O bond cleavage in 2-methyl-1-phenylpropan-2-yl hydroperoxide using iron(III) porphyrins has indicated that both homolytic and heterolytic cleavage mechanisms can operate depending upon the pH and/or the axial ligand attached to the porphyrin.32….

Peroxyl Radicals

A supramolecular steric effect has been postulated to explain the persistence of the diphenylmethyl radical when absorbed onto an MFI zeolite. During the course of theses studies this persistent radical was found to react reversibly with oxygen to give the zeolite bound peroxyl radical.33…

Fenton Chemistry continues to attract the interest of mechanistic chemists. An account entitled ‘Comments on the mechanism of the ‘Fenton-like’ reaction has appeared. In particular the question of whether hydroxyl and alkoxy radicals are intermediates were discussed.44….

The self combination of a range of peroxyl radicals has been studied.4, 6. Thus the dimerisation of both CH2ClO2· and CHCl2O2· radicals have been studied at low pressure using discharge-flow and laser induced fluorescence. Secondary reactions involving alkoxy radicals were identified in complicating this reaction.4…Other self recombination reactions of alkylperoxy radicals

(C5H11O2· and C10H21O2·) have been studied using excimer flash photolysis as well as conventional flash photolysis.6…

The generation and reactions of cumylperoxyl radicals has been explored in detail. Thus the rate constants for the reaction of cumylperoxyl radicals with Bu3SnH and (TMS) 3SiH at 72.5 C have been determined to be 1600 and 66 M-1 s-1 respectively.30…..The liquid phase co-oxidation of cumene with tetralin, octahydroanthracene and dodecahydrotriphenylene has been investigated. The rate constants fo rhte reaction of the cumylperoxyl radical with the cycloalkylbenzenes were determined during the study.38…The transfer of an electron from p-substituted N,N-dimethylanilines to the cumylperoxy radical has been investigated and the result compared to those obtained with Sc(III)- catalysed electron transfer reduction of the cumylperoxyl radical by ferrocene.40…In related work the oxidizability of the tetralines A-C was determined by studying their H-abstraction reactions by the cumylperoxyl radical. The order was shown to increase in the order A,B,C.35……..

Theoretical treatments of the reactions of peroxyl radicals have appeared this year. Thus the reaction of CH3OCH2· with O2, and subsequent decomposition reactions of the peroxylradical were studied using ab initio methods. CBS-q//MP2(full)/6-31G(d,p) method was used to determine the

16 enthalpies of formation and the quantum Rice-Ramsperger-Kassel analysis was used to determine the rate constants for the reactions..39…In other theoretical work AM1 and PM3 semiempirical MO methods (at the SCF/UHF level) were used to calculate the activation enthalpies for the addition of a range of peroxyl radicals to with HO2·

The reaction of o- and p-carboxyphenylperoxyl radicals with has been shown to produce both mono- and di-hydroxybenzoic acid. The reactions required 2 equivalents of superoxide.42….The reactions of the hydroperoxy radical with a range of 2,6-substituted benzoquinones have been investigated and found to satisfy the Hammet equation. 47.

Hydroxyl Radical

The role of ·OH in biological chemistry continues to be an important area of research. Thus EPR studies on the selectivity of ·OH attack on a range of amino acids (glycine, alanine, valine, leucine and their derivatives), dipeptides (16 derivatives) and tripeptides (9 derivatives) have been undertaken.

With glycine amino acid derivatives attack at the α -carbon predominates and in tripeptides containing glycine attack at the C-terminal site is preferred over the mid-chain site, which in turn is preferred over the N-terminal position. For alanine derivatives however abstraction of the side-chain methyl group is preferred in the amino acid derivatives but significant amounts of α -carbon abstraction occur in di- and tripeptides. For valine and leucine derivatives side-chain attack occurs irrespective of position in peptides. This work supports the hypothesis that protein fragmentation by ·OH occurs primarily as a result of attack at the α-carbon of glycine and alanine residues.24… In other biological work ·OH radicals produced by radiation induced decomposition of water or Fenton chemistry have been used to study the degradation of DNA. Thus addition of the ·OH to 2’-deoxyguanosine has been shown to lead to two different radical products which exhibit oxidising (A) and reducing properties (B) respectively.23…

Volatile organic compounds (VOCs) present on the atmosphere can undergo removal process with the ·OH in the troposphere. Many groups have thus studied the reactions of various VOCs with the with the ·OH are under a variety of conditions.25, 1, 3, 5, 8… Oxygenate organics are currently

17 under investigation as additives to increase ratings for fuels and as solvents for paints. The relative rate technique has been used to determine the rate coefficient for the reaction between the with the ·OH and one such candidate (methyl isobutyrate). The observed mechanism for the formation of the products ( 97% and methyl pyruvate 3%) were also discussed.1… The rate constants for the reactions of the ·OH with di-n-propyl and butyl ethers and their deuterated derivatives have been measured at 296 K. isotope effects were consistent with a H atom abstraction by the ·OH as the rate determining step.5…The products of the gas phase reaction between ·OH and n-butylmethyl ether in the prsence of NO have been investigated by GC and in situ atmospheric pressure mass spectrometry. A range of organic nitrates, as well as propanal, butanal, methyl butyrate and were detected.3… The ·OH reaction of pinonaldehyde (the product produced in the atmosphere between and the VOC pinene) has been investigated. Steady state estimates of pinonaldehyde were postulated in regions of substantial α-pinene emission.8… The addition of ·OH to toluene proceeds by both ·OH addition and H atom abstraction. These reactions have been studied by fast-flow chemical ionisation mass spectrometry and the intermediates identified.

In other studies on the reactivity of the ·OH with various functional groups have been investigated. The absolute rate constants for the reaction of the ·OH with a range of symmetrical acetals 10… and 2-propxyethanol 7… have been measured (using the relative rate technique). While the mechanism of ·OH addition to 14…, imidazole 27… and phenol 26…have been studied by practical and theoretical techniques. Thus the rates of the consecutive reactions of ·OH addition and

- H2O/HO elimination for phenol and o-, m-, and p-cresol were investigated in acidic and alkaline solutions using pulse .26… In theoretical work the addition of ·OH to propene in the

presence of O2 has been modelled using UMP2/6-31G** level calculations,14… While MP2 and

B3LXP methods (with large basis sets and SCI-PCM modelling of solvent effects) were used to investigate the reaction of the ·OH with imidazole and the subsequent elimination of H2O. The preference for addition at the 5-position was explained in terms of the barrier to addition and the exo anomeric effect stabilising the transition state. The calculate hyperfine structures for the intermediate radicals were in good agreement with experimental values.27…

18 The reaction of ·OH with HFC’s has attracted interest again this year. Thus the reaction

between the ·OH and CH3OCF2CF3, CH3OCF2CF2CF3 and CH3OCF(CF3)2 has been measured over the temperature range 250-430 K using flash and laser photolysis methods.9…..In addition ab initio molecular orbital calculations for the reaction of CF3CF2· with the ·OH using HF, MP2 and G2(MP2) methods have been carried out.28….

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