molecules

Review Functionalised Oximes: Emergent Precursors for Carbon-, Nitrogen- and Oxygen-Centred Radicals

John C. Walton

Received: 11 December 2015 ; Accepted: 30 December 2015 ; Published: 7 January 2016 Academic Editor: Roman Dembinski

EaStCHEM School of Chemistry, University of St. Andrews, St. Andrews, Fife KY16 9ST, UK; [email protected]; Tel.: +44-01334-463-864; Fax: +44-01334-463-808

Abstract: Oxime derivatives are easily made, are non-hazardous and have long shelf lives. They contain weak N–O bonds that undergo homolytic scission, on appropriate thermal or photochemical stimulus, to initially release a pair of N- and O-centred radicals. This article reviews the use of these precursors for studying the structures, reactions and kinetics of the released radicals. Two classes have been exploited for radical generation; one comprises carbonyl oximes, principally oxime esters and amides, and the second comprises oxime ethers. Both classes release an iminyl radical together with an equal amount of a second oxygen-centred radical. The O-centred radicals derived from carbonyl oximes decarboxylate giving access to a variety of carbon-centred and nitrogen-centred species. Methods developed for homolytically dissociating the oxime derivatives include UV irradiation, conventional thermal and microwave heating. Photoredox catalytic methods succeed well with specially functionalised oximes and this aspect is also reviewed. Attention is also drawn to the key contributions made by EPR spectroscopy, aided by DFT computations, in elucidating the structures and dynamics of the transient intermediates.

Keywords: oxime esters; oxime ethers; free radicals; organic synthesis; photochemical reactions; EPR spectroscopy; photoredox catalysis; N-heterocycles

1. Introduction A huge variety of compounds containing the carbonyl functional group is available from natural and commercial sources. Of these, aldehydes and ketones can readily and efficiently be converted to oximes R1R2C=NOH (1) by treatment with hydroxylamine hydrochloride and a base. Alternatively, oximes can be prepared from reaction of organic and inorganic nitrites with various compounds containing acidic C–H atoms. Consequently, oximes are accessible in great diversity for further functional group transformations. A few instances of oximes themselves being used directly for radical generation are known. However, their O–H bonds are comparatively weak, usually in the range of 76–85 kcal¨ mol´1 [1] and, therefore, any radicals X‚ generated in their presence abstract these H-atoms with production of iminoxyl radicals 2 (see Scheme1). Many iminoxyls have been generated and studied [2–4] and they resemble nitroxide (aminoxyl) radicals in a number of ways; especially in that most are persistent. Frequently, therefore, the presence of an oxime serves to impede further radical reactions. Oximes are easily derivatised so that oxime esters (O-alkanoyl and O-aroyl oximes) and oxime ethers (O-alkyl and O-aryl oximes) are straightforward to make. The N–O bonds in these compounds are usually comparatively weak; ~50 kcal¨ mol´1 in oximes [5] and only 33–37 kcal¨ mol´1 in O-phenyl oxime ethers [6]. Homolytic scission of these N–O bonds can be accomplished either by photochemical or by thermal means thus yielding for each type an N-centred radical accompanied by one equivalent of its O-centred counterpart. For this reason, oxime derivatives, especially carbonyl-oximes containing the

Molecules 2016, 21, 63; doi:10.3390/molecules21010063 www.mdpi.com/journal/molecules Molecules 2016, 21, 63 2 of 23

>C=N–OC(=O)–Molecules 2016, 21 unit,, 63 are finding increasing use as selective sources for free radicals. They offer2 of tangible 23 advantages over traditional initiators, such as diacyl peroxides, azo-compounds or organotin hydrides; all oftangible which haveadvantages well-known over traditional troublesome initiators, features. such as Mostdiacyloxime peroxides, derivatives azo-compounds are easily or organotin handled; are non-toxic,hydrides; non-pyrophoric all of which andhave have well- longknown shelf troublesome lives. The fieldfeatures. has Most expanded oxime to derivatives encompass are a hugeeasily range handled; are non-toxic, non-pyrophoric and have long shelf lives. The field has expanded to encompass of structural elements resulting in diverse and varied possibilities for subsequent transformations a huge range of structural elements resulting in diverse and varied possibilities for subsequent of the radicals. These compound types are being subsumed into more environmentally friendly transformations of the radicals. These compound types are being subsumed into more environmentally preparativefriendlymethods preparative and methods for new and means for new of means access of to access ranges to ofranges aza-heterocycles. of aza-heterocycles. This This article article reviews modernreviews methods modern of releasingmethods of radicals releasing from radicals both thesefrom both precursor these types.precursor Ithighlights types. It highlights how their how use has enabledtheir the use structures, has enabled reactions the structures, and kinetics reactions of and sets kinetics of C-, Nof- sets and ofO C-centred-, N- and radicalsO-centred to radicals be elucidated to in greaterbe elucidated detail than in greater heretofore. detail than heretofore.

SchemeScheme 1. Oximes, 1. Oximes, carbonyl carbonyl oximes oximesand and oximeoxime ethe ethers;rs; production production of ofiminoxyl iminoxyl radicals. radicals.

In earlier synthesis-orientated research, Forrester and co-workers employed oximeacetic Inacids earlier MeCR(CH synthesis-orientated2)2CR1=NOCH2CO2H research, and their Forrestert-butyl peresters and co-workers [7,8]. Hasebe’s employed group developed oximeacetic 1 acidsphotochemical MeCR(CH2)2 CRalkylations=NOCH and2CO arylations2H and theirwith t-butyloxime perestersesters Ph2C=NOC(O)R [7,8]. Hasebe’s [9,10] group and developedZard photochemicalestablished ingenious alkylations preparative and arylations methodology with from oxime oxime esters benzoates Ph2 C=NOC(O)RPhRC=NOC(O)Ph [9, 10[11],] andfrom Zard establishedO-benzoyl ingenious hydroxamic preparative acid derivatives methodology and from from sulfenylimines oxime benzoates R2C=NSAr PhRC=NOC(O)Ph [12–14]. Since the [ 11turn], from of the century, research has zeroed in on two particular sets of oxime-derived compounds: (a) carbonyl O-benzoyl hydroxamic acid derivatives and from sulfenylimines R2C=NSAr [12–14]. Since the turn of 1 2 the century,oxime derivatives research has and zeroed (b) O-aryl in on oxime two ethers particular R R C=NOAr. sets of oxime-derived Recent advances compounds:, important insights (a) carbonyl and details of some surprising outcomes are described with particular emphasis on mechanistic and oxime derivatives and (b) O-aryl oxime ethers R1R2C=NOAr. Recent advances, important insights computational aspects. and details of some surprising outcomes are described with particular emphasis on mechanistic and computational2. Oxime Esters aspects. and Related Carbonyl Oximes

2. Oxime2.1. General Esters Features and Related of Carbonyl Carbonyl Oxime Reactions Oximes

2.1. GeneralGeneralised Features ofstructures Carbonyl of Oxime the principal Reactions types of carbonyl oximes so far investigated are displayed in Chart 1. These carbonyl oxime types all have strong absorption bands in the 250–350 nm range and Generalisedreadily dissociate structures on UV of irradiation the principal in solution types ofby carbonyl cleavage oximesof their soN–O far bonds. investigated Cleavage are of displayed the in ChartO–C(O)1. These bonds carbonyl does not oximecompete types in solution all have under strong the absorption normal conditions bands infor the organic 250–350 reactions. nm range and readilyOccasional dissociate observations on UVof iminoxyl irradiation radicals in solution(R1R2C=NO by•), cleavageand products of theirtherefrom N–O can bonds. most probably Cleavage of the O–C(O)be attributed bonds to does residual not competetrace impurities in solution of the under oximes the from normal which conditions the carbonyl for organicoximes were reactions. Occasionalprepared. observations Density Functional of iminoxyl Theory radicals (DFT) (R 1computationsR2C=NO‚), and [B3LYP/6-31+G(d)] products therefrom with canmodel most oxime probably esters 3 also indicated N–O cleavage was thermodynamically favoured over O–C(O) cleavage. It is be attributed to residual trace impurities of the oximes from which the carbonyl oximes were prepared. apparent from Chart 1 that, by appropriate choice amongst these carbonyl oxime precursors, selective Density Functional Theory (DFT) computations [B3LYP/6-31+G(d)] with model oxime esters 3 also generation of radicals centred on either C-, N-, or O-atoms, with differing substitution patterns, can indicatedbe achieved. N–O cleavage The associated was thermodynamically chemistry has been inve favouredstigated over spectroscopically O–C(O) cleavage. and, of Itcourse, is apparent by end from Chartproduct1 that, byanalyses. appropriate The most choice successful amongst and helpful these carbonyl method for oxime mechanistic precursors, and dynamic selective information generation of radicalsabout centred the intermediates on either C-, has N-, been or EPR O-atoms, spectrosco withpy differing coupled with substitution QM computations. patterns, canThe besynergy achieved. The associatedachievable by chemistry their mutual has deployment been investigated has been demonstrated spectroscopically many and,times. of course, by end product analyses. The most successful and helpful method for mechanistic and dynamic information about the

Molecules 2016, 21, 63 3 of 23 intermediates has been EPR spectroscopy coupled with QM computations. The synergy achievable by theirMolecules mutual 2016, 21 deployment, 63 has been demonstrated many times. 3 of 23

Chart 1. Types of carbonyl oximes investigated for radical release.

The efficiencyefficiency of photochemical N–O bond homolysishomolysis depends strongly on the type of imine 1 2 unit. Best radical yieldsyields werewere obtainedobtained whenwhen RR1 and/orand/or RR2 werewere aromatic/heteroaromaticaromatic/heteroaromatic groups. groups. Furthermore, incorporation of methoxy substituents in in the the aryl rings was usually also also beneficial. beneficial. In mostmost photolyses,photolyses, use of aa photosensitizerphotosensitizer such asas 4-methoxyacetophenone4-methoxyacetophenone (MAP) also proved advantageous. Energy transfer between the the MAP excited state and the iminyl portion of the oxime π π derivative was probably promoted byby π–π-stacking of their aryl units. For all six types of carbonyl oxime (3–8), UV irradiation in hydrocarbon solutions, either straight For all six types of carbonyl oxime (3–8), UV irradiation in hydrocarbon solutions, either straight or or MAP sensitised, initially generated an iminyl radical (R1R2C=N•; designated Im) accompanied by MAP sensitised, initially generated an iminyl radical (R1R2C=N‚; designated Im) accompanied by an equivalentan equivalent of a of second a second species. species. All were All thereforewere therefore effective effective iminyl radicaliminyl sources.radical sources. Symmetrical Symmetrical dioxime dioxime oxalates 4 (R1 = R3 and R2 = R4) gave only one radical type and were particularly convenient oxalates 4 (R1 = R3 and R2 = R4) gave only one radical type and were particularly convenient for for the study of iminyls. The discovery of these precursors permitted detailed EPR spectroscopic study the study of iminyls. The discovery of these precursors permitted detailed EPR spectroscopic study of diverse iminyls’ structures and reactions. The second O-centred radicals released by carbonyl of diverse iminyls’ structures and reactions. The second O-centred radicals released by carbonyl oximes (other than 4) included acyls and carbamoyls as well as novel and exotic species such as oximes (other than 4) included acyls and carbamoyls as well as novel and exotic species such as alkoxycarbonyloxyl (alkyl carbonate radicals) R3OC(O)O• and carbamoyloxyl R3R4NC(O)O• radicals. alkoxycarbonyloxyl (alkyl carbonate radicals) R3OC(O)O‚ and carbamoyloxyl R3R4NC(O)O‚ radicals. Subsequent transformations enabled C-centred alkyl, acyl and carbamoyl radicals, as well as N-centred Subsequent transformations enabled C-centred alkyl, acyl and carbamoyl radicals, as well as N-centred aminyl radicals, to be benignly generated. Much inaccessible information about the behaviour of aminyl radicals, to be benignly generated. Much inaccessible information about the behaviour of these these species therefore became reachable. species therefore became reachable. None of the carbonyl oxime precursors dissociate cleanly by thermolyses in the usual temperature None of the carbonyl oxime precursors dissociate cleanly by thermolyses in the usual temperature range of organic preparations (T < ~120 °C). Flash Vacuum Pyrolysis (ca. 650 °C) led to electrocyclic range of organic preparations (T < ~120 ˝C). Flash Vacuum Pyrolysis (ca. 650 ˝C) led to electrocyclic rather than radical reactions though these also had useful preparative connotations [15]. rather than radical reactions though these also had useful preparative connotations [15].

2.2. Iminyl Radical Structures and Transformations In the the past, past, for for spectroscopic spectroscopic purposes, purposes, specialised specialised methods methods of generating of generating iminyl iminyl radicals radicals were wereemployed. employed. For example, For example,iminyls were iminyls obtained were from obtained organic nitriles from organicby electron nitriles bombardment by electron and bombardmentsubsequent protonation and subsequent and/or protonation by H-atom and/oraddition by [16]. H-atom Thermal addition dissociations [16]. Thermal of thionocarbamates dissociations of thionocarbamates[17], H-atom abstractions [17], H-atom from abstractionsimines [18] and from treatments imines [18 ]of and organic treatments azides of with organic t-BuO azides• radicals with t[19,20]-BuO‚ wereradicals also [ 19put,20 to] wereuse in also obtaining put to useiminyl in obtaining EPR and other iminyl spectra. EPR and The other range spectra. of accessible The range iminyl of accessibletypes has been iminyl considerably types has been broadened considerably as oxime broadened derivatives as oxime 3–8 have derivatives come into3–8 use.have come into use. For example, UV irradiation of dioxime oxalate 4a in tt-butylbenzene-butylbenzene solvent with MAP as photosensitizer, at 240 K, in thethe resonantresonant cavity of aa 99 GHzGHz EPREPR spectrometerspectrometer enabledenabled the spectrum shown inin FigureFigure1 a1a to to be be obtained. obtained. Absorption Absorption of radiationof radiation led led to scissionto scission of one of one of the of N–Othe N–O bonds bonds and productionand production of iminyl of iminyl radical radical9 plus O9 -centredplus O-centred radical 10 radical. The latter 10. The was latter probably was extremely probably short-livedextremely andshort-lived dissociated and dissociated with release with of a secondrelease copyof a second of 9 (Scheme copy of2). 9Thus, (Scheme the 2). EPR Thus, spectrum the EPR consisted spectrum of onlyconsisted iminyl of only9 in theiminyl accessible 9 in the temperature accessible temperature range. The range. 1:1:1 triplet The 1:1:1 hyperfine triplet hyperfine splitting (hfs)splitting from (hfs) the from the 14N-atom was slightly asymmetrical due to incomplete averaging of the radical tumbling at 240 K. Small hfs from the benzyl CH2 and the Me group were also resolved (Table 1).

Molecules 2016, 21, 63 4 of 23

14N-atom was slightly asymmetrical due to incomplete averaging of the radical tumbling at 240 K. MoleculesSmall hfs 2016 from, 21, 63 the benzyl CH2 and the Me group were also resolved (Table1). 4 of 23

Molecules 2016, 21, 63 4 of 23

(a)(b)

Figure 1. 9 GHz isotropic EPR spectra of selected iminyl radicals in t-butylbenzene solution. Left top Figure 1. 9 GHz isotropic(a)( EPR spectra of selected iminyl radicals in t-butylbenzeneb) solution. Left top ((aa)) Experimental Experimental spectrum spectrum of of 1-phenylpropan-2-yliminyl 1-phenylpropan-2-yliminyl radical radical 99, ,with with simulation simulation belowbelow ((redred),), during during Figure 1. 9 GHz isotropic EPR spectra of selected iminyl radicals in t-butylbenzene solution. Left top UVUV photolysis photolysis of of dioxime dioxime oxalate oxalate 4a4a. ;RightRight top top ((bb)) Experimental Experimental spectrum spectrum during during UV UV photolysis photolysis of of (a) Experimental spectrum of 1-phenylpropan-2-yliminyl radical 9, with simulation below (red), during oximeoxime ester ester 3a3a at at320 320 K showing K showing iminyl iminyl radical radical 11 (marked11 (marked Im) in Imblack) in with black simulation with simulation in red (below in red) UV photolysis of dioxime oxalate 4a. Right top (b) Experimental spectrum during UV photolysis of and double integral in green. The spectrum of adduct oxyaminyl radical 12 appears in the central region. (belowoxime) and ester double 3a at 320 integral K showing in green. iminyl The radical spectrum 11 (marked of adduct Im) in black oxyaminyl with simulation radical in12 redappears (below in) the centraland region. double integral in green. The spectrum of adduct oxyaminyl radical 12 appears in the central region.

SchemeSchemeScheme 2. 2. Photolytic Photolytic2. Photolytic generation generation generation of of iminyl iminyl radicals radicals from from from carbonyl carbonyl carbonyl oximes. oximes. oximes.

The spectrumThe spectrum in Figure in Figure 1b 1billustrates illustrates the the advantages advantages ofof precursorsprecursors prepared prepared from from aldoximes aldoximes The spectrum in Figure1b illustrates the advantages1 of precursors• prepared from aldoximes such such as 3a. The released ald-iminyls have structures R1CH=N • with β-H-atoms. Because of the large such as 3a. The released ald-iminyls have structures1 R CH=N‚ with β-H-atoms. Because of the large as 3ahfs. The from released its β-H-atom, ald-iminyls the spectrum have structuresof the 2,4,6-trimethoxyphenyliminyl R CH=N with β-H-atoms. radical Because 11 appears of as the sharp large hfs hfs from its β-H-atom, the spectrum of the 2,4,6-trimethoxyphenyliminyl radical 11 appears as sharp from1:1:1 its β triplets-H-atom, in either the spectrumwing (Im) leaving of the 2,4,6-trimethoxyphenyliminylan extensive central “window” in the radical field 11whereappears spectra as of sharp 1:1:1 triplets in either wing (Im) leaving an extensive central “window” in the field where spectra of 1:1:1other triplets radicals in either can appear wing ( Imwell) leavingresolved. an Ald-iminyl extensive radical central spectra “window” act as invaluable the field references where for spectra other radicals can appear well resolved. Ald-iminyl radical spectra act as valuable references for of otherdetermination radicals can of the appear g-factors well of resolved.other species. Ald-iminyl However, radicalmore importantly, spectra act photo-dissociation as valuable references of 3a, for determination of the g-factors of other species. However, more importantly, photo-dissociation of 3a, determination(and other carbonyl of the g-factors oximes) ofreleas otheres equimolar species. However,quantities of more the iminyl importantly, and its partner photo-dissociation radical. As of (and other carbonyl oximes) releases equimolar quantities of the iminyl and its partner radical. As 3a, (andFigure other 1 shows, carbonyl double oximes) integrations releases of such equimolar ald-iminyl quantities spectra ofare the usually iminyl easy and and, its hence, partner these radical. Figureiminyls 1 shows, also doubleact as key integrations references forof suchthe absolute ald-iminyl and/or spectra relative are concentrat usuallyions easy of and,other hence, radicals these As Figure1 shows, double integrations of such ald-iminyl spectra are usually easy and, hence, these iminylsgenerated. also act In as the key case references of dissociation for ofthe oxime absolute ester 3aand/or, the O- relativecentred partnerconcentrat radicalions rapidly of other lost COradicals2 iminylswith also production act as key of primary references C-centred for the radical absolute R3• (Scheme and/or 1). relative At lower concentrations temperatures (~240 of other K), radicalsthe generated. In the case of dissociation of oxime ester 3a, the O-centred partner radical rapidly lost CO2 generated. In the3• case of dissociation of oxime ester 3a, the O-centred3• partner radical rapidly lost CO2 spectrum of R was observed, whereas at higher3• temperatures R added to the precursor oxime ester with production of primary C-centred radical R 3‚ (Scheme 1). At lower temperatures (~240 K), the withand production generated of the primary N-centredC-centred radical radical12. The Rspectrum(Scheme of oxyaminyl1). At lower 12 was temperatures well resolved (~240 in the K), the spectrum of R3• was observed, whereas at higher temperatures R3• added to the precursor oxime ester spectrumcentral of window R3‚ was (Figure observed, 1b) [21,22]. whereas at higher temperatures R3‚ added to the precursor oxime ester and generated the N-centred radical 12. The spectrum of oxyaminyl 12 was well resolved in the and generatedThe EPR the parametersN-centred of radical a representative12. The spectrum set of imin of oxyaminylyl radicals are12 collectedwas well in resolved Table 1. inThey the all central central window (Figure 1b) [21,22]. 14 windowhave (Figure characteristic1b) [21 g,22-factors]. close to 2.0030 and isotropic a( N) hfs of about 10 G. The magnitude of The EPR parameters of a representative set of iminyl radicals are collected in Table 1. They all Thethe latter EPR is parameters similar to that of of a representativeπ-type N-centred set radicals of iminyl indicating radicals that are the collectedunpaired electron in Table (upe)1. They is all have characteristic g-factors close to 2.0030 and isotropic a(14N) hfs of about 10 G. Theβ magnitude of havemainly characteristic located ing-factors a nitrogen close 2p orbital to 2.0030 [18]. andIn addition, isotropic thea (large14N) values hfs of obtained about 10 for G. a(H The) point magnitude to a of the lattersubstantial is similar hyperconjugative to that of π-type interaction N-centred such radicalsthat the semi-occupiedindicating that molecular the unpaired orbital electron (SOMO) (upe)lies is mainlyin locatedthe nodal inplane a nitrogen of the C=N 2p πorbital-bond (Figure[18]. In 2a). addition, the large values obtained for a(Hβ) point to a substantial hyperconjugative interaction such that the semi-occupied molecular orbital (SOMO) lies in the nodal plane of the C=N π-bond (Figure 2a).

Molecules 2016, 21, 63 5 of 23 the latter is similar to that of π-type N-centred radicals indicating that the unpaired electron (upe) is mainly located in a nitrogen 2p orbital [18]. In addition, the large values obtained for a(Hβ) point to a substantial hyperconjugative interaction such that the semi-occupied molecular orbital (SOMO) lies in the nodal plane of the C=N π-bond (Figure2a).

Molecules 2016, 21, 63 5 of 23 Table 1. EPR Characteristics of iminyl radicals in solution a. Table 1. EPR Characteristics of iminyl radicals in solution a. Radical Solvent T/K g-Factor a(14N) a(Hβ) a(Other) Reference RadicalMolecules 2016, 21, 63Solvent T/K g-Factor a(14N) a(Hβ) a(Other) 5 of 23 Ref. ‚ H2C=N • c-C3H6 223 2.0028 9.7 85.2(2H) - [19] H2C=N‚ c-C3H6Table 1.223 EPR Characteristics2.0028 of iminyl 9.7 radicals85.2 in solution(2H) a. - [19] MeHC=N H2O 300 2.0028 10.2 82.0 2.5(3H) [16] MeHC=N‚ • H2O 300 2.0028 10.2 82.0 2.5(3H) [16] EtHC=N Radicalc-C 3H6 Solvent220 T/K 2.0028g-Factor a(14 9.6N) a(H 79.5β) 2.8(2H),a(Other) 0.5(3H)Ref. [20] EtHC=N‚ • c-C3H6 220 2.0028 9.6 79.5 2.8(2H), 0.5(3H) [20] PhHC=N H2C=NCCl• 4 c-C3H2706 223 2.00312.0028 10.09.7 85.2 (2H) 80.1 0.4(2H), - 0.3(1H) [19] [17] ‚ • ArHC=NPhHC=N(11MeHC=N) PhBu-• CClt 4 H2O300 270300 2.00342.00312.0028 10.2 10.710.0 82.0 84.080.1 2.5(3H) 0.4(2H), - 0.3(1H) [16] [17] [21] ‚ MeArHC=N2C=N • EtHC=N(11) c-C• PhBu-3H6 c-Ct 3H2236 300220 2.0029 2.0034 2.0028 9.610.7 9.6 79.5 84.0 - 2.8(2H), 1.4(6H)0.5(3H) - [20] [21] [19] PhHC=N• CCl4 270 2.0031 10.0 80.1 0.4(2H), 0.3(1H) [17] PhMeC=NMe2C=N• PhBu-c-Ct3H6 308223 2.0030 2.0029 10.0 9.6 - - 0.8(3H) 1.4(6H) [19] [23] ‚ ArHC=N• (11) PhBu-t 300 2.0034 10.7 84.0 - [21] BnMeC=NPhMeC=N(9) PhBuPhBu--t t 240308 2.00332.0030 10.0 9.8 - - 1.5(3H), 0.8(3H) 1.1(2H) [23][tw] Ph C=N‚ Me2C=NCCl• c-C3H3086 223 2.0033 2.0029 10.09.6 - - 1.4(6H) 0.4(8H) [19] [24] BnMeC=N2 • (9) PhBu4 -t 240 2.0033 9.8 - 1.5(3H),1.1(2H) [tw] PhMeC=N a PhBu-t 308 2.0030 10.0 - 0.8(3H) [23] • Isotropic g-factors; isotropic hfs in Gauss; tw = this work. Ph2C=NBnMeC=N • (9CCl) PhBu4 -t 308240 2.0033 2.0033 9.810.0 - - 1.5(3H),1.1(2H) 0.4(8H) [tw] [24] Ph2C=N• a IsotropicCCl4 g-factors;308 isotropic2.0033 hfs 10.0 in Gauss; - tw = this work. 0.4(8H) [24] The SOMO and isotropic spina Isotropic density g-factors; distribution isotropic hfs in Gauss; computed tw = this work. for the biphen-2-yliminyl radical at The SOMO and isotropic spin density distribution computed for the biphen-2-yliminyl radical the B3LYP/6-311+G(2d,p)The SOMO leveland isotropic are illustrated spin density distribution in Figure computed2b,c, respectively. for the biphen-2-yliminyl These radical show rather clearly at the B3LYP/6-311+G(2d,p) level are illustrated in Figure 2b,c, respectively. These show rather clearly the orientation atin the the B3LYP/6-311+G(2d,p) nodal plane of level the are C=N illustratedπ-bond in Figure of lobes 2b,c, respectively. containing These the show upe rather and clearly fully support the the orientationthe orientation in the nodalin the nodal plane plane of the of the C=N C=N π π-bond-bond ofof lobes lobes containing containing the upe the and upe fully and support fully supportthe the conclusionsconclusions fromconclusions thefrom EPR the from EPR data. the data.EPR data.

(a) (b)(c)

Figure 2. Electronic configuration of alkyl- and aryl-iminyl radicals. (a) hyperconjugative interaction; Figure 2. Electronic(b) (DFTa) configuration computed alpha SOMO; of alkyl- (c) DFT and computed(b aryl-iminyl)( spin density radicals. distribution. (a ) hyperconjugativec) interaction; (b) DFT computed alpha SOMO; (c) DFT computed spin density distribution. Figure 2.End Electronic product configuration characterizations of alkyl- and EPR and observationsaryl-iminyl radicals.with iminyls (a) hyperconjugative [16,25] demonstrated interaction; that (b) DFTthey computedterminate by alpha bimolecular SOMO; combination (c) DFT computed with production spin density of bismethylenehydrazines distribution. 13 (Scheme 3) End productor by characterizations combination with alkyl and radicals EPR to yield observations imines. Ingold with and co-workers iminyls established [16,25] demonstrated that these that they Endtermination product characterizationsreactions are fast and and diffusion EPR controlledobservations for small with iminyls iminyls (2kt =[16,25] 4 × 107, 2demonstrated × 108, and that terminate by bimolecular9 −1 −1 combination1 with2 production of bismethylenehydrazines 13 (Scheme3) or they terminate4 × 10 Mby ·sbimolecular at 238 K for Rcombination and R i-Pr, Ph, with and production CF3, respectively) of bismethylenehydrazines [18]. 13 (Scheme 3) by combinationor by combination with alkyl with radicalsalkyl radicals to yield to yield imines. imines. IngoldIngold and and co-workers co-workers established established that these that these 7 8 terminationtermination reactions reactions are fastare fast and and diffusion diffusion controlled controlled for small small iminyls iminyls (2kt (2 =k 4t ×= 10 4 7ˆ, 210 × 10,8 2, andˆ 10 , and 9 ´19 ´−1 −1 1 2 2 4 ˆ 10 4M × 10¨ sM ·sat at 238 238 K Kfor for R andand R R i-Pr,i-Pr, Ph, Ph, and and CF3, CFrespectively)3, respectively) [18]. [18].

Scheme 3. Combination, dissociation and H-atom abstraction reactions of iminyl radicals.

SchemeScheme 3. Combination, 3. Combination, dissociation dissociation and and H-atomH-atom abstraction abstraction reactions reactions of iminyl of iminyl radicals. radicals.

Molecules 2016, 21, 63 6 of 23

Molecules 2016, 21, 63 ‚ 6 of 23 As expected, sterically shielded iminyls like t-Bu2C=N terminated much more slowly 2 ´1 ´1 (2kt = 4 ˆ 10 M ¨ s at 238 K). Iminyl radical termination reactions and rates are, therefore, quite As expected, sterically shielded iminyls like t-Bu2C=N• terminated much more slowly (2kt = similar to those of C-centred analogues. 4 × 102 M−1·s−1 at 238 K). Iminyl radical termination reactions and rates are, therefore, quite similar to Iminyls also undergo dissociation by β-scission with production of nitriles 14 and release of those of C-centred analogues. C-centred radicals (Scheme3). When R 1 and R2 are aryl or primary-alkyl groups, this dissociation is Iminyls also undergo dissociation by β-scission with production of nitriles 14 and release of slow at room temperature and does not compete with, for example, ring closure. However, at higher C-centred radicals (Scheme 3). When R1 and R2 are aryl or primary-alkyl groups, this dissociation is temperatures, and for R1 or R2 = sec- or tert-alkyl, β-scission is rapid. For example, if R1 = R2 = t-Bu slow at room temperature and does not compete with, for example, ring closure. However, at higher then k = 42 s´1 at 300 K [18]. Occasionally, iminyl radical dissociations have been put to use in temperatures,d and for R1 or R2 = sec- or tert-alkyl, β-scission is rapid. For example, if R1 = R2 = t-Bu then preparations of organic nitriles [14,26]. Iminyl radicals are also known to abstract H-atoms from kd = 42 s−1 at 300 K [18]. Occasionally, iminyl radical dissociations have been put to use in preparations suitable substrates producing imines (16) and C-centred radicals. Kinetic studies are scarce but the of organic nitriles [14,26]. Iminyl radicals are also known to abstract H-atoms from suitable substrates diphenylhex-5-en-2-iminyl radical 15 abstracts H-atoms from thiophenol with a rate constant of producing imines (16) and C-centred radicals. Kinetic studies are scarce but the diphenylhex-5-en-2- 6 ˆ 106 M´1¨ s´1 at 298 K [27]. Comparing with C-centred analogues suggests that iminyls abstract iminyl radical 15 abstracts H-atoms from thiophenol with a rate constant of 6 × 106 M−1·s−1 at 298 K [27]. H-atoms 10–20 times more slowly. Comparing with C-centred analogues suggests that iminyls abstract H-atoms 10–20 times more slowly. Iminyl radicals with alkenyl side chains ring close selectively in the 5-exo mode with formation Iminyl radicals with alkenyl side chains ring close selectively in the 5-exo mode with formation of pyrrolomethyl type radicals. This cyclisation forms the basis of several preparative procedures of of pyrrolomethyl type radicals. This cyclisation forms the basis of several preparative procedures of pyrrole and dihydropyrrole containing heterocycles [26,28–30]. Some rate data has been determined pyrrole and dihydropyrrole containing heterocycles [26,28–30]. Some rate data has been determined by LFP [27] and steady state kinetic EPR methods [31], and key data is displayed in Table2. by LFP [27] and steady state kinetic EPR methods [31], and key data is displayed in Table 2.

Table 2. Rate parameters for cyclisations of unsaturated iminyl radicals in solution a. Table 2. Rate parameters for cyclisations of unsaturated iminyl radicals in solution a.

1 1 2 2 3 3 −´1 1 ´−11 Radical;Radical; R R,R, R,R, R mode kkcc//ss (300(300 K) K) EEcc//kcalkcal·mol¨ mol 1717b b 5-exo 1010 ׈ 101033 9.29.2 1818;; H, H, H, H, H H 5-exo 8.88.8 ׈ 101033 8.38.3 3 1818;; H, H, Me, Me, H H 5-exo 0.150.15 ׈ 10103 10.710.7 18; H, H, Et 5-exo 60 ˆ 103 7.2 18; H, H, Et 5-exo 60 × 103 7.2 18; Me, H, H 5-exo 0.31 ˆ 103 10.3 3 18; Me,19 H, H 5-exo 0.3122 ˆ × 10103 10.37.8 2019c 6-endo5-exo 22<5 ׈ 101033 7.8>9 c 3 a Data from reference20 [31 ] except as indicated6-endo otherwise; all <5 in hydrocarbon× 10 solution.>9 Arrhenius A-factors ´1 b c a Dataassumed from to ref. be log( [31]Ac except/s ) = as 10.0; indicatedData from otherwise; references all [31 in,32 hydrocarbon]; Data from referencesolution. [33 Arrhenius]. A-factors assumed to be log(Ac/s−1) = 10.0. b Data from refs. [31,32]. c Data from ref. [33]. The rate constants for 5-exo-cyclisations of the iminyls 17 and 18 (R2 = R2 = R3 = H) are smaller thanThe that rate of theconstants archetype for 5-exoC-centred-cyclisations hex-5-enyl of the radicaliminyls by17 and a factor 18 (R of2 = about R2 = R 25.3 = H) A are Me smaller substituent than thatat the of attacked the archetype end of C the-centred double hex-5-enyl bond reduced radicalkc bybut a an factor Et substituent of about 25. at theA Me terminus substituent of the at C=C the attackeddouble bond end of increased the doublekc (Table bond 2reduced). These k trendsc but an are Et thesubstituent same as at observed the terminus with of C-centred the C=C radicaldouble bondcyclisations. increased Surprisingly, kc (Table 2). These the bismethyl trends are substituted the same as iminyl observed18 (Rwith1 = C-centred Me, R2 = radical R3 = H) cyclisations. displayed 1 2 3 Surprisingly,an inverse gem-dimethyl the bismethyl effect substituted (Table2 ).iminyl However 18 (Rk c=for Me, iminyl R = 19R , = lacking H) displayed the Ph substituent,an inverse gem-dimethylbut with a single effect Me (Table in its 2). pentenyl However chain, kc for showed iminyl 19 the, lacking expected the increase Ph substituent, in kc. Thus, but with the a inverse single Megem-dimethyl in its pentenyl effect chain, is specially showed related the expected to the presence increase ofin thekc. Thus, Ph substituent the inverse on gem- the iminedimethyl centre. effect DFT is speciallycomputations related implied to the presence it was due of tothe steric Ph substituent interaction on between the imin thise centre. Ph and DFT the computations bis-Me groups implied in the italkenyl was due chain to steric [31]. DFTinteraction computations between of this ring Ph closure and the reactions bis-Me groups of C-, N in- and the Oalkenyl-centred chain radicals [31]. withDFT computationsthe high-quality of ring quantum closure composite reactions methodof C-, N- Gaussian-4 and O-centred [34] radicals suggested with that the the high-quality stiffness and quantum lack of compositeflexibility associatedmethod Gaussian-4 with the C=N[34] suggested bond was that responsible the stiffness for the and comparatively lack of flexibility slow associated ring closure with of theiminyl C=N radicals, bond was rather responsible than any for effect the comparatively from their higher slow electronegativity. ring closure of iminyl In general, radicals, iminyls rather withthan anyaromatic effect acceptors from their such higher as 20 electrcyclisedonegativity. in 6-endo Inmode general, with productioniminyls with of aromatic 6-member acceptors rings (see, such however, as 20 cyclisedSection 2.7in ).6-endo Kinetic mode data with is sparse production but implies of 6-member that the rings rate (see, constants however, for iminyl Section ring 2.7). closures Kinetic ontodata isaromatics sparse but are implies also about thatan the order rate constants of magnitude for imin lessyl than ring those closures of C-centred onto aromatics analogues are [also33]. about an order of magnitude less than those of C-centred analogues [33].

Molecules 2016, 21, 63 7 of 23 Molecules 2016, 21, 63 7 of 23

2.3. Radical Based Transformations ofof OximeOxime EstersEsters andand DioximeDioxime OxalatesOxalates Oxime esters were the firstfirst oxime derivatives to be used for radical generation and they remain the most popular. They have been put to use in two ways; either as sources of C-centred radicals or for generating iminyl radicals. On homolysis of their weak N–O bonds, an iminyl radical is accompanied by anan acyloxylacyloxyl type type radical radical21 (Scheme21 (Scheme4). Most 4). Most acyloxyls acyloxyls decarboxylate decarboxylate and release and Crelease-centred C-centred radicals veryradicals rapidly very rapidly [35] making [35] making these precursors these precursors very effective very effective sources sources of the of latter.the latter. UV UV photolyses photolyses of appropriateof appropriate3, 3 with, with and and without without sensitisers, sensitisers, have have proved proved effective effective for for generating generating aa broadbroad rangerange of primary, secondary and tertiary C -centred radicals as well as allylic types and even σ-radicals such as cyclopropyl and trifluoromethyltrifluoromethyl [[21,22].21,22].

Scheme 4. Photo-induced oxime ester transformations [[22].22].

The good quality EPR spectra obtainable enabled the configurations and conformations of The good quality EPR spectra obtainable enabled the configurations and conformations of these these radical types to be elucidated. The reactions they underwent with their parent oxime esters, or radical types to be elucidated. The reactions they underwent with their parent oxime esters, or with other partners or co-reactants (see Figure 1b for an example), were also monitored. A recent with other partners or co-reactants (see Figure1b for an example), were also monitored. A recent time-resolved EPR spectroscopic investigation of the photo-cleavage of several oxime esters enabled time-resolved EPR spectroscopic investigation of the photo-cleavage of several oxime esters enabled effective spin-spin relaxation times T2* to be determined [36]. From the T2* dependences on monomer effective spin-spin relaxation times T2* to be determined [36]. From the T2* dependences on monomer concentrations, rate data was deduced for addition reactions with acrylate monomers. concentrations, rate data was deduced for addition reactions with acrylate monomers. Oxime esters 3 proved to be clean and convenient sources of C-centred radicals that could be Oxime esters 3 proved to be clean and convenient sources of C-centred radicals that could be used used in syntheses of various alicyclic and heterocyclic compounds [22]. Scheme 4 depicts one example in syntheses of various alicyclic and heterocyclic compounds [22]. Scheme4 depicts one example in in which photolysis of precursor 3a released cyclohexenyloxyethyl radical 22 which underwent which photolysis of precursor 3a released cyclohexenyloxyethyl radical 22 which underwent 5-exo-ring 5-exo-ring closure and yielded octahydrobenzofuran 23 after H-atom transfer. The accompanying closure and yielded octahydrobenzofuran 23 after H-atom transfer. The accompanying iminyl radical iminyl radical simply abstracted H-atoms with production of an imine that was hydrolysed to the simply abstracted H-atoms with production of an imine that was hydrolysed to the easily separable easily separable aldehyde during work-up. aldehyde during work-up. O-Acetyl oxime esters R1R2C=NOC(O)Me were established as highly effective sources of iminyl O-Acetyl oxime esters R1R2C=NOC(O)Me were established as highly effective sources of iminyl radicals for synthetic purposes because the partner MeC(O)O• radicals were simply converted to radicals for synthetic purposes because the partner MeC(O)O‚ radicals were simply converted to volatile CO2 and CH4 [37–39]. Because symmetrical dioxime oxalates also cleanly yield only one volatile CO2 and CH4 [37–39]. Because symmetrical dioxime oxalates also cleanly yield only one iminyl radical, they too proved to be very successful in UV promoted preparative procedures [40,41]. iminyl radical, they too proved to be very successful in UV promoted preparative procedures [40,41]. Convenient photochemical routes, starting from these precursors, were described for pyrroles, Convenient photochemical routes, starting from these precursors, were described for pyrroles, dihydropyrroles, quinolines, phenanthridines and other aza-arenes with a range of functionality. dihydropyrroles, quinolines, phenanthridines and other aza-arenes with a range of functionality.

2.4. Oxime Esters and Photoredox Catalysis Recently, in the interests of environmental protecti protectionon and energy efficiency efficiency,, research has expanded dramatically into finding finding procedures that require only visible light, plus catalytic quantities of some special promoter. For generating ra radicals,dicals, photoredox catalysts (PCs (PCs)) of several types that require only visible light (sometimes UVA) havehave beenbeen developed.developed. Heterogeneous PCs are mainly inorganic semiconductors, particularly titania (TiO2), which has found numerous applications in conjunction semiconductors, particularly titania (TiO2), which has found numerous applications in conjunction with allylic alkenes, alkyl amines, carboxylic acids and other compounds [42–45]. Development of the alternative homogeneous type PCs has flourished exceptionally well. The most widely used

Molecules 2016, 21, 63 8 of 23 with allylic alkenes, alkyl amines, carboxylic acids and other compounds [42–45]. Development of the alternative homogeneous type PCs has flourished exceptionally well. The most widely used members 2+ of thisMolecules class are2016,complexes 21, 63 of Ru or Ir, particularly Ru(bpy)3 and fac-[Ir(ppy)3], that usually8 of operate 23 in conjunction with bromocarbonyl compounds and other organic halides [46–50]. Most PCs adsorb a photonmembers from the of this incident class are light complexes and are of thereby Ru or Ir, raised particularly to a long Ru(bpy) lived32+ triplet and fac state-[Ir(ppy) PC*3],that that canusually act both as a reductantoperate in conjunction and/or an with oxidant. bromocarbonyl In the presence compou ofnds an and acceptor other organic molecule halides A, with[46–50]. a suitableMost PCs redox potential,adsorb electron a photon transfer from the from incident the PC*light generatesand are thereby the radical raised anionto a long A´‚ lived. These triplet radical state PC* anions that then convertcan toact neutral both as a radicals reductant A ‚and/orby loss an ofoxidant. an anion In the such presence as halide of an acceptor X´ or carboxylate. molecule A, with Alternatively, a suitable PC* redox potential, electron transfer from the PC* generates the radical anion A−•. These radical anions may accept an electron from a suitable donor molecule D, thus creating the radical cation D`‚ that then convert to neutral radicals A• by loss of an anion such as halide X− or carboxylate. Alternatively, then converts to a neutral radical by loss of a cation, usually H+. PC* may accept an electron from a suitable donor molecule D, thus creating the radical cation D+• Expresslythat then converts designed to a neutral oxime radical ester typesby loss wereof a cation, trialled usually recently H+. to function as acceptors with fac-Ir(ppy)Expressly3 as PC [51designed,52]. Oxime oxime esters ester 25atypes,b, containingwere trialledO -benzoylrecently to moieties function substituted as acceptors with with strong electronfac-Ir(ppy) withdrawing3 as PC [51,52]. groups Oxime such esters as 25a 4-CN,b, containing and 4-CF O-3,benzoyl were shown moieties to substituted be effective with in strong this role (Schemeelectron5). withdrawing groups such as 4-CN and 4-CF3, were shown to be effective in this role (Scheme 5).

SchemeScheme 5. Reactions 5. Reactions of of designer designeroxime oxime esters catalysed catalysed by by facfac-[Ir(ppy)-[Ir(ppy)3] [51,52].3][51, 52].

Electrons were transferred to these oxime esters from the [fac-Ir(ppy)3]* triplet states so generating Electronstransient radical were transferredanions 26. Loss to theseof the oximesubstituted esters benzoate from the anions [fac-Ir(ppy) from 263 generated]* triplet states iminyl so radicals generating transient27. Cyclisation radical anions onto the26. adjacent Loss of aryl the substitutedrings afforded benzoate cyclohexadienyl anions fromtype radicals26 generated 28b. Oxidation iminyl radicals to 27. Cyclisationthe corresponding onto the cyclohexadienyl adjacent aryl ringstype cations afforded 29 took cyclohexadienyl place via SET type to the radicals previously28b .produced Oxidation to the correspondingPC+ ions. Proton cyclohexadienyl loss then led to the type product cations phenanthridines29 took place 30 via. A SET wide to range the previously of the latter produced was PC+ ions.obtainable Proton in this loss way then and, led for to 24 the with product Ar = 4-CNC phenanthridines6H4, the procedure30. could A wide be carried range out of in the one latter pot was from the aldehydes without isolation of 25a (Scheme 5). Analogous PC mediated routes to quinoline obtainable in this way and, for 24 with Ar = 4-CNC6H4, the procedure could be carried out in one pot fromand the pyridine aldehydes derivatives without were isolation also demonstrated. of 25a (Scheme 5). Analogous PC mediated routes to quinoline and pyridine derivatives were also demonstrated. 2.5. Photodissociation of Ketoxime Glyoxalates Bucher and co-workers investigated the LFP induced dissociation of 9-fluorenone oxime phenylglyoxylate 31 in CCl4 solution by a variety of spectroscopic methods [53]. They used time resolved FTIR and time-resolved EPR to identify intermediate radicals. By these means, dissociation was shown to produce the expected iminyl radical 32 together with very short-lived benzoylcarbonyloxyl

Molecules 2016, 21, 63 9 of 23

2.5. Photodissociation of Ketoxime Glyoxalates Bucher and co-workers investigated the LFP induced dissociation of 9-fluorenone oxime phenylglyoxylate 31 in CCl4 solution by a variety of spectroscopic methods [53]. They used timeMolecules resolved 2016, 21, 63 FTIR and time-resolved EPR to identify intermediate radicals. By these means,9 of 23 dissociation was shown to produce the expected iminyl radical 32 together with very short-lived benzoylcarbonyloxylradical 33. Rapid loss radicalof CO2 33from. Rapid 33 yielded loss of benzoyl CO2 from radicals33 yielded 34 and benzoyl their subsequent radicals 34 chemistryand their subsequentdominated the chemistry system dominated(Scheme 6). the system (Scheme6). Benzoyl radicals abstracted chlorine atom atomss from solvent to yield benzoyl chloride 35b (or a bromine atom from CCl3Br to yield benzoyl bromide). In the presence of oxygen, coupling occurred with generation of peroxyls 36.. PreparativePreparative sequences based around oxime glyoxalates have not so far been established, but it seems clear they could be exploited as new clean sources of acyl or aroyl radicals as well as for iminyl radicals.

Scheme 6. Photodissociation and subsequent reac reactionstions of an oxime glyoxalate [[53].53].

2.6. Carbamoyl Radicals from Oxime Oxalate Amides: Ring Closures to β-- and and γγ-Lactams.-Lactams Oxime oxalate amides 6 may be obtained in good yields from O-chlorooxalyl oximes 37 and amines (Scheme7 7).).

Scheme 7. Oxime oxalate amides and ring clos closuresures of carbamoyl radicals [[54,55].54,55].

UV photolyses of solutions in PhBu- tt delivered exclusive scissions scissions of of their their weak weak N–O N–O bonds. bonds. A number of iminyl and, after CO2 extrusion, carbamoyl (aminoacyl) radicals 38, were observed by A number of iminyl and, after CO2 extrusion, carbamoyl (aminoacyl) radicals 38, were observed by EPR spectroscopy [[54,55].54,55]. Some representative EPR data for carbamoyls, including literature values, values, is collected collected in in Table Table 3.3. The The N–C N–C bonds bonds of of amides amides have have partial partial double double bond bond character character and, and, hence, hence, high −1 highinternal internal rotation rotation barriers barriers (20 (20± 5˘ kcal·mol5 kcal¨ mol). ´High1). High barriers barriers are are therefore therefore expected expected in in carbamoyl radicals. Experimental data is lacking, but a DFT computation [B3LYP/6-311+G(2d,p)] on radicals 38a and 38b provided an internal rotation barrier (about the N–C(O) bond) of 19.8 kcal·mol−1. It follows that carbamoyls will be capable of existing as E and Z isomers. Not surprisingly, only one isomer, presumably the E-isomer, was detected in each case. Carbamoyls such as 38b, with cis-structures in which the NH hydrogen is trans to the orbital containing the upe, have been generated by H-abstraction from N-alkyl formamides [56]. The hfs from the NH hydrogens of these conformers are of much larger magnitude (see Table 3).

Molecules 2016, 21, 63 10 of 23 radicals. Experimental data is lacking, but a DFT computation [B3LYP/6-311+G(2d,p)] on radicals 38a and 38b provided an internal rotation barrier (about the N–C(O) bond) of 19.8 kcal¨ mol´1. It follows that carbamoyls will be capable of existing as E and Z isomers. Not surprisingly, only one isomer, presumably the E-isomer, was detected in each case. Carbamoyls such as 38b, with cis-structures in which the NH hydrogen is trans to the orbital containing the upe, have been generated by H-abstraction from N-alkyl formamides [56]. The hfs from the NH hydrogens of these conformers are of much larger magnitude (see Table3). Molecules 2016, 21, 63 10 of 23

Table 3. EPR parameters of carbamoyl (aminoacyl) radicals in solution. Molecules 2016, 21,Table 63 3. EPR parameters of carbamoyl (aminoacyl) radicals in solution. 10 of 23

Table 3. EPR parameters of carbamoyl (aminoacyl) radicals in solution.

RadicalRadical SolventSolvent T/K T/Kg-Factorg-Factora(N)a(N) a(Other)a(Other) ReferenceRef. • Me(H)NC‚(O)(O)Radical (38a (38a, trans, trans)) PhMePhMeSolvent 208208 T/K 2.0015g-Factor2.0015 24.0a(N) 24.00.9(NH), 0.9(NH),a(Other) 0.9(3H) 0.9(3H) Ref. [56[56]] Me(H)NCMe(H)NC‚(O)•(O)• ((O)38b (38b (,38acis, cis), trans) ) PhMePhMePhMe 208208208 2.00152.0015 21.2 24.0 21.2 0.9(NH), 25.1(NH) 25.1(NH) 0.9(3H) [56] [56 [56]] •‚ but-4-enyl(Bn)NCMe(H)NC (O)(O)•(O) ( (38b38e (38e,) cis)) PhBu-PhBu-PhMet t 230230208 2.00172.00152.0017 21.7 21.2 21.7 0.8(1H) 25.1(NH) 0.8(1H) [56] [55 [55]] ‚ • but-2-enyl(Bn)NCbut-2-enyl(Bn)NCbut-4-enyl(Bn)NC(O)•(O) (38e) DTBP DTBPPhBu- t 360 360230 2.00192.00172.0019 22.1 21.722.1 0.8(1H) [55] [57 [57]] n-Bu(Bn)NCbut-2-enyl(Bn)NC‚(O)•(O) DTBPDTBP 360360 2.00192.0019 21.922.1 0.9(4H) [57] [57 ] n-Bu(Bn)NC•(O) DTBP 360 2.0019 21.9 0.9(4H) [57] n-Bu(Bn)NC38c •(O) PhBu-DTBPt 220360 2.00182.0019 23.321.9 0.9(4H) [57] [58 ] 38c PhBu-t 220 2.0018 23.3 [58] 38d 38c PhBu-PhBu-t t220 220 2.0018 2.0018 21.0 23.3 1.6(1H) [58] [55 ] 38d38d PhBu-PhBu-t t 220220 2.0018 21.0 21.0 1.6(1H) 1.6(1H) [55] [55] A noteworthy feature of carbamoyl radicals’ EPR spectra is that their g-factors are comparatively A noteworthyA noteworthy feature feature of carbamoylof carbamoyl radicals’ radicals’ EPREPR spectra is is that that their their g-factors g-factors are arecomparatively comparatively small and actually less than that of the free electron (g = 2.0023). Only a few other radicals share this smallsmall and actuallyand actually less less than than that that of of the the free free electron electron (g == 2.0023).2.0023). Only Only a fewa few other other radicals radicals share share this this characteristic so the g-factor is an aid in identification [59]. The comparatively large a(N) hfs indicate characteristiccharacteristic so the so theg-factor g-factor is anis an aid aid in in identificati identification [59]. The The comparatively comparatively large large a(N) a (N)hfs indicatehfs indicate σ carbamoylscarbamoyls have have-electronic σ-electronic structures structures and and this this waswas supported by by DFT DFT computations. computations. Figure Figure 3 shows3 shows carbamoyls have σ-electronic structures and‚ this was supported by DFT computations. Figure 3 shows the σ-lobe of the SOMO of the Ph(Me)NC (O)• radical, computed at the B3LYP/6-311+G(2d,p) level, the σthe-lobe σ-lobe of the of theSOMO SOMO of ofthe the Ph(Me)NC Ph(Me)NC•(O)(O) radical,radical, computedcomputed at at the the B3LYP/6-311+G(2d,p) B3LYP/6-311+G(2d,p) level, level, in the nodal plane of the CO π-system. The spin density distribution (Figure3b) mirrors this feature. in the innodal the nodal plane plane of the of theCO CO π-system. π-system. The The spin spin density density distributiondistribution (Figure (Figure 3b) 3b) mirrors mirrors this thisfeature. feature.

(a) (b)

• FigureFigure 3. (a )3. DFT (a) DFT computed computed(a alpha) alpha SOMO SOMO of of Ph(Me)NC Ph(Me)NC ‚(O)(O) radical; radical; (b ()(b DFTb)) DFT computed computed spinspin density density • distribution of Ph(Me)NC‚ (O) radical. Figuredistribution 3. (a) ofDFT Ph(Me)NC computed(O) alpha radical. SOMO of Ph(Me)NC•(O) radical; (b) DFT computed spin density distributionCarbamoyl of Ph(Me)NC radicals •(O)containing radical. suitably situated acceptor groups readily underwent ring Carbamoylclosure. For example, radicals containingthe N-but-4-enyl suitably oxime situated oxalate acceptor amide 6e groups furnished readily the carbamoyl underwent radical ring 38e closure. For example,Carbamoyland this cyclised the radicalsN-but-4-enyl efficiently containing in oxime the normal oxalatesuitably 5-exo amide -modesituated6e to affordfurnished acceptor pyrrolidin-2-one thegroups carbamoyl readily derivative radical underwent 40 38ein goodand ring this closure.cyclisedyield efficientlyFor [55] example, (Scheme in the the7). normal Interestingly,N-but-4-enyl5-exo-mode carbamoyl oxime to oxalate afford radica pyrrolidin-2-one amidels functionalised 6e furnished derivativewith theallylic carbamoyl40 sidein chains good radical yieldalso [38e55] (Schemeand thisunderwent 7cyclised). Interestingly, ring efficiently closure carbamoyl inin the the rare normal radicals 4-exo -mode5-exo functionalised-mode with eventual to afford with production pyrrolidin-2-one allylic side of 4-member chains derivative also ring underwent azetidin- 40 in good ring 2-ones. For example, precursor 6f produced carbamoyl 38f that, after 4-exo-cyclisation to azetidinylalkyl yieldclosure [55] in the(Scheme rare 4-exo 7). -modeInterestingly, with eventual carbamoyl production radica ofls 4-memberfunctionalised ring azetidin-2-ones.with allylic side For chains example, also radical 41, yielded β-lactam 42. precursorunderwent6f ringproduced closure carbamoyl in the rare38f 4-exothat,-mode after with4-exo eventual-cyclisation production to azetidinylalkyl of 4-member radical ring41 azetidin-, yielded The azetidinone ring system occurs as a key feature in the β-lactam family of antibiotics so 2-ones.β For example, precursor 6f produced carbamoyl 38f that, after 4-exo-cyclisation to azetidinylalkyl -lactampreparative42. methods are of special interest. Radical closures to 4-member rings are normally slow in radical 41, yielded β-lactam 42. comparison to the reverse ring opening which is fast because of the strain in the 4-member rings [60–62]. The azetidinone ring system occurs as a key feature in the β-lactam family of antibiotics so Note the rate constants (kc) for 4-exo-closure of the but-3-enyl 43 and ring opening (kd) of the preparativecyclobutylmethyl methods areradical of special 44 in Scheme interest. 8. TheRadical 4-member closures azetidinone to 4-member ring system rings arehas normallyproved to slowbe in comparisonexceptional to the because reverse β -lactamsring open haveing beenwhich prepared is fast because by cyclisations of the strain of carbamoyl in the 4-member radicals [63–65], rings [60–62]. of Note amidoalkylthe rate constants radicals [66–70] (kc) for and 4- ofexo- amidylclosure radicals of the[71]. but-3-enyl This topic has 43 beenand reviewedring opening in the context(kd) of the cyclobutylmethylof homolytic ring radical closures 44 in geneSchemeral [72]. 8. EPRThe spectra4-member obtained azetidinone from UV irradiationsring system of oximehas proved oxalate to be exceptionalamides becausemade possible β-lactams kinetic have studies been of preparedseveral carbamoyl by cyclisations radical cyclisationsof carbamoyl [58,73]. radicals Carbamoyl [63–65], of amidoalkyl38g was radicals obtained [66–70] from photodissociation and of amidyl of radicals precursor [71]. 6g andThis the topic rate hasconstant been for reviewed its 4-exo-cyclisation in the context of homolytic ring closures in general [72]. EPR spectra obtained from UV irradiations of oxime oxalate amides made possible kinetic studies of several carbamoyl radical cyclisations [58,73]. Carbamoyl 38g was obtained from photodissociation of precursor 6g and the rate constant for its 4-exo-cyclisation

Molecules 2016, 21, 63 11 of 23

The azetidinone ring system occurs as a key feature in the β-lactam family of antibiotics so preparative methods are of special interest. Radical closures to 4-member rings are normally slow in comparison to the reverse ring opening which is fast because of the strain in the 4-member rings [60–62]. Note the rate constants (kc) for 4-exo-closure of the but-3-enyl 43 and ring opening (kd) of the cyclobutylmethyl radical 44 in Scheme8. The 4-member azetidinone ring system has proved to be exceptional because β-lactams have been prepared by cyclisations of carbamoyl radicals [63–65], of amidoalkyl radicals [66–70] and of amidyl radicals [71]. This topic has been reviewed in the context of homolytic ring closures in general [72]. EPR spectra obtained from UV irradiations of oxime oxalate amides made possible kinetic studies of several carbamoyl radical cyclisations [58,73]. Carbamoyl 38g was obtained from photodissociation of precursor 6g and the rate constant for its 4-exo-cyclisation onto a C=CMolecules bond 2016 to, 21 yield, 63 bicyclic radical 45 was determined to be four orders of magnitude11 of 23 greater than that of archetype pent-4-enyl radical 43 (Scheme8). The rate constant for 4 -exo-cyclisation of carbamoylonto38h a onC=C to bond a C=N to yield bond bicyclic to produce radical 45 aminylwas determined radical to48 be wasfour orders of the of same magnitude order greater of magnitude. than that of archetype pent-4-enyl radical 43 (Scheme 8). The rate constant for 4-exo-cyclisation of Note that the rate constant for opening of the azetidinone ring of 48 was not much different from that carbamoyl 38h on to a C=N bond to produce aminyl radical 48 was of the same order of magnitude. of model 44Notebut that was the sufficiently rate constant for smaller opening than of thekc azetidinone(for 38b) soring that of 48 ring was closednot much products different from could that be isolated. As expected,of model all the 44 but4-exo was sufficientlyrate constants smallerwere than kc smaller(for 38b) so than that ring the closed archetype productskc couldfor 5-exobe isolated.cyclisation of hex-5-enylAs46 expected,[74,75] andall the analogue 4-exo rate constants49 [76] (Scheme were smaller8). Itthan is worththe archetype mentioning kc for 5-exo that cyclisation4-exo-ring of closures hex-5-enyl 46 [74,75] and analogue 49 [76] (Scheme 8). It is worth mentioning that 4-exo-ring closures of cyclic carbamoyl radicals containing thiazolidine rings 38d, to directly give bicyclic penicillanic of cyclic carbamoyl radicals containing thiazolidine rings 38d, to directly give bicyclic penicillanic structures,structures, were not were achieved not achieved [73]. [73].

Scheme 8.SchemeKinetic 8. Kinetic data data for for ring ring closures closures of of carbamoyl carbamoyl and model and modelradicals at radicals 300 K in atsolution. 300 KRate in solution. constants k/s−1 [54,73–76]. Rate constants k/s´1 [54,73–76]. 2.7. Dissociation of Oxime Carbonates and Generation of Alkoxycarbonyloxyl Radicals 2.7. DissociationOxime of Oxime carbonates Carbonates 51, like most and of Generation the fore-going of Alkoxycarbonyloxyloxime esters, have a bi-modal Radicals character and can operate either as sources of iminyl radicals or for production of the little known alkoxycarbonyloxyl Oxime carbonates 51, like most of the fore-going oxime esters, have a bi-modal character and can radicals, depending on the pattern of functionality [77]. For generation of iminyls, oxime carbonates operate eitherwith O as-ethoxycarbonyl sources of iminyl 51 (R2 = Et) radicals or O-phenoxycarbonyl or for production 51 (R2 = Ph) of thesubstitution little known were easily alkoxycarbonyloxyl prepared radicals, dependingby condensation on of the oximes pattern with ofthe functionalitycorresponding chloroformates. [77]. For generation Photolyses ofof the iminyls, aldoxime oxime derived carbonates with O-ethoxycarbonylprecursors 51 (R1 =51 H) (Rin benzotrichloride2 = Et) or O-phenoxycarbonyl solvent afforded nitrile51 products(R2 = 52 Ph). However, substitution good yields were easily of phenanthridines 53 with a range of functionality were obtained from 51 (R1 = Me) (Scheme 9). The prepared by condensation of oximes with the corresponding chloroformates. Photolyses of the by-products, ethanol or phenol (R2OH), were easily separated [23,78]. 1 aldoxime derivedAn intriguing precursors dichotomy51 (R of behaviour= H) in was benzotrichloride observed during transformations solvent afforded of oxime nitrile carbonates products 52. functionalised with benzofuran 54a and benzothiophene 54b groups. In biphen-2-yliminyl radicals (e.g., 20), the SOMO on the N-atom is well placed for orbital overlap at either the ipso-C-atom (5-exo-ring closure) or the ortho-C-atom (6-endo-ring closure); see Figure 2b,c (Section 2.2). In analogous fashion, iminyls 55a and b were capable of undergoing either 5-exo-ring closure to spiro-radical 56a,b or 6-endo-ring closure to 57a,b. In preparative photolyses with 54a and 54b at ambient temperature (~330 K)

Molecules 2016, 21, 63 12 of 23

However, good yields of phenanthridines 53 with a range of functionality were obtained from 51 (R1 = Me) (Scheme9). The by-products, ethanol or phenol (R 2OH), were easily separated [23,78]. An intriguing dichotomy of behaviour was observed during transformations of oxime carbonates functionalised with benzofuran 54a and benzothiophene 54b groups. In biphen-2-yliminyl radicals (e.g., 20), the SOMO on the N-atom is well placed for orbital overlap at either the ipso-C-atom (5-exo-ring closure) or the ortho-C-atom (6-endo-ring closure); see Figure2b,c (Section 2.2). In analogous fashion, iminyls 55a and b were capable of undergoing either 5-exo-ring closure to spiro-radical 56a,b or 6-endo-ring closure to 57a,b. In preparative photolyses with 54a and 54b at ambient temperature (~330 K) exclusively,Molecules 2016 the, 21, 63 benzofuro[3,2- c]isoquinoline and benzo[4,5]thieno[3,2-c]isoquinoline12 of 23 products derived from the endo-radicals 57a and 57b were isolated in good yields [78]. Curiously, EPR spectra Moleculesexclusively, 2016, the21, 63 benzofuro[3,2- c]isoquinoline and benzo[4,5]thieno[3,2-c]isoquinoline products derived12 of 23 taken duringfrom photolyses the endo-radicals of 54a 57aand and 54b57b werein solution isolated in at good 230 yields K showed [78]. Curiously, solely EPR the spectraspiro -radicalstaken 56a and 56b [33]. Theexclusively,during structures photolyses the andbenzofuro[3,2- of energies 54a and c54b]isoquinoline of in the solution iminyl and at benzo[4,5]thieno[3,2-230 and K showed cyclised solely radicalsc ]isoquinolinethe spiro were-radicals products computed 56a andderived 56b by DFT at the from[33]. Thethe endostructures-radicals and 57a energies and 57b of were the iminyl isolated and in cyclisedgood yields radicals [78]. wereCuriously, computed EPR byspectra DFT takenat the B3LYP/6-311+G(2d,p)duringB3LYP/6-311+G(2d,p) photolyses level of of 54alevel theory and of theory 54b with in with solution the the Gaussian at 230 K 09showed package 09 package solely [79]. the [spiro79].-radicals 56a and 56b [33]. The structures and energies of the iminyl and cyclised radicals were computed by DFT at the B3LYP/6-311+G(2d,p) level of theory with the Gaussian 09 package [79].

Scheme 9.SchemeReactions 9. Reactions of iminyl of iminyl radicals radicals deri derivedved from from oxime oxime carbonates carbonates [33,78]. [33,78].

The transitionScheme states 9. Reactions for spiro of andiminyl endo radicals ring dericlosureved from were oxime also carbonates located. The[33,78]. intrinsic reaction The transitioncoordinate states scans are for illustratedspiro and in Figureendo 4 forring the benzofuro closure system were 55a also. located. The intrinsic reaction The transition states for spiro and endo ring closure were also located. The intrinsic reaction coordinate scanscoordinate are illustratedscans are illustrated in Figure in Figure4 for 4 for the the benzofuro benzofuro system system 55a. 55a.

Figure 4. DFT computed reaction coordinates for spiro (red) and endo (blue) ring closure of benzofuro-iminyl radical 55a. Figure 4. DFT computed reaction coordinates for spiro (red) and endo (blue) ring closure of Figure 4. DFT computed reaction coordinates for spiro (red) and endo (blue) ring closure of benzofuro-iminyl radical 55a. benzofuro-iminyl radical 55a.

Molecules 2016, 21, 63 13 of 23

´1 The DFT computations showed spiro ring closure to be exoenthalpic (∆H298 = ´6.9 kcal¨ mol ) ´1 but the endo mode was thermodynamically more favourable (∆H298 = ´8.1 kcal¨ mol ). However, the ‡ ´1 computed enthalpy of activation for spiro-closure (∆E 298 = 9.3 kcal¨ mol ) was significantly lower ‡ ´1 than that for endo-closure (∆E 298 = 13.1 kcal¨ mol ) (see Figure4). Similar trends were computed for the benzothieno system from radical 55b. These DFT energies supported the conclusion that, at the low temperature of the EPR experiments, kinetic control led to spiro radicals 56a,b. However, at the temperature of the preparative experiments (~100 K higher), the spiro-cyclisations were reversible but the endo were not. Consequently, thermodynamic control steered the processes towards accrual of the endo products. The alternative possibility that the spiro-radicals 56a,b rearranged to the endo radicals 57a,b by 1,2-shifts via tetracyclic structures could be discounted because DFT computations indicated much higher energy requirements. In the past, a few alkoxycarbonyloxyl radicals [ROC(O)O‚] had been generated from hazardous dialkyl peroxydicarbonate precursors (58) and studied by EPR spectroscopy [80] and LFP [81]. By means of suitably functionalised oxime carbonates, a much wider range of these radicals became accessible and their chemistry could be explored in greater detail. Remarkably, alkoxycarbonyloxyl radicals dissociate to release CO2 much more slowly than ‚ acyloxyl radicals (RCO2 ). Thus, they have sufficient lifetimes to participate in a range of abstraction, addition and cyclisation processes. They are not directly detectable by EPR spectroscopy [80] due to fast relaxation times but their broad absorptions centred at around 640 nm in the UV-visible spectrum have been observed in the LFP studies [81]. They are very reactive and, for example, propyloxycarbonyloxyls 59 abstract H-atoms from secondary CH2 sites to produce esters of carbonic acid 60 with a rate constant of 1.9 ˆ 107 M´1¨ s´1. They add to unactivated alkenes nearly a factor of 100 faster and also add to aromatics to produce cyclohexadienyl type radicals 62 with ease (see Scheme 10). In accord with this, the methoxycarbonyloxyl radical MeOC(O)O‚ was also observed to add to the alkenic sites of lipid components more rapidly than it abstracted allylic type H-atoms [82]. Furthermore, EPR spectroscopic ‚ 3 ´1 data showed it dissociated to CO2 and MeO radicals with a rate constant of about 2 ˆ 10 s at 300 K. Oxime carbonate 63 released benzyloxycarbonyloxyl radical 64 and surprisingly this (and derivatives) underwent exclusively spiro-cyclisation to produce spiro-cyclohexadienyl radical 66 [23,83]. From steady state kinetic EPR concentration measurements, the rate constant for CO2 loss from 64 3 ´1 ‚ was determined to be 3.4 ˆ 10 s at 300 K. The similarity in the kd values for MeOC(O)O and ‚ BnOC(O)O verified that alkoxycarbonyloxyls lose CO2 about seven orders of magnitude more slowly than acyloxyl radicals. The rate constant for spiro-cyclisation was measured to be 2 ˆ 105 s´1 and this is about an order of magnitude greater than for spiro-cyclisation of C-centred analogues [84–86]. Similarly, oxime carbonates with allylic side-chains, e.g., 67 released the corresponding allyloxycarbonyloxyl radicals 68 on photolysis. The latter ring closed in the 5-exo-mode to produce 1,3-dioxolan-2-on-4-ylmethyl 6 ´1 radicals 69 very rapidly. The cyclisation rate constant (kc = 5 ˆ 10 s at 300 K) was obtained from kinetic EPR measurements. Scheme 10 illustrates that the cyclisation rates of alkoxycarbonyloxyl radicals onto aromatic and alkenic acceptors are significantly faster than analogous rates of C-centred radicals. In this respect, they resemble alkoxyl radicals, such as pent-4-enyloxyl, that are also known to ring close much more rapidly than C-centred analogues [87,88]. Factors influencing the rapidity of 5-exo-cyclisations of C-, N- and O-centred radicals have been reviewed [34]. Products containing the 1,3-dioxolan-2-one unit (cyclic carbonates) were isolated from cyclisations of species such as 69; though in meagre yields. H-atom abstractions from solvents or substrates by alkoxycarbonyloxyl radicals were also rapid so that alkylcarbonate esters such as 70 formed very easily. These were mono-esters of carbonic acid and as such were known to be unstable and extrude CO2 [89,90]. The resulting alcohols e.g., 71 were usually the major products isolated from alkoxycarbonyloxyl reactions. A synthetic protocol to trap and isolate products containing the cyclic carbonate structural unit has yet to be devised. Molecules 2016, 21, 63 14 of 23 Molecules 2016, 21, 63 14 of 23

SchemeScheme 10. Reaction10. Reaction channels channels and and rate rateconstants constants fo forr alkoxycarbonyloxyl alkoxycarbonyloxyl radicals radicals [23,81,83]. [23,81 ,83].

2.8. Oxime Carbamates: Precursors for Iminyl and Aminyl Radicals 2.8. Oxime Carbamates: Precursors for Iminyl and Aminyl Radicals Previous interest in oxime carbamates 71 (O-carbamoyl oximes) centred on their biological Previousactivities [91,92] interest and in their oxime known carbamates inhibition of71 se(veralO-carbamoyl enzymes [93,94]. oximes) Designer centred compounds on their of biological this activitiesclass [have91,92 recently] and their been known adapted inhibition for release of of several specific enzymes radicals [95]. [93,94 UV]. Designerirradiation compounds leads again to of this classselective have recently scission been of their adapted N–O bonds for release with formation of specific of radicalsiminyls together [95]. UV with irradiation the rare and leads exotic again to selectivecarbamoyloxyl scission of radicals their N–O 72. DFT bonds computations with formation predicted of iminylsthat N,N- togetherdi-substituted with thecarbamoyloxyls rare and exotic carbamoyloxylwould dissociate radicals very 72rapidly. DFT to CO computations2 and di-substituted predicted aminyl that radicalsN,N 73-di-substituted. However, the computations carbamoyloxyls implied that N-mono-substituted carbamoyloxyls (72, R1 or R2 = H) might have sufficient lifetime to would dissociate very rapidly to CO2 and di-substituted aminyl radicals 73. However, the computations impliedbe trapped that N -mono-substitutedat low temperatures. carbamoyloxylsStudy of UV photolys (72es,R of1 ora set R2 of= oxime H) might carbamates have sufficientin solution lifetimeby EPR spectroscopy revealed that for N,N-di-substitution only Im and aminyl radicals 73 were produced to be trapped at low temperatures. Study of UV photolyses of a set of oxime carbamates in solution in the accessible temperature range. However, with the mono-substituted N-allyl-precursor 71 by EPR spectroscopy revealed that for N,N-di-substitution only Im and aminyl radicals 73 were (R1 = H, R2 = allyl), the EPR spectrum of the oxazolidinylmethyl radical 76, from ring closure of the producedcorresponding in the accessible carbamoyloxyl temperature radical range.75, wasHowever, discerned at with about the 150 mono-substituted K. So, this N-mono-substitutedN-allyl-precursor 1 2 71 (Rexample= H, R did= allylhave), sufficient the EPR spectrumstructural integrity of the oxazolidinylmethyl to undergo 5-exo-cyclisation; radical 76 in, fromconfirmation ring closure of the of the correspondingtheoretical carbamoyloxylprediction. radical 75, was discerned at about 150 K. So, this N-mono-substituted example didAt room have temperature sufficient and structural above, decarboxylation integrity to undergo is rapid so5-exo both-cyclisation; N-mono- and in N,N- confirmationdi-substituted of the theoreticaloxime prediction.carbamates provide much needed benign and serviceable alternatives for aminyl radical Atgeneration. room temperature The EPR parameters and above, of a representative decarboxylation set of isaminyl rapid radicals so both obtainedN-mono- mainly and in thisN,N -di- substitutedway are oxime listed in carbamates Table 4. It should provide be muchnoted neededthat only benign a very few and N serviceable-monoalkylaminyl alternatives radicals for have aminyl been detected in solution; though monoarylaminyls do provide good isotropic spectra in which the radical generation. The EPR parameters of a representative set of aminyl radicals obtained mainly in upe is delocalised into the ring [96]. N this way areThe listedEPR data in Tableindicate4. Itthat should dialkylaminyl be noted radicals that only are abent; very the few magnitudes-monoalkylaminyl of the a(N) values radicals haveare been consistent detected with in solution; π-type electronic though monoarylaminylsconfigurations. The doDFT provide computed good SOMO isotropic and spectraspin density in which the upe[B3LYP/6-311+G(2d,p)] is delocalised into thefor the ring Et [296N•]. radical in Figure 5 clearly show the π-type orbital associated Thewith EPRthe N-atom data indicate and the considerable that dialkylaminyl spin density radicals distributed are bent; to the the Et groups. magnitudes In this respect, of the a aminyl(N) values are consistentradicals resemble with π -typethe familiar electronic C-centred configurations. alkyl radicals The although, DFT computedas the cyclisation SOMO rate and constant spindensity in ‚ [B3LYP/6-311+G(2d,p)]Scheme 11 illustrates, forthey the generally Et2N reactradical more in slowly. Figure 5 clearly show the π-type orbital associated withthe N-atom and the considerable spin density distributed to the Et groups. In this respect, aminyl radicals resemble the familiar C-centred alkyl radicals although, as the cyclisation rate constant in

Scheme 11 illustrates, they generally react more slowly. Molecules 2016, 21, 63 15 of 23 Molecules 2016, 21, 63 15 of 23

‚ a TableTable 4. 4.Isotropic Isotropic EPR EPR parameters parameters forfor selectedselected dialkylaminyl radicals radicals R R2N2N• a. . Molecules 2016, 21, 63 15 of 23 Radical T/K g-Factor a(N)/G a(Hβ)/G a(Hβ)/G Ref. Radical T/K g-Factor a(N)/G a(Hβ)/G a(Hβ)/G Reference • b Me2NTable 4.183 Isotropic 2.0044EPR parameters 14.8 for selected27.4 dialkylaminyl (6H) radicals R2N [97,98]• a. ‚ b Me2N •183 2.0044 14.8 27.4 (6H) [97,98] ‚ Et2NRadical 210 T/K 2.0047g-Factor a 14.4(N)/G 35.7a(Hβ )/G(2H) a(H35.7(2H)β)/G Ref. [95] Et2N 210 2.0047 14.4 35.7 (2H) 35.7(2H) [95] 2 • ‚ Bn NMe 2N220• 183 b 2.00462.0044 14.314.8 27.437.1 (6H) (2H) 37.1 (2H) [97,98] [95] Bn2N 220 2.0046 14.3 37.1 (2H) 37.1 (2H) [95] • allyl‚ 2NEt 2N•210 210 2.00482.0047 14.6 14.4 35.736.0 (2H) (2H) 35.7(2H)36.0 (2H) [95] [95] allyl2N 210 2.0048 14.6 36.0 (2H) 36.0 (2H) [95] • BnN‚PeBnN•PeBn 230 2N230 2202.0048 2.00482.0046 14.2 14.2 14.3 37.136.9 36.9 (2H) (2H) (2H) 37.135.4 (2H) 35.4 (2H) (2H)[95] [95] [95] • a allyl2N 210 2.0048 14.6 36.0 (2H)b 36.0 (2H) [95] Ina PhBu-t solutiont unless otherwise specified;b In cyclopropane solution. InBnN PhBu-•Pesolution 230 unless2.0048 otherwise 14.2 specified;36.9 (2H)In cyclopropane35.4 (2H) solution.[95] a In PhBu-t solution unless otherwise specified; b In cyclopropane solution.

(a) (b) (a) (b) Figure 5. (a) DFT computed SOMO for diethylaminyl radicals; (b) Spin density distribution. FigureFigure 5. 5.(a ()a DFT) DFT computed computed SOMOSOMO forfor diethylaminyl radicals; radicals; (b (b) )Spin Spin density density distribution. distribution.

Scheme 11. Photochemical reactions of oxime carbamates [95].

The viability of the alternative mode of oxime carbamate usage, as precursors of iminyl radicals 1 2 (Im), was effectivelySchemeScheme demonstrated 11. 11.Photochemical Photochemical with diethyl reactions substituted of of oxime oxime precursors carbamates carbamates 71 (R = [95]. R [95 = ].Et). Good yields of phenanthridines were obtained when the Ar group was a biphenyl moiety. Photolysis of precursor 71 with a pent-4-enyl (Pe) chain released aminyl radical 73 (R2 = Bn, R1 = Pe) that was characterised The viability of the alternative mode of oxime carbamate usage, as precursors of iminyl radicals The viabilityby EPR spectroscopy of the alternative (Table 4). modeCyclisation of oxime took place carbamate above about usage, 250 asK and precursors ring closure of kinetic iminyl radicals (Im), was effectively demonstrated with diethyl substituted precursors 71 (R1 = R2 = Et). Good yields (Im), was effectivelyparameters were demonstrated derived for this with N-centred diethyl species substituted (Scheme 11). precursors 71 (R1 = R2 = Et). Good yields of phenanthridines were obtained when the Ar group was a biphenyl moiety. Photolysis of precursor of phenanthridines were obtained when the Ar group was a biphenyl moiety. Photolysis of precursor 71 with 3.a pent-4-enylOxime Ethers (Pe)in Radical-Mediated chain released Reactions aminyl radical 73 (R2 = Bn, R1 = Pe) that was characterised 71 73 2 1 bywith EPR a pent-4-enylspectroscopy (Pe) (Table chain 4). releasedCyclisation aminyl took radicalplace above(R about= Bn, 250 R =K Pe)and that ring was closure characterised kinetic 3.1. Homolytic Reactions of O-alkyl and O-aryl Oxime Ethers byparameters EPR spectroscopy were derived (Table for4 ).this Cyclisation N-centred species took place (Scheme above 11). about 250 K and ring closure kinetic parameters wereThe derivedN–O bonds for of thismostN oxime-centred ethers species 78 do not (Scheme readily undergo 11). homolysis on irradiation with UVA or UVB and only low conversions to ketones and/or nitriles could be achieved even after 3. Oxime Ethers in Radical-Mediated Reactions 3. Oximeprolonged Ethers in photolyses Radical-Mediated [99]. Radicals of Reactions many types add to the C=N bonds of oxime ethers particularly rapidly [100]. Not surprisingly, therefore, when t-BuO• radicals are generated in the presence of an 3.1. Homolytic Reactions of O-alkyl and O-aryl Oxime Ethers 3.1. HomolyticO-alkyl, Reactions oxime ether of O-alkyl 78 addition and takes O-aryl place Oxime with production Ethers of oxyaminyl radicals 79 (Scheme 12). The N–O bonds of most oxime ethers 78 do not readily undergo homolysis on irradiation with The N–O bonds of most oxime ethers 78 do not readily undergo homolysis on irradiation with UVA or UVB and only low conversions to ketones and/or nitriles could be achieved even after UVAprolonged or UVB photolyses and only [99]. low Radicals conversions of many to types ketones add and/or to the C=N nitriles bonds could of oxime be achievedethers particularly even after prolongedrapidly [100]. photolyses Not surprisi [99]. Radicalsngly, therefore, of many when types t-BuO add• to radicals the C=N are bonds generated of oxime in the ethers presence particularly of an ‚ rapidlyO-alkyl, [100 oxime]. Not ether surprisingly, 78 addition therefore, takes place when witht -BuOproductionradicals of oxyaminyl are generated radicals in 79 the (Scheme presence 12). of an O-alkyl, oxime ether 78 addition takes place with production of oxyaminyl radicals 79 (Scheme 12).

Molecules 2016, 21, 63 16 of 23 Molecules 2016, 21, 63 16 of 23

Scheme 12. Radical addition to oxime ethers and radical induced dissociations [[99].99].

However, if the oxime ether contains an O–CH or O–CH2 group, then H-atom abstraction However, if the oxime ether contains an O–CH or O–CH2 group, then H-atom abstraction competes with addition such that C-centred radicals 80 are alsoalso formed.formed. The latter readily undergo β-scission to to release release an an iminyl iminyl radical radical together together with with an analdehyde aldehyde or ketone or ketone (Scheme (Scheme 12) [99].12)[ The99]. Theimportance importance of abstraction of abstraction relative relative to toaddition addition de dependspends on on the the substitution substitution pattern pattern and and temperature temperature and consequently this is seldom a clean, selective mode of radical generation from from oxime ethers. Photoredox catalytic systems for puttingputting oxime ethers to work have now been developed (see below) but recent attention has focused mainlymainly onon thermolyticthermolytic methods.methods.

3.2. Conventional and Microwave MediatedMediated Thermolyses of Oxime EthersEthers Conventional thermal dissociationsdissociations of oxime ethersethers RR11R2C=NOBn can can be be brought about by heating them in hydrocarbon solvents at T >> ~150 °C.˝C. However, products from scission of the N–O bond (BnOH(BnOH andand RR11RR22C=NH) together with products fromfrom O–CO–C bondbond breakingbreaking (R(R11RR22C=NOHC=NOH and PhCH3)) were were obtained; so, these substrate types are not suitable as clean radical sources [[101].101]. It was found, however, thatthat OO-phenyl-phenyl ketoximeketoxime ethersethers RR11RR22C=N–OPh (R 1,,R R22 == alkyl alkyl or aryl) undergo selective N–O homolysis upon heating inin hydrocarbon solventssolvents atat moderatemoderate temperaturestemperatures ((TT ~~ 90 °C)˝C) to yieldyield iminyliminyl andand phenoxylphenoxyl radicalsradicals [[6].6]. The substantialsubstantial resonance stabilisation of the phenoxyl radical predisposes the homolysis inin favour of N–O scission. In principle, this constituted a new and promising route toto iminyl radicals because the phenoxyl radicals usually ended up as the acidic, and therefore easilyeasily separable,separable, PhOH.PhOH. Thermal methods are generally advantageous for preparativepreparative work because of their simplicity and ease of scale-up.scale-up. In practice,practice, however,however, conventionalconventional thermolyses of O-phenyl-phenyl oximeoxime ethersethers requiredrequired long reaction reaction times times with with consequent consequent poor poor selectivit selectivityy and and yields. yields. Fortunately, Fortunately, it was it wasdiscovered discovered that thatmicrowave microwave heating heating (MW) (MW) was very was veryadvantageous advantageous for cleanly for cleanly generating generating iminyl iminyl radicals radicals from a from large a largerange rangeof O-phenyl of O-phenyl oxime oximeethers [29,30]. ethers [The29,30 optimum]. The optimum conditions conditions for oxime for ethers oxime with ethers alkene with acceptors alkene acceptors81 involved81 MWinvolved irradiation MW irradiation at 160 °C for at 16015–30˝C min for 15–30in an minH-donor in an solvent H-donor such solvent as toluene. such as The toluene. ionic Theliquid ionic 1-ethyl-3-methylimidazolium liquid 1-ethyl-3-methylimidazolium hexafluorophosphate hexafluorophosphate (emimPF (emimPF6) was 6added) was added to improve to improve the themicrowave microwave absorbance absorbance level level of ofthe the medium. medium. Intermediate Intermediate iminyl iminyl radicals radicals such such as as 82 underwent 5-exo cyclisationcyclisation toto radicalsradicals83 83and and these these abstracted abstracted H-atoms H-atoms from from the the solvent solvent to to afford afford good good yields yields of 3,4-dihydropyrrolesof 3,4-dihydropyrroles84 84(Scheme (Scheme 13). 13). O-Phenyl oxime ethers containing appropriately placed aromatic acceptors 85 also dissociateddissociated cleanly under under MW MW radiation. radiation. The The final final step step required required an oxidation an oxidation in this in thiscase caseso PhBu so PhBu--t provedt proved to be toa better be a bettersolvent solvent enabling enabling aza-arenes aza-arenes of type of 86 type and86 othersand othersto be isolated to be isolated in good in yields. good As yields. a further As a furtherelaboration elaboration of the ofprocess, the process, 2-aminoarylalkanone 2-aminoarylalkanone O-phenylO-phenyl oxime oxime precursors precursors 8787 werewere prepared. prepared. Mixtures of of these, these, with with an an equivalent equivalent of of an an al aldehyde,dehyde, on on MW MW irradiation irradiation in intoluene toluene with with emimPF emimPF6 as6 asadditive, additive, initially initially yielded yielded imines imines 88. These88. These were not were isolated not isolated but dissociated, but dissociated, released released iminyl radicals iminyl radicalsthat cyclised that exclusively cyclised exclusively in 6-endo inmode6-endo to producemode to aminyl produce radicals aminyl 89 radicals. The latter89. were The latterreduced were to reduceddihydroquinazolines to dihydroquinazolines 90 under the90 reactionunder the conditions reaction (Scheme conditions 13) (Scheme [102,103]. 13 )[With102 ,ZnCl103].2 Withas additive ZnCl2 to promote condensation the MW reaction proceeded in one pot to afford directly the oxidised quinazolines.

Molecules 2016, 21, 63 17 of 23 as additive to promote condensation the MW reaction proceeded in one pot to afford directly the Moleculesoxidised 2016 quinazolines., 21, 63 17 of 23

Scheme 13.13.MW MW assisted assisted preparations preparations of dihydropyrroles, of dihydropyrroles, aza-arenes aza-arenes and quinazolines and quinazolines from O-phenyl from Ooxime-phenyl ethers oxime [30 ,ethers103]. [30,103].

A recent article described micr microwaveowave promoted reactions of O-phenyl oxime ethers 91 with alkynyl side chains that afforded iminyls 92 as intermediates [104]. [104]. In In th thee presence presence of of excess excess TEMPO, TEMPO, these iminyls ring closed and then coupled with the TEMPO with production of dihydropyrrole intermediates 93 (Scheme 14).14). These These rearranged rearranged to to pyrrole pyrrole structures structures 94 thatthat spontaneously spontaneously underwent H-atom transfer and fragmentation with production of 2-acylpyrroles 95. The The O-phenyl-phenyl oximes oximes 91 were easily obtained from ketones so the whole process provided ready access to a good range of functionalised pyrroles. It is is worth worth mentioning mentioning the the report report that that indolyl-alkenyl indolyl-alkenyl OO-methyl-methyl oxime oxime ethers ethers 9696 werewere converted converted to pyridoindolesto pyridoindoles 97 (97α-carbolines)(α-carbolines) on MW on MWheating heating to 240 to °C 240 (Sch˝Ceme (Scheme 14) [105]. 14 )[Superficially,105]. Superficially, the reaction the resemblesreaction resembles that of the that O-phenyl of the O oxime-phenyl ethers oxime but ethers in this but case in thisthe casemechanism the mechanism was believed was believed to involve to electrocyclisation.involve electrocyclisation.

Scheme 14. Cyclisations of O-phenyl-phenyl and O-methyl oxime ethers [104,105]. [104,105].

3.3. Oxime Ethers and Photoredox Catalysis O-Aryl oxime ethers containing electron withdrawing groups (EWG) in their aryl rings released O-Aryl oxime oxime ethers ethers containing containing electron electron withdraw withdrawinging groups groups (EWG) (EWG) in their in aryl their rings aryl released rings iminyl radicals on irradiation with UVA or visible light when photoredox catalysts (PC) were iminylreleased radicals iminyl on radicals irradiation on irradiation with UVA with or UVA visible or visiblelight when light photoredox when photoredox catalysts catalysts (PC) were (PC) 2 3 employed. For example, oxime ether 98a containing 4-CN (or 2,4-di-NO2 or 4-CF3) aryl substitution with a catalytic amount of 1,5-dimethoxynaphthalene (DMN) on irradiation with UV light (λ > 320 nm) in 1,4-cyclohexadiene (CHD) afforded good yields of dihydropyrroles 101 (Scheme 15) [28]. Electron transfer from the excited state of the PC generated the oxime ether radical anion 99 and this

Molecules 2016, 21, 63 18 of 23

were employed. For example, oxime ether 98a containing 4-CN (or 2,4-di-NO2 or 4-CF3) aryl substitution with a catalytic amount of 1,5-dimethoxynaphthalene (DMN) on irradiation with UV light (λ > 320 nm) in 1,4-cyclohexadiene (CHD) afforded good yields of dihydropyrroles 101 (Scheme 15)[28]. Electron transfer from the excited state of the PC generated the oxime ether radical Moleculesanion 99 2016and, 21 this, 63 dissociated to give the arene-oxide 100a together with the iminyl radical. The18 latter of 23 ring closed and the product 101 was formed by H-atom abstraction from the CHD H-donor present dissociatedin excess. to give the arene-oxide 100a together with the iminyl radical. The latter ring closed and the productMore recently, 101 was it formed was shown by H-atom that the abstraction reduction fr potentialsom the CHD of oxime H-donor ethers present with O in-2,4-dinitroaryl excess. substitutionMore recently,98b were it was sufficiently shown that low the for redu thection dye potentials eosin Y to of be oxime used ethers as the with PC andO-2,4-dinitroaryl then light of visiblesubstitution wavelength 98b were only sufficiently was needed low for [106 the]. dye An eosin additional Y to be interestingused as the findingPC and then was light that withof visible98b wavelengthEt3N could beonly employed, was needed in place[106]. ofAn eosin additional Y. Irradiation interesting with finding visible was light that in with CH3 CN98b thenEt3N ledcould to beisolation employed, of imino-alcohols in place of eosin105. Y. The Irradiation proposed with mechanism visible light involved in CH fast3CN formation then led to of isolation an electron of imino-alcoholsdonor–acceptor 105 complex. The proposed between mechanism Et3N and theinvolved electron-poor fast formation ring of of98b an .electron Excitation donor–acceptor with visible complexlight then between generated Et3N the and radical the electron-poor anion analogous ring of to 98b98. Excitationthat fragmented with visible to give light stable then phenoxide generated 103the radicaland, after anion5-exo analogous-cyclisation, to 98 that pyrrolidinylmethyl fragmented to give radical stable102 phenoxide. Oxygenation 103 and, took after place 5-exo by-cyclisation, attack of pyrrolidinylmethylradical 102 onto the radical NO2 group 102. Oxygenation of 103 leading took to intermediateplace by attack104 of. Homolysisradical 102 ofonto the the N–O NO bond2 group of 104of 103gave leading nitroso-phenoxide to intermediate106 104and. Homolysis an O-centred of the radical N–O bond that rapidlyof 104 gave abstracted nitroso-phenoxide hydrogen to 106 furnish and anthe O product-centred imino-alcohol radical that rapidly105 (Scheme abstracted 15)[107 hy].drogen The scope to furnish of the the process product was imino-alcohol found to be wide 105 (Schemeaffording 15) iminoalcohols [107]. The scope in good of the to high process yields was from found alkenes to be with wide a affording range of substituents iminoalcohols and in including good to highbicyclic yields products. from alkenes with a range of substituents and including bicyclic products. In another interesting investigation, the O-methyl oxime ethers derived from 1,1 ′1-biphenyl-2--biphenyl-2- carbaldehydes were shown to yield phenanthridine derivatives on treatment with visible light and catalytic 9,10-dicyanoanthracene9,10-dicyanoanthracene [107 [107].]. However, However, the the mechanism mechanism of this of systemthis system was believed was believed to involve to photo-electroninvolve photo-electron transfer transfer to the PC to the with PC formation with formation and cyclisation and cyclisation of radical of radical cation cation intermediates. intermediates.

EWG EWG 2 2 R R 1 PC, CHD EWG R 1 CHD 2 vis. light 2 N R R R N - O -PC O 1 R N R1 N R O R R R 98 99 100 Im 101 a, EWG = 4-CN & PC = DMM in CH3CN b,EWG=2,4-di-NO2 & PC = Eosin Y in acetone O O 1 O O Et N, 2 O O R 2 OH 2 3 R R1 2 N R 1 Ar R ACN, rt N R O R N O O vis. light ZH N R1 N N N -Z -Et3N O N R R 2 O2N R R O2N 98b 102 103 104 105 106 Scheme 15. Photoredox catalyzed reactions of O-aryl oxime ethers [[107,108].107,108].

4. Conclusions Conclusions It is clear that an appropriate oxime derivative can be found to provide a benign route, free of toxic metals, unstable peroxides or hazardous azo- azo-compounds,compounds, to to almost any radical centred on a firstfirst row element. These precursors have been exploited for uncomplicated production of known and exotic transient species, enabling th thee structures and reaction selectivity to be examined; particularly by EPR spectroscopy supported by DFT computations.computations. In addition, they offer platforms for study of the kinetics of ring closures of C-, N-- and and OO-centred-centred radicals radicals and for for kine kinetictic study study of of decarboxylations decarboxylations of several short-lived OO--centredcentred species. These compound type typess also deliver novel and convenient preparative procedures for aza-heterocycles containing both 5-member ring pyrrole type and 6-member ring pyridine structural units. Oxime ethers with O-aryl functionality proved particularly suitable for use with the convenient and innocuous MW technology [108]. There remains ample scope for development of synthetic protocols employing the acyl radicals from ketoxime glyoxalates and the aminyl radicals generated from oxime carbamates. Comparatively few O-containing heterocycles have been made from carbonyl oxime precursors so there is opportunity for developments in that area. Photoredox catalytic methods have been developed for specific oxime ester and oxime ether types. It seems certain that additional photoredox catalysts suitable for this purpose will be developed and applied to a wider range of oxime derivatives.

Molecules 2016, 21, 63 19 of 23 ring pyridine structural units. Oxime ethers with O-aryl functionality proved particularly suitable for use with the convenient and innocuous MW technology [108]. There remains ample scope for development of synthetic protocols employing the acyl radicals from ketoxime glyoxalates and the aminyl radicals generated from oxime carbamates. Comparatively few O-containing heterocycles have been made from carbonyl oxime precursors so there is opportunity for developments in that area. Photoredox catalytic methods have been developed for specific oxime ester and oxime ether types. It seems certain that additional photoredox catalysts suitable for this purpose will be developed and applied to a wider range of oxime derivatives.

Acknowledgments: The author thanks EaStCHEM for financial support. Conflicts of Interest: The authors declare no conflict of interest.

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