Heteroatom Substitution at Amide Nitrogen—Resonance Reduction and HERON Reactions of Anomeric Amides

Review Heteroatom Substitution at Amide Nitrogen—Resonance Reduction and HERON Reactions of Anomeric Amides

Stephen A. Glover * and Adam A. Rosser

Department of Chemistry, School of Science and Technology, University of New England, Armidale, NSW 2351, Australia; [email protected] * Correspondence: [email protected]

Received: 6 October 2018; Accepted: 24 October 2018; Published: 31 October 2018

Abstract: This review describes how resonance in amides is greatly affected upon substitution at nitrogen by two electronegative atoms. Nitrogen becomes strongly pyramidal and resonance stabilisation, evaluated computationally, can be reduced to as little as 50% that of N,N-dimethylacetamide. However, this occurs without significant twisting about the amide bond, which is borne out both experimentally and theoretically. In certain conﬁgurations, reduced resonance and pronounced anomeric effects between heteroatom substituents are instrumental in driving the HERON (Heteroatom Rearrangement On Nitrogen) reaction, in which the more electronegative atom migrates from nitrogen to the carbonyl carbon in concert with heterolysis of the amide bond, to generate acyl derivatives and heteroatom-substituted nitrenes. In other cases the anomeric effect facilitates SN1 and SN2 reactivity at the amide nitrogen.

Keywords: amide resonance; anomeric effect; HERON reaction; pyramidal amides; physical organic chemistry; reaction mechanism

1. Introduction Amides are prevalent in a range of molecules such as peptides, proteins, lactams, and many synthetic polymers [1]. Generically, they are composed of both a carbonyl and an amino functional group, joined by a single bond between the carbon and nitrogen. The contemporary understanding of the resonance interaction between the nitrogen and the carbonyl in amides is that of an interaction between the lowest unoccupied molecular orbital (LUMO) of the carbonyl, π*C=O, and the highest occupied molecular orbital (HOMO) of the amide nitrogen (N2pz) (Figure1). This molecular orbital model highlights the small contribution of the carbonyl oxygen to the LUMO, which indicates that limited charge transfer to oxygen occurs, in line with the resonance model presented in Figure2, which signiﬁes that charge at oxygen is similar to that in polarized ketones or aldehydes and nitrogen lone pair density is transferred to electron deﬁcient carbon rather than to oxygen. The major factor in the geometry of amides, and the restricted rotation about the amide bond, is the strong π-overlap between the nitrogen lone pair and the C2pz component of the LUMO, which dominates the π*C=O orbital, on account of the polarisation in the πC=O [2,3].

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FigureFigure 1. The 1. Theinteraction interaction between between the nitrogenthe nitrogen highesthighes highest occupiedt occupied molecular molecular orbital orbital (HOMO) (HOMO) and and the the Figure 1. The interaction between the nitrogen highest occupied molecular orbital (HOMO) and the carbonylcarbonyl lowest lowest unoccupied unoccupied molecular molecular orbitalorbital orbital (LUMO)(LUMO) (LUMO) inin amides.amides. in amides. carbonyl lowest unoccupied molecular orbital (LUMO) in amides.

FigureFigure 2. Resonance 2. Resonance hybrid hybrid contribution contributions in samides, in amides, showing showing that thatthe majoritythe majority of charge of charge transfer transfer FigureFigure 2.2. Resonance hybrid contributionscontributions in amides, showing that the majority of chargecharge transfertransfer occursoccurs between between nitrogen nitrogen and andcarbon. carbon. occursoccurs betweenbetween nitrogennitrogen andand carbon.carbon.

AmideAmide resonance resonance resonance can can canbe be diminished be diminished diminished by by limiting by limiting limiting the the overlapthe overlap overlap between between between the the nitrogenthe nitrogennitrogen lone lonelone pair, pair, nN, nN, Amide resonance can be diminished by limiting the overlap between the nitrogen lone pair, nN, nandN, and andπ*C=O ππ *orbitals.*C=OC=O orbitals.orbitals. In most In Inmost instances, most instances, instances, this thiscan this canoccur can occur by occur twisting by twisting by twisting the aminothe amino the group amino group about group about the about N–C(O)the N–C(O) the and π*C=O orbitals. In most instances, this can occur by twisting the amino group about the N–C(O) N–C(O)bondbond and/or bond and/or pyramidalising and/or pyramidalising pyramidalising the nitrogen,the nitrogen, the nitrogen,which which amounts which amounts amountsto introducing to introducing to introducing “s” character“s” character “s” characterinto into the N2pthe into N2pz z bond and/or pyramidalising the nitrogen, which amounts to introducing “s” character into the N2pz theorbital. N2porbital. z orbital. orbital. ComputationalComputational modelling modelling modelling of of N–C(O)of N–C(O)N–C(O) rotation rotationrotation and and andnitrogen nitrogen nitrogen pyramidalisation pyramidalisation pyramidalisation in Nin, N inN- ,N- Computational modelling of N–C(O) rotation and nitrogen pyramidalisation in N,N- Ndimethylacetamide,Ndimethylacetamide-dimethylacetamide 1, at 1 ,,the at thetheB3LYP/6-31G(d) B3LYP/6-31G(d)B3LYP/6-31G(d) level, level,level, illustrates illustrates illustrates the the theenergetic energetic energetic changes changes changes (Figure (Figure (Figure 3)3) [[4]. 43)]. [4]. dimethylacetamide 1, at the B3LYP/6-31G(d) level, illustrates the energetic changes (Figure 3) [4]. χ τ χ ◦ DistortionDistortion ofof thethe of amide amidethe amide linkage linkage linkage can can be canbe quantified qu beantified quantified by by Winkler–Dunitz Winkler–Dunitz by Winkler–Dunitz parameters parameters parametersand χ and ,χ where andτ, where τ, where= 60χ = χ = Distortion of the amide linkage can be qu◦ antified by Winkler–Dunitz parameters χ and τ, where χ = for60° a60°for fully afor fully pyramidal a fully pyramidal pyramidal nitrogen, nitrogen, andnitrogen,τ =and 90 andτfor = 90°τ a = completely for90° afor completely a completely twisted amidetwisted twisted where amide amide the where lone where pair the orbitallonethe lone pair on pair nitrogen60° for a isfully orthogonal pyramidal to the nitrogen, C2p orbital and τ [ 5=, 690°]. Deformation for a completely from twisted the non-twisted, amide where sp2 planar the lone ground pair orbitalorbital on nitrogenon nitrogen is orthogonal is orthogonalz to the to theC2p C2pz orbitalz orbital [5,6]. [5,6]. Deformation Deformation from from the thenon-twisted, non-twisted, sp2 sp2 orbital on nitrogen is orthogonal to the C2pz orbital [5,6].3 Deformation from the non-twisted, sp2 stateplanarplanar (Figure ground ground3a) state through state (Figure (Figure rehybridisation 3a) through3a) through rehybridisation of nitrogen rehybridisation to sp of nitrogen(Figure of nitrogen3b) to issp to accompanied3 (Figuresp3 (Figure 3b) is3b) by accompanied anis accompanied increase planar ground state (Figure−1 3a) through rehybridisation of nitrogen to sp3 (Figure 3b) is accompanied inby energyanby increase an (~27increase kJin molenergy in energy), (~27 but (~27 thekJ mol majoritykJ mol−1), but−1), of butthe amide majoritythe majority resonance of amide of remains amide resonance resonance intact. remains A much remains intact. larger intact. A increase much A much by an increase in energy−1 (~27 kJ mol−1), but the majority of amide resonance◦ remains intact. A much2 inlarger energylarger increase (~100increase in kJ energy molin energy) (~100 results (~100 kJ from mol kJ mol− twisting1) results−1) results the from N–C(O) from twisting twisting bond the through N–C(O)the N–C(O) 90 bondwhilst bond throughmaintaining through 90° whilst90° sp whilst larger increase in energy (~100 kJ mol−1) results from twisting the N–C(O)3 bond through 90° whilst planaritymaintainingmaintaining at nitrogen sp2 spplanarity2 (Figureplanarity 3atd), nitrogen at and nitrogen as the (Figure nitrogen (Figure 3d), is 3d), allowedand andas totheas relax thenitrogen tonitrogen sp ishybridisation allowed is allowed to (Figurerelax to relax to3c), sp to a3 sp3 maintaining sp2 planarity at nitrogen (Figure 3d), and as the nitrogen−1 is allowed to relax to sp3 fullyhybridisationhybridisation twisted amide (Figure (Figure devoid 3c), of3c),a fully resonance a fully twisted twisted is obtained. amide amide devoid The devoid loss of of resonance ~31of resonance kJ mol is obtained. inis thisobtained. final The step Theloss is loss indicativeof ~31 of ~31kJ kJ hybridisation (Figure 3c), a fully twisted amide devoid of resonance is obtained. The loss of ~31 kJ ofmol themol−1 in concomitant− 1this in thisfinal final step twisting step is indicative andis indicative pyramidalisation of the of concomitantthe concomitant observed twisting in twisting a variety and and ofpyramidalisation twisted pyramidalisation amides. observed observed in a in a mol−1 in this final step is indicative of the concomitant twisting and pyramidalisation observed in a varietyvariety of twisted of twisted amides. amides. variety of twisted amides.

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125.0 )

-1 100.0

75.0

50.0

25.0 Relative energy (kJ mol

90 0.0 80 6070 0 50 10 20 3040 30 20 τ° 40 50 10 χ° 600

Figure 3. A B3LYP/6-31G(d) generated energy surface for the deformation of the amide moiety in Figure 3. A B3LYP/6-31G(d) generated energy surface for the deformation of the amide moiety N,N-dimethylacetamide 1 [4]. χ and τ are Winkler–Dunitz parameters for pyramidalisation and twist, in N,N-dimethylacetamide 1 [4]. χ and τ are Winkler–Dunitz parameters for pyramidalisation respectively [5,6]. (a) The ground state planar structure for N,N-dimethylacetamide; (b) untwisted and twist, respectively [5,6]. (a) The ground state planar structure for N,N-dimethylacetamide; system with sp3 hybridised nitrogen; (c) 90° rotation about N–C(O), whilst maintaining sp3 (b) untwisted system with sp3 hybridised nitrogen; (c) 90◦ rotation about N–C(O), whilst maintaining hybridisation at nitrogen; and (d) the fully twisted moiety, 90° N–C(O) rotation and sp2 hybridised sp3 hybridisation at nitrogen; and (d) the fully twisted moiety, 90◦ N–C(O) rotation and sp2 nitrogen. hybridised nitrogen.

Typically,Typically, amides amides exhibit exhibit restricted restricted rotation rotation about about the N–C(O)the N–C(O) bond, bond, in the in order the oforder 67–84 of kJ67–84 mol− kJ1, alongmol−1, aalong sigmoid a sigmoid pathway pathway with little with change little change in energy in uponenergy moderate upon moderate pyramidalisation pyramidalisation (χ = 0–40 (◦χ) and= 0– minor40°) and twisting minor (τ =twisting 0–20◦). Clearly,(τ = 0–20°). rotation Clearly, without rotation pyramidalisation without pyramidalisation is energetically unfavourable is energetically and manyunfavourable examples and of twistedmany amidesexamples are of testament twisted toamides this. The are shift testament to sp3 hybridisationto this. The atshift the amidicto sp3 nitrogenhybridisation is clearly at the demonstrated amidic nitrogen when twistingis clearly of demonstrated the N–C(O) bond when is geometrically twisting of the enforced N–C(O) by tricyclicbond is andgeometrically bicyclic bridged enforced lactams by tricyclic [7–13]. Kirby’sand bicyclic “most bridged twisted lactams amide” [7–13]. 1-aza-2-adamantanone, Kirby’s “most twisted synthesised amide” in 19981-aza-2-adamantanone, [10,12], and Tani and synthesised Stoltz’s 2-quinuclidone, in 1998 [10,12], synthesised and Tani and in 2006 Stoltz’s [14], 2-quinuclidone, exemplify the fully synthesised twisted amide,in 2006 geometrically[14], exemplify and the chemically. fully twisted Intramolecular amide, geometrically steric hindrance and chemically. is another Intramolecular source of non-planar steric twistedhindrance amides is another [15,16], assource exemplified of non-planar by the thioglycolurils twisted amides [17,18 ][15,16], and other as systems. exemplified Ring strainby the in nontwistedthioglycolurils amides, [17,18] such and as other 1-acylaziridines systems. Ring [19, 20strain] and inN nontwisted-acyl-7-azabicyclo[2.2.1]heptanes amides, such as 1-acylaziridines [21–24] can result[19,20] in and pyramidality N-acyl-7-azabicyclo[2.2.1]heptanes at the amide nitrogen, despite [21–24] retaining can a noticeableresult in npyramidalityN–π*C=O interaction. at the amide nitrogen,The structuraldespite retaining changes a noticeable accompanying nN–π* theC=O interaction. loss of amide resonance include the lengthening of theThe N–C(O) structural bond changes and minor accompanying shortening the of loss the of (N)C=O amide bond.resonance Comparing include the the lengthening fully twisted of 1-aza-2-adamantanonethe N–C(O) bond and minor to an analogous shortening unstrained of the (N)C=O tertiary bond.δ-lactam, Comparing the N–C(O) the fully bond twisted shortens 1-aza-2- from 1.475adamantanone Å to 1.352 to Å, an and analogous the (N)C=O unstrained bond lengthens tertiary δ from-lactam, 1.196 the Å N–C(O) to 1.233 Åbond [12 ,shortens25]. Spectroscopically from 1.475 Å to 1.352 Å, and the (N)C=O bond lengthens from 1.196 Å to 1.233 Å [12,25]. Spectroscopically and chemically, the amide carbonyl trends towards ketonic behaviour at large twist angles. In tricyclic 1-

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Molecules 2018, 23, x FOR PEER REVIEW 4 of 38 and chemically, the amide carbonyl trends towards ketonic behaviour at large twist angles. In tricyclic 13 aza-2-adamantanone,1-aza-2-adamantanone, the carbonyl the carbonyl carbon carbon C NMR13C resonance NMR resonance is at 200.0 is at 200.0ppm and ppm the and IR the carbonyl IR carbonyl −1 −1 vibrationalvibrational frequency frequency (1732 (1732 cm ) cm is −significantly1) is signiﬁcantly higher higher than regular than regular amides amides (1680 (1680cm ) cm[10,12].−1)[ 10,12].

2. Properties2. Properties of Anomeric of Anomeric Amides Amides

2.1. Structural2.1. Structural Properties Properties AnotherAnother way in way which in which amides amides may be may dispossessed be dispossessed of their of theirplanarity planarity and resonance and resonance is through is through bisheteroatom-substitutionbisheteroatom-substitution by electronegative by electronegative heteroatoms heteroatoms at the amide at the nitrogen amide nitrogen in 2. We innamed2. We this named class this‘anomeric class ‘anomeric amides’ on amides’ account on of the account pronounced of the pronounced anomeric effects anomeric that can effects and do that occur can andbetween do occur the heteroatomsbetween the [26–35]. heteroatoms However, [26–35 the]. However,physical, th theeoretical, physical, and theoretical, chemical andproperties chemical of propertiesvarious of congenersvarious differ congeners from those differ of from conventional those ofconventional primary, secondary, primary, and secondary, tertiary andalkylamides. tertiary alkylamides. ElectronegativeElectronegative atoms atoms demand demand an electron an electron density density redistribution redistribution which which is facilitated is facilitated by bya shift a shift in 3 3 in thethe hybridisation hybridisation at nitrogen at nitrogen towards towards sp sp, in ,accordance in accordance with with Bent’s Bent’s rule rule [36,37]. [36,37 Reduced]. Reduced nN–π nN*C=O–π *C=O overlapoverlap due to due pyramidalisation to pyramidalisation (Figure (Figure 4) together4) together with withthe increased the increased ‘2s’ character ‘2s’ character of the of lone the lonepair pair on nitrogenon nitrogen results results in structural, in structural, electronic, electronic, spectr spectroscopic,oscopic, and chemical and chemical differences differences in comparison in comparison to to traditionaltraditional amides. amides. Their Their unique unique properties properties of have of havebeen beenreviewed reviewed in recent in recent years years [31,35]. [31 ,35].

Figure 4. Reduced n –π* overlap due to pyramidalisation. Figure 4. ReducedN nC=ON–π*C=O overlap due to pyramidalisation.

MuchMuch of our of ourinterest interest into, into, and and indeed indeed the the di discoveryscovery of, of, anomeric anomeric amide amide chemistry chemistry emanates from from ourour investigations investigations of theof the biological biological activity, activity, structure, structure, and reactivity and reactivity of N-acyloxy- of NN-acyloxy--alkoxyamidesN- alkoxyamides(NAA’s) (NAA’s)2b [31,38 2b–49 [31,38–49]] a class a class of anomeric of anomeric amides. amides. Readily Readily synthesised synthesised by bytreatment treatment of of N-alkoxy-N-alkoxy-N-chloroamidesN-chloroamides 2a, 2athemselves, themselves a aform form ofof anomericanomeric amide, amide, with with silver silver or sodium or sodium carboxylate carboxylatesalts in salts anhydrous in anhydrous solvents solvents [45,46 [45,46,48,49],,48,49], NAA’s NAA’s are are direct-acting direct-acting mutagens mutagens which which react react with with nucleophilicnucleophilic centres centres in DNAin DNA [31, 39[31,39–46,49,50]–46,49,50]. Additionally,. Additionally, they react they with react a varietywith a of variety nucleophiles of to nucleophilesproduce otherto produce congeners, other including, congeners, reactive including, anomeric reactive amides anomeric in the form amides of N -alkoxy-in the formN-aminoamides of N- alkoxy-2dN[44-aminoamides,47,51] and N -alkoxy-2d [44,47,51]N-thioalkylamides and N-alkoxy-2e N[52-thioalkylamides]. We have also encountered2e [52]. We several have anomericalso encounteredreactive intermediatesseveral anomeric through reactive reactions intermediates of N-acyloxy- throughN-alkoxyamides: reactions reaction of N-acyloxy- of 2b withN- base alkoxyamides:generates Nreaction-alkoxy- ofN -hydroxamate2b with base generates anions 2g N[45-alkoxy-] and reactionN-hydroxamate with azide anions ultimately 2g [45] generatesand reaction1-acyl-1-alkoxydiazenes, with azide ultimately which generates are aminonitrenes 1-acyl-1-alkoxydiazenes,2h [53,54]. We havewhich generated are aminonitrenesN,N-dialkoxyamides 2h [53,54].2c inWe related have generated studies by N solvolysis,N-dialkoxyamides of N-alkoxy- 2c Nin-chloroamides related studies2a byin solvolysis aqueous alcohols of N-alkoxy- and throughN- chloroamidesthe reaction 2a in of aqueous hydroxamic alcohols esters and with through hypervalent the reaction iodine of reagents hydroxamic in appropriate esters with alcohols hypervalent [30,55 ,56]. iodineOther reagents anomeric in appropriate amides of alcohols theoretical [30,55,56]. interest Other to us anomeric are N-amino- amidesN-chloroamides of theoretical interest2f [34], asto us well as are NN-amino--amino-NN-chloroamides-thioalkylamides 2f 2i[34],and asN well-chloro- as NN-thioalkyamides-amino-N-thioalkylamides2j. 2i and N-chloro-N- thioalkyamidesThe impact 2j. of heteroatom substitution at amide nitrogen is clearly demonstrated by comparing TheN,N -dimethylacetamideimpact of heteroatom1 substitutionto N-methoxy- at amideN-methylacetamide nitrogen is clearly3b and demoN,nstratedN-dimethoxyacetamide by comparing 4b. N,N-dimethylacetamideIn 1996, we reported 1 onto N the-methoxy- B3LYP/6-31G(d)N-methylacetamide theoretical 3b properties and N,N of-dimethoxyacetamide the corresponding formamides 4b. In 1996,3a weand reported4a [27 on]. the The B3LYP/6-31G(d) substitution of theoreti hydrogencal properties by methoxyl of the in corresponding3a led to an increaseformamides in N–C(O)3a and 4abond [27]. length The substitution from 1.362 of Åhydrogen to 1.380 by Å methoxyl and a second in 3a led substitution to an increase at nitrogen in N–C(O) in bond4a resulted length in a from similar1.362 Å increaseto 1.380 Å to and 1.396 a second Å; the substitution carbonyl bond at nitrogen contracted in 4a marginally resulted in bya similar 0.006 increase Å. Nitrogen to in 1.396N Å;-methoxy- the carbonylN-methylformamide bond contracted and Nmarginally,N-dimethoxyformamide by 0.006 Å. becomesNitrogen distinctly in N-methoxy- pyramidalN- with ◦ methylformamideaverage angles and at nitrogenN,N-dimethoxyformamide of ~114 . With similar becomes degrees distinctly of pyramidality pyramidal (χ withN), the average increased angles N–C(O) bond length in N,N-dimethoxyformamide could not solelyχ be attributed to deformation at nitrogen. at nitrogen of ~114°. With similar degrees of pyramidality ( N), the increased N–C(O) bond length in Energetic lowering of the lone pair electrons is also responsible for reduced overlap with the adjacent N,N-dimethoxyformamide could not solely be attributed to deformation at nitrogen. Energetic C2pz orbital. This is dramatically exempliﬁed by the rotational barriers for N,N-dimethylformamide, lowering of the lone pair electrons is also responsible for reduced overlap with the adjacent C2pz orbital. This is dramatically exemplified by the rotational barriers for N,N-dimethylformamide, N-

Molecules 2018, 23, x FOR PEER REVIEW 5 of 38 Molecules 2018, 23, 2834 5 of 39 methoxy-N-methylformamide, and N,N-dimethoxyformamide, which were computed to be of the order of 75, 67, and 29 kJ mol−1, respectively [27]. N-methoxy-N-methylformamide, and N,N-dimethoxyformamide, which were computed to be of the Deformation energy surfaces for N-methoxy-N-methylacetamide 3b and N,N- order of 75, 67, and 29 kJ mol−1, respectively [27]. dimethoxyacetamide 4b, for comparison with that of N,N-dimethylacetamide 1, are depicted in Deformation energy surfaces for N-methoxy-N-methylacetamide 3b and N,N-dimethoxyacetamide Figure 5. In contrast to N,N-dimethylacetamide (Figure 3), the lowest energy forms clearly deviate 4b, for comparison with that of N,N-dimethylacetamide 1, are depicted in Figure5. In contrast to χ fromN,N -dimethylacetamideplanarity at nitrogen (Figure with 30), in the the lowest region energy of 40° forms and 50°, clearly respectively. deviate from In both planarity structures, at nitrogen the ◦ ◦ highestwith χ 0pointin the corresponding region of 40 and to 50χ,= respectively. 0°, τ= 90° In is both metastable, structures, and the the highest planar point fully corresponding twisted, and to ◦ ◦ thereforeχ = 0 , τ =nonconjugated 90 is metastable, forms, and relax the planar to fully fully pyramidal twisted, and conformations therefore nonconjugated (τ= 90°, χ forms,= 60°), relax the to ◦ ◦ energyfully pyramidal of which conformationsreflects the B3LYP/6-31G(d) (τ = 90 , χ = 60 barriers), the energy to amide of which isomerisation reflects the in B3LYP/6-31G(d) each case, which barriers are −1 approximatelyto amide isomerisation 67 and 44 in kJ each mol− case,1, respectively. which are approximatelyWhile the energy 67 andlowering 44 kJ for mol N-methoxyacetamide, respectively. While isthe modest, energy the lowering attachment for N of-methoxyacetamide two electronegative is modest, oxygens the to attachmentthe amide nitrogen of two electronegative radically lowers oxygens the −1 isomerisationto the amide barrier nitrogen by radically some 29 lowers to 33 kJ the mol isomerisation−1. Inversion barrier barriers by at some nitrogen 29 to are 33 kJlow mol on account. Inversion of thebarriers gain atinnitrogen resonance are lowstabilisation on account inof the the planar gain in resonanceform, though stabilisation the barrier in the is planar higher form, for thoughN,N- dimethoxyacetamidethe barrier is higher forwhereN,N -dimethoxyacetamidethe resonance capability where would the resonancebe less and capability a six π-electron would be repulsive less and a effectsix π -electronwould repulsiveoperate; effectplanarisation would operate; in the planarisation hydroxamic in theester hydroxamic is less estercostly is lessthan costly in thanN,N- in −1 dimethoxyacetamideN,N-dimethoxyacetamide (~6.3 vs. (~6.3 14.6 vs. kJ 14.6 mol kJ−1 mol, respectively)., respectively).

150

) 125 -1

100

Relative energy (kJ mol 25

90 0 7080 5060 0 10 40 20 30 20 30 40 50 10 τ° χ° 600

(A)

Figure 5. Cont.

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150150 ) ) -1 -1 125125

100100

7575

5050

2525 Relative energy (kJ mol Relative energy (kJ mol 9090 00 8080 60607070 00 405050 1010 2020 303040 3030 4040 2020 χ°χ° 5050 606000 1010 τ°τ°

((BB))

FigureFigure 5.5. B3LYP/6-31G(d)B3LYP/6-31G(d) energyenergy surfaces surfaces for for deformation deformation of of ( (AA))) NN-methoxy--methoxy--methoxy-NN-methylacetamide-methylacetamide-methylacetamide 3b3b andand ( (BB)) NN,,NN-dimethoxyacetamide-dimethoxyacetamide 4b4b..(. ((aaa))) Untwisted UntwistedUntwisted system system with with sp sp33 hybridisedhybridised nitrogen; nitrogen; ( (bb))) planar planarplanar untwisteduntwisted structure; structure; ( (ccc))) 90° 9090°◦ rotatedrotatedrotated structure structurestructure with with sp sp33 hybridisationhybridisation at at nitrogen; nitrogen; and and ( (dd)) the thethe fully fullyfully twistedtwistedtwisted moiety moiety with with sp sp22 hybridisedhybridised nitrogen. nitrogen.

InInIn a a recentrecent publication,publication, we we outlined outlined two two concurringconcurring isodesmic isodesmic methods methods for for estimating estimating the the amidicityamidicity of of amides amides and and lactams lactams [4]. [[4].4]. CarbonylCarbonyl su substitution,substitution,bstitution, nitrogen nitrogen atom atom replacement replacement (COSNAR), (COSNAR), developeddeveloped by by Greenberg Greenberg evaluates evaluates the the energy energy stabilis stabilisationstabilisationation when when the the target target amide amide is is generated generated from from correspondingcorresponding ketone ketone andand amineamineamine accordingaccordingaccording to toto isodesmic isodisodesmicesmic Equation ReactionReaction (1) 11 [57–59].[57–59]. [57–59]. Steric Steric oror substituentsubstituent effectseffects areare conservedconserved throughoutthroughout thethe reactionreactireactionon soso stericsteric correctionscorrections areareare not notnot required. required.required.

(1)

In the secondReactionReaction approach, 1.1. DeterminationDetermination the transamidation ofof resonanceresonance method energy,energy, (TA), RE,RE, thebyby thethe energy COSNARCOSNAR change method.method. is determined when N,N-dimethylacetamide 1 transfers the carbonyl oxygen to a target amine according to Equation (2). In the second approach, the transamidation method (TA), the energy change is determined when The limitingIn the second energy approach, increase forthe formationtransamidation of fully method twisted, (TA), unstrained the energy 1-aza-2-adamantanone change is determined by when the N,N-dimethylacetamide 1 transfers the carbonyl oxygen to a target amine according to Reaction 2. correspondingN,N-dimethylacetamide reaction with 1 transfers 1-azaadamantane, the carbonyl constitutes oxygen to completea target amine loss of according resonance to stabilisation Reaction 2. TheThe limitinglimiting energyenergy− increaseincrease1 forfor formationformation ofof fullyfully twisted,twisted, unstrainedunstrained 1-aza-2-adamantanone1-aza-2-adamantanone byby thethe (∆ETA = 76.0 kJ mol ). However, where heteroatom substituents are present at nitrogen, ∆ETA must correspondingcorresponding reactionreaction withwith 1-azaadamantane,1-azaadamantane, constitutesconstitutes completecomplete lossloss ofof resonanceresonance stabilisationstabilisation −−11 ((ΔΔEETATA == 76.0 76.0 kJkJ molmol ).). However,However, wherewhere heteroatomheteroatom substituentssubstituents areare presentpresent atat nitrogen,nitrogen, ΔΔEETATA mustmust bebe

Molecules 2018, 23, x FOR PEER REVIEW 7 of 38

MoleculesMoleculescorrected 2018, 232018, xfor ,FOR23 ,any 2834PEER additional REVIEW inductive destabilisation of the carbonyl (ΔEind) in the absence7 of 387 of of 39 Moleculesresonance, 2018, 23, x whichFOR PEER we REVIEW obtain isodemically from reactions such as Reaction 3 [33]. 7 of 38 corrected for any additional inductive destabilisation of the carbonyl (ΔEind) in the absence of resonance,correctedbe corrected forwhich any we foradditional obtain any additional isodemically inductive inductive destabilisationfrom reactions destabilisation suchof the as of Reactioncarbonyl the carbonyl 3( Δ[33].Eind ()∆ inEind the) in absence the absence of of resonance,resonance, which which we obtain we obtain isodemically isodemically from from reactions reactions such such as Reaction as Equation 3 [33]. (3) [33].

Reaction 2. Isodesmic determination of transamidation destabilisation energy, ΔETA. (2)

Reaction 2. Isodesmic determination of transamidation destabilisation energy, ΔETA.

(3) Reaction 3. Isodesmic determination of inductive destabilisation energy, ΔEind.

Reaction 3. Isodesmic determination of inductiveRE destabilisation energy, ΔEind. By the TA method,method, thethe residualresidual resonance,resonance, RETATA, is given byby EquationEquation (4).1. Reaction 3. Isodesmic determination of inductive destabilisation energy, ΔEind. −1 RETA = −76.0 kJ mol−1 + (ΔETA − ΔEind) (1) By the TA method, the residualRE resonance,TA = −76.0 RE kJTA mol, is given+ (∆ byETA Equation− ∆Eind )1. (4) By the TA method, the residual resonance, RETA, is given by Equation 1. −1 InIn bothboth the the TA TA and and COSNAR COSNARRETA = approaches, −76.0 approaches, kJ mol zero +zero point(ΔE TApoint energies− ΔE energiesind) largely largely cancel cancel and meaningful and meaningful(1) results RE = −76.0 kJ mol−1 + (ΔE − ΔE ) areresults obtained are obtained without without the need the forTA frequencyneed for frequenc calculationsy TAcalculations [58,60ind]. RE [58,60]. by both RE methods, by both the methods, negative(1) the of Inthenegative both traditional the of TA the representation and traditional COSNAR ofrepresentation approaches, resonance stabilisation zero of pointresonance energy,energies stabilisation should largely correlate cancel energy, and [4,30 shouldmeaningful,33,34,61 correlate,62] and In both the TA and COSNAR approaches, zero point energies−1 largely cancel−1 and meaningful resultsRE[4,30,33,34,61,62] are as aobtained percentage without and of −RE76.0 the as kJaneed percentage mol for−1 (orfrequenc− of77.5 −76.0y kJ calculations molkJ mol−1 in (or the [58,60].− case77.5 ofkJ RE COSNAR)mol by inboth the yields methods,case theof COSNAR) amidicity the results are obtained without the need for frequency calculations [58,60]. RE by both methods, the negativerelativeyields of the tothe amidicityN ,Ntraditional-dimethylacetamide relative representation to N,N-dimethylacetamide1 (by deﬁnitionof resonance 100%). stabilisation1 (by definition energy, 100%). should correlate negative of the traditional representation of resonance−1 stabilisation −energy,1 should correlate [4,30,33,34,61,62]The resonance and RE energyas a percentage andand amidicity of −76.0 of N kJ-methoxy- mol (orN −-methylacetamide77.5 kJ mol in the 3b case has of been COSNAR) determined [4,30,33,34,61,62] and RE as a percentage−1 of −76.0 kJ mol−1 (or −77.5 kJ mol−−11 in the case of COSNAR) yieldswithwith the amidicityCOSNAR relative( (−−62.162.1 kJ to kJ mol N mol,N-dimethylacetamide,− 80%1, 80% amidicity) amidicity) and 1 andTA (by ( TAdefinition−61.25 (− 61.25kJ mol 100%). kJ, mol81% − 1amidicity), 81% amidicity) and accords and yields the amidicity relative to N,N-dimethylacetamide 1 (by definition 100%).−1 Theaccordsnicely resonance with nicely the energy withlowest the and rotational lowest amidicity rotational barrier of N -methoxy-from barrier Figure fromN-methylacetamide 5a Figureof 67.55 akJ of mol 67.5 3b. In kJ has contrast, mol been−1 .determined Infor contrast, the bisoxyl- for −1 −1 with ThesubstitutedCOSNAR resonance (− acetamide,62.1 energy kJ mol and the, 80% amidicityRE amidicity) and of N RE-methoxy- and were TA determined(−N61.25-methylacetamide kJ mol at −35.9, 81% kJ 3bamidicity) mol has−1 ,been respectively and determined accords just 47%−1 the bisoxyl-substituted acetamide,COSNAR the RETACOSNAR and RETA were determined at −35.9 kJ mol , with COSNAR (−62.1 kJ mol−1, 80% amidicity) and TA (−61.25 kJ mol−−11, 81% amidicity) and accords nicelyrespectivelyor with 46% the that lowest justof N 47%, Nrotational-dimethylacetamide or 46% thatbarrier of Nfrom,N-dimethylacetamide [33]. Figure From 5a Figureof 67.5 5bkJ [33 themol]. From rotational. In Figurecontrast, barrier5b thefor rotationalwasthe bisoxyl-44.4 kJ barrier mol−1 −1 substitutednicely with acetamide,the lowest− therotational RE barrier and RE from were Figure determined 5a of 67.5 at kJ −35.9 mol kJ. molIn contrast,−1, respectively for the just bisoxyl- 47% wasand 44.4therefore kJ mol most1 and of the thereforeCOSNAR barrier most can beTA of accounted the barrier for can by be loss accounted of resonance. for by loss of resonance. −1 orsubstituted 46% that acetamide,of N,N-dimethylacetamide the RECOSNAR and [33].RETA Fromwere determinedFigure 5b the at −rotational35.9 kJ mol barrier, respectively was 44.4 justkJ mol 47%−1 andor 46% therefore that of most N,N -dimethylacetamideof the barrier can be [33].accounted From forFigure by loss 5b theof resonance. rotational barrier was 44.4 kJ mol−1 and therefore most of the barrier can be accounted for by loss of resonance.

The unusual structure of a number of stable anomeric amides (5–9) has been confirmed by X-ray crystallographyThe unusual (Figure structure 6) and of a relevant number structural of stable anomeric parameters amides of these (5–9 are) has given been in conﬁrmed Table 1. The by X-ray Thecrystallographystructures unusual of structure anomeric (Figure of 6amides )a andnumber relevant 5–9 ofprovide stable structural anomericclear parametersevidence amides of of(reduced5– these9) has are beenamide given confirmed resonance. in Table by1. The TheX-ray data X-ray in crystallographystructuresTheTable unusual 1 shows of(Figure structure anomeric that 6)as and theof amides a relevantcombined number5– 9structural of provideelectron stable anomeric pa cleardemarameters evidencends amides of of X theseand of (5 reduced –Y 9are )increase, has given been amide in N–C(O) confirmed Table resonance. 1. bond The by lengthX-rayX-ray The dataand structurescrystallographyinpyramidalisation Table of 1anomeric shows (Figure that atamides 6) nitrogen asand the relevant5– combined9 provideboth structural increase. electronclear evidence paThe demandsrameters reported of reducedof of theseaverage X and areamide Y N–C(O)given increase, resonance. in Tablebond N–C(O) 1.lengthThe The bond data X-rayin lengthinacyclic Tablestructuresandamides 1 shows pyramidalisation of isanomeric that 1.359 as Å the amides(median combined at nitrogen 5 –1.3539 provideelectron bothÅ), generated increase.clear dema evidencends Thefr ofom X reported Cambridgeofand reduced Y increase, average amideStructural N–C(O)N–C(O) resonance. Database bondbond The lengthlength (CSD) data inand [29,63], acyclicin pyramidalisationTableamideswhich 1 shows is is significantly that 1.359 at as nitrogen Å the (median combined shorter both 1.353 thanincrease. electron Å), the generated average demaThe reportednds 1. from418 of X Å Cambridge andaverage from Y theseincrease, N–C(O) Structural seven N–C(O) bond X-ray Database length bondstructures. length in (CSD) acyclic While and [29 , 63the], amidespyramidalisationwhich(N)C=O is 1.359 is bond signiﬁcantly Å at(median (average nitrogen shorter1.353 1.207 both Å), Å) than increase. generatedcontracts the average The slightlyfr omreported 1.418 Cambridge compared Å average from Structuraltheseto simpleN–C(O) seven acyclicDatabase bond X-ray amideslength structures. (CSD) in(1.23 [29,63],acyclic While Å), there the whichamides(N)C=O is is significantly 1.359 bond Å (median (average shorter 1.353 1.207 than Å), Å) the contractsgenerated average slightly 1. fr418om Å Cambridge compared from these to Structural seven simple X-ray acyclic Database structures. amides (CSD) (1.23 While [29,63], Å), the there is (N)C=Owhich is bond significantly (average shorter 1.207 Å) than contracts the average slightly 1.418 compared Å from tothese simple seven acyclic X-ray amides structures. (1.23 WhileÅ), there the (N)C=O bond (average 1.207 Å) contracts slightly compared to simple acyclic amides (1.23 Å), there

Molecules 2018, 23, 2834 8 of 39 little to no correlation seen between change in (N)C=O bond length and degree of lone pair dislocation; this may be attributed to bias towards carbon in the LUMO (Figure1)[ 2,26,35,64]. Deviation from 2 the usual sp hybridisation at the amide nitrogen (χN = 0) is significant and in line with the electron ◦ ◦ ◦ demands of substituents. N-acyloxy-N-alkoxyamides 6a, 6b, and 7 (χN = 65.33 , 65.62 and 59.7 , respectively) are pyramidalised at nitrogen to the extent of, and beyond, what is expected for a pure sp3 hybridisation. The 4-nitrobenzamide 7 is less pyramidal than the benzamides 6a and 6b presumably on account of greater positive charge at the carbonyl carbon and attendant increase in nitrogen lone ◦ ◦ pair attraction. Both N,N-dialkoxyamides 5a and 5b (χN = 58.3 and 55.6 , respectively) are also strongly pyramidalised. For Shtamburg’s N-alkoxy-N-chloroamide 9, X-ray data reveals a small χN of 52.5◦, similar to N,N-dialkoxyamides 5a and 5b. Both amide nitrogens in hydrazine 34 are the least ◦ ◦ pyramidalised with χN1 and χN2 of 47 and 49 , respectively. Despite high degrees of pyramidalisation in this set of anomeric amides, there is minimal twist about the N–C(O) bond (τ = 6.7–15.5◦). This indicates that lone pair orbital overlap with the carbonyl C2pz orbital, though clearly less effective on electronic and geometric grounds, remains a stabilizing influence (Table1). As can be seen in the B3LYP/6-31G(d) deformation surface for N,N-dimethoxyacetamide 4b (Figure5b), the strongly pyramidal structure requires twist angles ( τ) beyond 20◦ before there is significant loss of stabilization.

Table 1. Selected structural data for anomeric amides 5–9 from X-ray structures (Figure6).

◦ ◦ ◦ 1 ◦ Structure N–C(O)/Å (N)C=O/Å θ/ χN/ τ/ Anomeric Twist / C10-O3-N1-O2: 95.9 5a [33] 1.409 1.206 331.2 58.3 6.7 C8-O2-N1-O3: −114.1 C8-O2-N1-O3: −101.6 5b [33] 1.421 1.211 334.5 55.6 13.9 C15-O3-N1-O2: −63.8 C18-O3-N1-O1: 96.2 6a [29] 1.439 1.205 323.5 65.3 15.5 C7-O1-N1-O3: −141.6 C14-O3-N1-O1: 96.7 6b [29] 1.441 1.207 324.1 65.6 13.9 C7-O1-N1-O3: −137.6 C8-O1-N1-O5: −91.8 7 [65] 1.411 1.203 330.3 59.7 −14.0 C9-O5-N1-O1: 116.2 8(N1) [32] 1.412 1.213 343.2 47.3 −8.5 LP (N2)-N2 -N1-O2: 47.3 8(N2) 1.410 1.207 341.1 48.9 −11.4 LP (N1)-N1-N2-O3: 178.6 9 [65] 1.408 1.204 337.5 52.5 −13.3 C8-O2-N1-Cl1: −84.2 1 Anomeric alignments in bold-face.

Pyramidal nitrogens and corresponding anomeric interactions have also been observed in the structures of a number of urea and carbamate analogues of anomeric amides (10–14) studied by Shtamburg and coworkers and selected structural data are presented in Table2[ 66–69]. Where substituent electronic effects are largely similar as in 11b and 13, it can be deduced that the stronger conjugative effect of the α-nitrogen lone pair in the urea 11b, relative to the α-oxygen in the carbamate 13, results in signiﬁcantly less amide resonance interaction and, hence, signiﬁcant increase in pyramidality at the amide nitrogen. Comparison of the ONCl structures 9 and 10a and b, again indicates greater pyramidality in the ureas where competing acyl nitrogen resonance reduces the anomeric amide resonance interaction. Molecules 2018, 23, 2834 9 of 39 Molecules 2018, 23, x FOR PEER REVIEW 9 of 38

(a) (b)

(c)

(d)

(e)

(f) (g)

Figure 6. X-ray structures for (a) N-ethoxy-N-methoxy-4-nitrobenzamide 5a [33], (b) N-methoxy-N- (4-nitrobenzyloxy)benzamideFigure 6. X-ray structures for (a5b) N-ethoxy-[33],N (c-methoxy-4-nitrobenzamide) N-acetoxy-N-methoxy-4-nitrobenzamide 5a [33], (b) N-methoxy-7 [65N],- ((4-nitrobenzyloxy)benzamided) N-benzoyloxy-N-(4-tert-butylbenzyloxy) 5b [33], (c) benzamide N-acetoxy-6bN[-methoxy-4-nitrobenzamide29], (e) N-(4-tert-butylbenzoyloxy)- 7[65],N -(4-(d)tert N- butylbenzyloxy)-4-benzoyloxy-N-(4-terttert-butylbenzyloxy)benzamide-butylbenzamide 6a [29], (f6b) N-[29],chloro- (e) NN-methoxy-4-nitrobenzamide-(4-tert-butylbenzoyloxy)-N-(4-9 [tert65],- andbutylbenzyloxy)-4- (g) N,N0-4-chlorobenzoyl-tert-butylbenzamideN,N0-diethoxyhydrazine 6a [29], (f) N-chloro-8 [32]. N-methoxy-4-nitrobenzamide 9 [65], and (g) N,N′-4-chlorobenzoyl-N,N′-diethoxyhydrazine 8 [32].

Pyramidal nitrogens and corresponding anomeric interactions have also been observed in the structures of a number of urea and carbamate analogues of anomeric amides (10–14) studied by Shtamburg and coworkers and selected structural data are presented in Table 2 [66–69]. Where substituent electronic effects are largely similar as in 11b and 13, it can be deduced that the stronger conjugative effect of the α-nitrogen lone pair in the urea 11b, relative to the α-oxygen in the carbamate 13, results in significantly less amide resonance interaction and, hence, significant increase in pyramidality at the amide nitrogen. Comparison of the ONCl structures 9 and 10a and b, again indicates greater pyramidality in the ureas where competing acyl nitrogen resonance reduces the anomeric amide resonance interaction.

Molecules 2018, 23, 2834 10 of 39 Molecules 2018, 23, x FOR PEER REVIEW 10 of 38

Table 2.2. Selected structural datadata forfor ureasureas 1010––1212 andand carbamatescarbamates 1313––1414 fromfrom X-rayX-ray structures.structures.

θ ◦ χ χ ◦ τ ◦ 2 2 ◦ StructureStructure N–C(O)/ÅN–C(O)/Å (N)C=O/Å(N)C=O/Å θ/°/ N/° N/ τ/° / AnomericAnomeric Twist Twist /° / 10a10a[66 [66]] 1.4431.4431 1 1.2261.226 329.1 329.1 59.9 59.9 8.2 8.2 C-O-C-O-N-Cl:N –90.9-Cl: –90.9 10b10b[66 [66]] 1.4721.4721 1 1.2101.210 325.8 325.8 61.9 61.9 −13.4 −13.4 C-O-C-O-N-Cl:N –100.1-Cl: –100.1 11a11a[67 [67]] 1.4261.4261 1 1.2221.222 333.6 333.6 −57.1− 57.1 −6.8 −6.8 C-O-C-O-N-Oacyl:N-Oacyl: –104.0 –104.0 11b11b[68 [68]] 1.4411.4411 1 1.2331.233 323.7 323.7 64.6 64.6 11.8 11.8 C-O-C-O-N-Oacyl:N-Oacyl: –98.2 –98.2 C-O2-N1-O1:C-O2-N1-O1: –89.3 –89.3 1212[68 [68]] 1.4381.4381 1 1.2201.220 331.8 331.8 57.4 57.4 0.8 0.8 C-O1-N1-O2:C-O1-N1-O2: 55.2 55.2 1313[67 [67]] 1.4241.424 1.1981.198 334.2 334.2 −56.3− 56.32.9 2.9 C-O-C-O-N-Oacyl:N-Oacyl: –95.5 –95.5 1414[69 [69]] 1.4081.408 1.1941.194 340.0 340.0 59.8 59.8 −9.4 −9.4 LP (N1)-N1-N2-O:LP (N1)-N1-N2-O: 189.2 189.2 (N1)/(N2)(N1)/(N2)3 3 1 1Anomeric Anomeric amideamide bond;bond;2 2 Anomeric alignments in bold-face;bold-face; 33 Equivalent nitrogens.

TheseThese andand otherother anomericanomeric amidesamides havehave beenbeen modelledmodelled atat B3LYP/6-31G(d)B3LYP/6-31G(d) level in the simpliﬁedsimplified acetamideacetamide system and ground state models of 15a–d systems display high degrees of pyramidality, littlelittle N–C(O)N–C(O) twist, twist, long long N–C(O) N–C(O) bonds, bonds, and and slightly slightly shortened shortened (N)C=O (N)C=O bonds, bonds, in line within line the with electron the demandselectron demands of substituents of substituents and, where and, applicable, where app arelicable, reasonable are reasonable approximations approximations of their respective of their X-rayrespective structure X-ray counterparts structure counterparts (Figure7, Table (Figure3). ONS7, Table and 3). NNCl ONS analogues, and NNCl analogues,15d and 15e 15d, have and only 15e, beenhave generatedonly been generated as intermediates as intermediates in reactions in butreaction theirs theoreticalbut their theoretical structures structures are in line are with in line those with of anomeric systems 15a–d; N–C(O) bond lengths and pyramidality at nitrogen (χ ) are broadly in line those of anomeric systems 15a–d; N–C(O) bond lengths and pyramidality at nitrogenN (χ ) are broadly with the gross electronegativity of substituents at nitrogen. Sulphur, with its low electronegativity,N in line with the gross electronegativity of substituents at nitrogen. Sulphur, with its low results in a less pyramidal nitrogen, while the NNCl system 15e is completely planar (and untwisted) electronegativity, results in a less pyramidal nitrogen, while the NNCl system 15e is completely for steric reasons. Nonetheless, its N–C(O) bond is comparatively long. The carbamate and the urea planar (and untwisted)◦ for steric reasons.◦ Nonetheless, its N–C(O) bond is comparatively long. The 16a (χN = 46.3 ) and 16b (χN = 49.6 ) are both more pyramidal than the corresponding acetamide ◦ χ χ 15ccarbamate(χN = 41.8 and), the presumably urea 16a as( N a result= 46.3°) of and competing 16b ( N resonance = 49.6°) are from both the moreα-oxygen pyramidal and α-nitrogen than the lone pairs. χ corresponding acetamide 15c ( N = 41.8°), presumably as a result of competing resonance from the α- oxygen and α-nitrogen lone pairs.

Molecules 2018, 23, 2834 11 of 39

Molecules 2018, 23, x FOR PEER REVIEW 11 of 38

C4 C1 O1 C4 C5 C1 O1 N1 O4 O1 C1 N1 C2 C4 N1 C2 C3 O3 O2 O3 O2 O2 C3

Cl C2 (a) (b) (c)

C2 C1 O1 C2 C1 C3 C1 C3 N2 N1 N1 O2 N1 N2 O1 S1 O2

C2 C4 Cl C3 O1

C4 (d) (e) (f)

C3 O3 C3 N3 N2 N2 N1 C1 C1 N1 C4 O2 C4 O2 O1 O1 C2 C2

(g) (h) FigureFigure 7. 7.B3LYP/6-31G(d) B3LYP/6-31G(d) lowest lowest energy energy ground state ground conformers state of conformersmodel anomeric of acetamides model ( anomerica) acetamidesN-chloro- (a)N-methoxyacetamideN-chloro-N-methoxyacetamide 15a, (b) N-acetoxy-15a, N(b-methoxyacetamide) N-acetoxy-N-methoxyacetamide 15b, (c) N,N- 15b, dimethoxyacetamide 4b, (d) N-methoxy-N-dimethylaminoacetamide 15c, (e) N-methoxy-N- (c) N,N-dimethoxyacetamide 4b,(d) N-methoxy-N-dimethylaminoacetamide 15c,(e) N-methoxy-N- methylthiylacetamide 15d, (f) N-chloro-N-dimethylaminocetamide 15e, (g) O-methyl N-methoxy-N- methylthiylacetamidedimethylaminoacetamide15d,(f) 16aN-chloro-, and (h) N-methoxy--dimethylaminocetamideN-dimethylaminourea15e 16b,(.g ) O-methyl N-methoxy-N- dimethylaminoacetamide 16a, and (h) N-methoxy-N-dimethylaminourea 16b. Table 3. Selected structural data for B3LYP/6-31G(d) lowest energy conformers of model acetamides Table 3.4bSelected, 15a–e, and structural 16a,b. data for B3LYP/6-31G(d) lowest energy conformers of model acetamides 4b, 15a–e, and 16a,b. χ 1 Structure N–C(O)/Å (N)C=O/Å (N–X,N–Y)/Å θ/° N/° τ/° Anomeric Twist Angles /° Structure N–C(O)/Å (N)C=O/Å (N–X,Cl:1.787N–Y)/Å θ/◦ χ /◦ τ/◦ Anomeric Twist Angles 1/◦ 15a ONCl [34] 1.432 1.207 337.6 52.3 N −5.3 C2-O2-N1-Cl: 88.8 O2:1.389 Cl:1.787 15a ONCl15b [ 34ONOAc] 1.432 1.207 O2:1.423 337.6 52.3 −5.3 C2-O2-N1-Cl: 88.8 1.429 1.209 O2:1.389 332.1 58.0 2.3 C4-O3-N1-O2: 101.1 [61] O3:1.395 O2:1.423 15b ONOAc [61] 1.429 1.209 O2:1.387 332.1 58.0 2.3 C2-O2-N1-O3:C4-O3-N1-O2: 66.6 101.1 4b ONO [33] 1.417 1.212 O3:1.395 342.9 48.1 8.5 O3:1.412 C3-O3-N1-O2: 83.8 O2:1.387 C2-O2-N1-O3: 66.6 4b ONO [33] 1.417 1.212 O1:1.430 342.9 48.1 8.5 15c NNO [62] 1.404 1.217 O3:1.412 346.5 41.8 5.4 LP (N2)-N2-N1-O1:C3-O3-N1-O2: 190 83.8 N2:1.387 O1:1.430 15c S1:1.717 C4-S1-N1-O2:LP (N2)-N2-N1-O1: −79 190 NNO15d [ONS62] [61] 1.4041.408 1.2171.215 352.4346.5 31.7 41.8 −4.6 5.4 N2:1.387O2:1.420 C3-O2-N1-S1: −86.6 S1:1.717 C4-S1-N1-O2: −79 15d ONS [61] 1.408 1.215 Cl:1.820 352.4 31.7 −4.6 15e NNCl [34] 1.414 1.209 360.0 0 0 LP(N2)N2-N1-Cl: 180 − O2:1.420N2:1.351 C3-O2-N1-S1: 86.6 Cl:1.820O1:1.404 15e NNCl16a NNO [34] [61] 1.4141.406 1.2091.212 342360.0 46.3 0 0 0 LP (N2)-N2-N1-O1:LP(N2)N2-N1-Cl: 169.4 180 N2:1.351N2:1.383 O1:1.404 16a NNO [61] 1.406 1.212 342 46.3 0 LP (N2)-N2-N1-O1: 169.4 N2:1.383 O1:1.397 16b NNO 1.428 1.217 340.0 49.6 −1.7 LP (N2)-N2-N1-O1: 167.5 N2:1.428 1 Anomeric alignment in bold face. Molecules 2018, 23, 2834 12 of 39

2.2. Resonance Energies and Amidicities The resonance energy and the amidicity of anomeric amides 4b and 15a–e have been calculated at the B3LYP/6-31G(d) level by both the TA and COSNAR methods and by the COSNAR method using dispersion corrected M06/6-311++G(d,p). ∆ECOSNAR (Equation (1)), reaction energies (∆ETA) (Equation (2)), inductive destabilization corrections (∆Eind) (Equation (3)), resultant RETA (Equation (4)) together with COSNAR, and TA amidicities are presented in Table4.

Table 4. B3LYP/6-31G(d), B3LYP/6-311++G(d,p), and M06/6-311++G(d,p) derived resonance energies and amidicities of model anomeric acetamides 4b, 15a–e, and 16a.

1 −1 −1 −1 1, 2 −1 Amide (R = Me) ∆ECOSNAR /kJ mol ∆ETA /kJ mol ∆Eind /kJ mol RETA /kJ mol 15a (ONCl) [34] −29.6(38) 69.9 23.4 −29.5(39) 15a 3 −27.2 (36) 15a 4 −34.4(45) 15b (ONOAc) [61] −39.7(52) 65.3 29.7 −40.5(53) 15b 4 −39.5 (52) 4b (ONO) [35] −36.0(47) 58.2 18.0 −36.0(47) 4b 4 −39.5(53) - 15c (ONN) [62] −52.3(69) 35.1 10.0 −51.0(67) 15c 4 −55.7(73) 15d (ONS) [61] −48.6(64) 26.8 5.0 −48.6(64) 15d 4 −47.3(62) 15e (NNCl) [34] −28.7(38) 64.5 17.6 −29.0(37) 15e 3 −28.6(38) 15e 4 −48.7(64) 16a (ONN) [61] −47.7(63) 31.8 14.6 −50.6(67) 1 −75.9(100) 1 4 [34] −75.9(100) 1 Amidicity (%) in parentheses; 2 From Equation (4); 3 At B3LYP/6-311++G(d,p);4 M06/6-311++G(d,p).

The TA and COSNAR methodologies give almost identical resonance energies for all the anomeric amides (4b and 15a–e) at the B3LYP/6-31G(d) level. ∆ECOSNAR determined at M06 with the expanded basis set yields very similar results to B3LYP/6-31G(d) for N,N-dimethylacetamide 1 and the anomeric amides with the exception of 15e, where resonance is computed to be worth 49 kJ mol−1, just over 60% that of N,N-dimethylacetamide and substantially higher than that predicted from B3LYP/6-311++G(d,p), which was identical to the B3LYP/6-31G(d) value (29 kJ mol−1)[34]. The RE parity for 15a and 15e at B3LYP is no longer observed with M06, in line with the lower overall electronegativity of nitrogen and chlorine. These results impute the necessity for inclusion of dispersion corrections in treatments of molecules where anomeric interactions are likely to have a pronounced influence. It is clear that resonance in anomeric amides is impaired, broadly in line with the gross electronegativity or negative inductive effect of the atoms/groups bonded to nitrogen. Interestingly, the ONN and ONS acetamides, 15c and 15d, have very similar resonance energies despite the much lower electronegativity of sulphur. From Bent’s rule, the opposite effect would be expected, since s-character in the lone pair orbital should decrease with decreasing electronegativity of X. This is likely to be a manifestation of the role of orbital size since the influence of second period elements is significant; nitrogen increases p-character in the bond to sulphur to effect better overlap with the larger, 3p orbital of sulphur. Consequently, the nitrogen lone pair gains more “s” character relative to the amide nitrogen in the NNO acetamide 15c, resulting in less amide resonance [36,37,70]. Comparing the M06 values, ONCl and ONO systems have about half the resonance of N,N-dimethylacetamide while NNO, NNCl, and ONS systems are computed to preserve some 60 to 70% of the resonance of N,N-dimethylacetamide. Molecules 2018, 23, x FOR PEER REVIEW 13 of 38

2.3. The Anomeric Effect In addition to their reduced amide resonance, anomeric amides are exemplars of XNY systems

featuring an anomeric effect [26,35]. There are two possible anomeric interactions designated as nX–

σ*NY, and nY–σ*NX and where X and Y are different electronegative atoms, one of these interactions will be favoured over the other (Figure 8). By analogy with anomeric carbon centres [26,35,71–73], the relative electronegativities of heteroatoms X and Y at nitrogen and the relative sizes of interacting orbitals contribute to the strength of an anomeric interaction. Heteroatoms Y and X directly influence the relative energies of nY and σ*NX, which, in turn, affect the net stability gain for the lone pair Moleculeselectrons2018 (Figure, 23, 2834 9a). 13 of 39 Molecules 2018, 23, x FOR PEER REVIEW 13 of 38

2.3. The Anomeric Effect In addition to their reduced amide resonance, anomeric amides are exemplars of XNY systems featuring an an anomeric anomeric effect effect [26,35]. [26,35]. There There are are two two possible possible anomeric anomeric interactions interactions designated designated as n asX– nσX*NY–σ, *andNY, andnY–σ n*YNX–σ and*NX andwhere where X and X and Y are Yare different different electroneg electronegativeative atoms, atoms, one one of of these these interactions interactions will be favoured over the other (Figure8 8).). ByBy analogyanalogy withwith anomericanomeric carboncarbon centrescentres [[26,35,71–73],26,35,71–73], the relative electronegativities ofof heteroatoms XX andand Y at nitrogen and the relative sizes of interacting Figure 8. Two possible anomeric interactions in anomeric amides (a) nY–σ*NX and (b) nX–σ*NY. orbitals contribute to the strength of an anomeric interaction. Heteroatoms Y and X directly influence inﬂuence the relative energies of n and σ* , which, in turn, affect the net stability gain for the lone pair the relativeAs the energies electronegativity of nYY and of σ *XNX and, which, Y increases in turn, by affect going the across net stabilitythe p-block gain row for onthe the lone periodic pair electrons (Figure9 9a).a). table, σ*NX (and σNX) decreases in energy as does nY. Additionally, as X decreases in electronegativity

by going down a p-block group, σ*NX decreases in energy due to reduced orbital overlap [26,35,36,71,72]. An optimal anomeric effect can be achieved when Y is an early p-block element and X is a p-block element to the right of Y on the periodic table; more specifically an anomeric

stabilisation will be greater when the energy gap between nY and σ*NX is lower (Figure 9b) [74,75]. In the unusual case of anomeric amides, where the nitrogen may range between planar sp2 and pyramidal sp3 hybridisation, the geometry of the central nitrogen atom in XNY systems also plays a 2 role, as pyramidal nitrogen is more conducive to edge-on nY and σ*NX overlap than is planar, sp FigureFigure 8.8. TwoTwopossible possibleanomeric anomeric interactions interactions in in anomeric anomeric amides amides ( a(a)) n nY––σσ**NX and (b)) nnX–σ*NY. . hybridised nitrogen (Figure 10a) [26,35]. Y NX X NY As the electronegativity of X and Y increases by going across the p-block row on the periodic table, σ*NX (and σNX) decreases in energy as does nY. Additionally, as X decreases in electronegativity by going down a p-block group, σ*NX decreases in energy due to reduced orbital overlap [26,35,36,71,72]. An optimal anomeric effect can be achieved when Y is an early p-block element and X is a p-block element to the right of Y on the periodic table; more specifically an anomeric stabilisation will be greater when the energy gap between nY and σ*NX is lower (Figure 9b) [74,75]. In the unusual case of anomeric amides, where the nitrogen may range between planar sp2 and pyramidal sp3 hybridisation, the geometry of the central nitrogen atom in XNY systems also plays a (a) (b) 2 role, as pyramidal nitrogen is more conducive to edge-on nY and σ*NX overlap than is planar, sp hybridisedFigureFigure 9.nitrogen 9.(a ()a Stabilisation) Stabilisation (Figure of10a) of a lonea [26,35].lone pair pair through through a naY n–Yσ–*σNX*NXanomeric anomeric interaction interaction and and (b ()b the) the energetics energetics ofof the the anomeric anomeric effect effect in in15c 15c. .

AsSimilar the electronegativity to XCY configurations, of X and Y increasesin an XNY by system, going across a stabilising the p-block nY– rowσ*NX on anomeric the periodic effect, table, for σ*example,NX (and σ canNX) cause decreases the amide in energy to adopt as does a gauche nY. Additionally, conformation as in X which decreases the lone in electronegativity pair of Y is coplanar by going down a p-block group, σ* decreases in energy due to reduced orbital overlap [26,35,36,71,72]. with the vicinal to C–X bond (FigureNX 10b) [71,74]. In anomeric amides, when nY is divalent oxygen or Ansulphur, optimal an anomeric R-Y-N-X effectdihedral can angle be achieved close to when|90°| Yaligns is an the early p-type p-block lone elementpair on those and X atoms is a p-block with the element to the right of Y on the periodic table; more speciﬁcally an anomeric stabilisation will be greater vicinal σ*NX (Figure 10b). Where the donor is nN, an optimum anomeric effect would need the lone when the energy gap between nY and σ*NX is lower (Figure9b) [ 74,75]. In the unusual case of anomeric pair on nitrogen to be antiperiplanar to X, LP(N)-N-N-X = 180°2 (Figure 10c). Consequences3 of the nY– amides, where the nitrogen may range between planar sp and pyramidal sp hybridisation, the σ* interaction include an increased barrier to rotation about the N–Y bond (Figure 10d), a geometryNX of the central nitrogen(a) atom in XNY systems also plays a role,( asb) pyramidal nitrogen is more contraction of the N–Y bond,σ and an extension of the N–X bond2 as electrons from Y populate the σ*NX conduciveFigure to9. edge-on(a) Stabilisation nY and of a* NXloneoverlap pair through than isa n planar,–σ* anomeric sp hybridised interaction nitrogen and (b (Figure) the energetics 10a) [26 ,35]. orbital. Y NX of the anomeric effect in 15c.

Similar to XCY configurations, in an XNY system, a stabilising nY–σ*NX anomeric effect, for example, can cause the amide to adopt a gauche conformation in which the lone pair of Y is coplanar with the vicinal to C–X bond (Figure 10b) [71,74]. In anomeric amides, when nY is divalent oxygen or sulphur, an R-Y-N-X dihedral angle close to |90°| aligns the p-type lone pair on those atoms with the vicinal σ*NX (Figure 10b). Where the donor is nN, an optimum anomeric effect would need the lone pair on nitrogen to be antiperiplanar to X, LP(N)-N-N-X = 180° (Figure 10c). Consequences of the nY–

σ*NX interaction include an increased barrier to rotation about the N–Y bond (Figure 10d), a contraction of the N–Y bond, and an extension of the N–X bond as electrons from Y populate the σ*NX orbital.

Molecules 2018, 23, 2834 14 of 39 Molecules 2018, 23, x FOR PEER REVIEW 14 of 38

Figure 10. (a) sp2 2hybridised nitrogen hinders overlap with heteroatom Y in an n –σ* system; (b) Figure 10. (a) sp hybridised nitrogen hinders overlap with heteroatom Y in anY nYNX–σ*NX system; optimum(b) optimum conformation conformation in an innY an–σ* nNXY anomeric–σ*NX anomeric interaction; interaction; (c) optimum (c) optimum conformation conformation in an nN– inσ*NX an

anomericnN–σ*NX interaction;anomeric interaction; and (d) restricted and (d) rotation restricted abou rotationt the aboutN–Y bond the N–Y in an bond nY–σ in*NX an anomeric nY–σ*NX interaction.anomeric interaction.

InSimilar each of to the XCY X-ray configurations, structures in inFigure an XNY 6 there system, is clear a stabilisingevidence of n Ythese–σ*NX anomericanomeric interactions effect, for (Tableexample, 1, bold-face can cause torsion the amide angles). to adopt On the a gauche basis of conformation energetics, the in expected which the anomeric lone pair interactions of Y is coplanar are with the vicinal to C–X bond (Figure 10b) [71,74]. In anomeric amides, when nY is divalent oxygen or nO–σ*NOAc in 6a, 6b, and 7, nN–σ*NO in 8, and nO–σ*NCl in 9. In 5a and 5b one nO–σ*NO would be expected sulphur, an R-Y-N-X dihedral angle close to |90◦| aligns the p-type lone pair on those atoms with to prevail. Dihedral angles about the N–O bonds in 5–7 and 9 show a preferred p-type lone pair the vicinal σ* (Figure 10b). Where the donor is n , an optimum anomeric effect would need the alignment withNX the adjacent σ* , σ* , or σ* bond.N In hydrazine 8, the lone pair on N1 is almost lone pair on nitrogen to be antiperiplanarNO NOAc to X,NCl LP(N)-N-N-X = 180◦ (Figure 10c). Consequences of perfectly aligned with the N2–O3 bond while the N2 lone pair makes an angle of only 47° to the N1– the nY–σ*NX interaction include an increased barrier to rotation about the N–Y bond (Figure 10d), O2 bond (1.403 Å), which is shorter than the anomerically destabilised bond N2–O3 (1.411 Å). The a contraction of the N–Y bond, and an extension of the N–X bond as electrons from Y populate the structure is asymmetrical with a donor N1 and recipient N2. Similar anomeric interactions are σ*NX orbital. observable in ureas 10–12 and carbamates 13 and 14 (Table 2). In each of the X-ray structures in Figure6 there is clear evidence of these anomeric interactions All computed structures exhibit an anomeric interaction (Table 3, bold-face torsion angles) and, (Table1, bold-face torsion angles). On the basis of energetics, the expected anomeric interactions are besides the ONO system where one nO–σ*NO prevails, an anomeric nO–σ*NX prevails in ONCl, nO–σ*NOAc in 6a, 6b, and 7, nN–σ*NO in 8, and nO–σ*NCl in 9. In 5a and 5b one nO–σ*NO would be ONOAc,expected and to prevail. ONS in Dihedral line with angles expectations about the based N–O on bonds electronegativity. in 5–7 and 9 show The asize preferred of the p-typesulphur lone p- orbital and lower energy of the σ* renders an n –σ* anomeric interaction less likely than a n –σ* pair alignment with the adjacent NSσ*NO, σ*NOAc,S or σNO*NCl bond. In hydrazine 8, the lone pair onO N1NS is ◦ stabilisation.almost perfectly Where aligned nitrogen with is the present, N2–O3 the bond nN–σ while*NO and the n N2N–σ lone*NCl interactions pair makes are an clearly angle of in only evidence. 47 to the N1–O2The anomeric bond (1.403 effects Å), not which only is dictate shorter stereochemistr than the anomericallyy at nitrogen destabilised but, as will bond be N2–O3seen, combined (1.411 Å). withThe structurereduced amide is asymmetrical resonance, with they ahave donor a profou N1 andnd recipient impact upon N2. Similarspectroscopic anomeric properties interactions and the are reactivityobservable of inanomeric ureas 10 amides.–12 and carbamates 13 and 14 (Table2). All computed structures exhibit an anomeric interaction (Table3, bold-face torsion angles) and, 2.4.besides Spectroscopic the ONO Properties system of where Anomeric one Amides nO–σ* NO prevails, an anomeric nO–σ*NX prevails in ONCl, ONOAc,Spectroscopic and ONS properties in line with of anomeric expectations amides based are strongly on electronegativity. influenced by Thereduced size resonance of the sulphur due σ σ top-orbital electronegativity and lower of energy substitu ofents the at*NS nitrogen.renders Infrared an nS– *andNO anomeric 13C NMR interactiondata for a lessdiverse likely range than of a σ σ σ ONCl,nO– * NSONOAcylstabilisation. [26,31,35], Where and nitrogen ONO sy isstems present, [35,55] the nhaveN– * beenNO and reported nN– * NClas wellinteractions as for a number are clearly of ONNin evidence. N,N′-dialkoxy-N,N′-diacylhydrazines [76–78]. Representative infrared carbonyl stretch frequenciesThe anomeric in solution effects for not stable only anomeric dictate stereochemistry amides (Table at5) nitrogenare significantly but, as will higher be seen, (1700 combined to 1750 cmwith−1) [32,47,55,79–81] reduced amide resonance,than those theyof their have precursor a profound hydroxamic impact uponesters spectroscopic (1650 to 1700 cm properties−1) and primary and the (1690reactivity cm−1 of), secondary anomeric amides.(1665 to 1700 cm−1), and tertiary (1630 to 1670 cm−1) alkylamides [26,35,82]. While there is a slight tightening of the (N)C=O bond, the increase in νC=O has been attributed 2.4. Spectroscopic Properties of Anomeric Amides primarily to electronic destabilisation of single-bond resonance form of the carbonyl as electron densitySpectroscopic is pulled towards properties the electronegative of anomeric amides heteroatoms are strongly on nitrogen, influenced resulting by reduced in a more resonance ketonic 13 carbonyldue to electronegativity bond [2,64]. Likewise, of substituents anomeric amides at nitrogen. exhibit Infrared more ketonic and carbonylC NMR 13 dataC chemical for a diverse shifts (CDClrange3 of), with ONCl, downfield ONOAcyl shifts [26 ,31of ,35approximately], and ONO systems8.0 ppm [from35,55 ]their have hydroxamic been reported ester as precursors. well as for 0 0 Deshieldinga number of of ONN theN carbonyl,N -dialkoxy- carbonN,N is-diacylhydrazines an expected consequence [76–78]. Representative of the electron-withdrawing infrared carbonyl substituents.stretch frequencies However, in solution like acid for chlorides stable anomericand anhydr amidesides, the (Table carbonyls5) are significantly resonate upfield higher of ketones, (1700 to −1 −1 relative1750 cm to which) [32,47 the,55 electron,79–81] thandensity those at the of carbonyl their precursor is increased hydroxamic on account esters of greater (1650 to double 1700 cmbond) −1 −1 −1 character.and primary (1690 cm ), secondary (1665 to 1700 cm ), and tertiary (1630 to 1670 cm ) alkylamides [26,35,82]. While there is a slight tightening of the (N)C=O bond, the increase in νC=O has been attributed primarily to electronic destabilisation of single-bond resonance form of the carbonyl as electron density is pulled towards the electronegative heteroatoms on nitrogen, resulting in a

Molecules 2018, 23, 2834 15 of 39 more ketonic carbonyl bond [2,64]. Likewise, anomeric amides exhibit more ketonic carbonyl 13C chemical shifts (CDCl3), with downﬁeld shifts of approximately 8.0 ppm from their hydroxamic ester precursors. Deshielding of the carbonyl carbon is an expected consequence of the electron-withdrawing substituents. However, like acid chlorides and anhydrides, the carbonyls resonate upﬁeld of ketones, relative to which the electron density at the carbonyl is increased on account of greater double bond character.

Table 5. Typical spectroscopic data for stable anomeric alkanamides and arylamides (RC(O)NXY), and their hydroxamic ester precursors.

Hydroxamic Ester System X Y R Amide ν/cm−1 (δ13C) ν/cm−1 (δ13C) 2a [79] Cl OBu Me 1740 1(175.3) 1678 (167.9) 2a [35] Cl OBu Ph 1719 (174.2) 1654 (165.7) 2b [79] OAc OBu Me 1746 (176.2) 1678 (167.9) 2b [80] OAc OBu Ph 1732 (173.9) 1654 (165.7) 2c [81] OBu OBu Me 1707 (174.1) 16781 (167.9) 2c [55] OMe OMe Ph 1711 (174.3) 1683 (166.4) 2d [76] 4-MeBnONAc 4-MeBnO Me 1734/1700 (171.3) 1693 (168.0) 2d [76] BzNOEt OEt Ph 1708 (170.0) 1685 (166.5) 1 Neat.

Common primary, secondary, and tertiary amides have significant cis–trans isomerisation barriers for rotation about the N–C(O) bond, due to the stabilising effect of amide resonance in their ground state [2]. Restricted rotation through lone pair overlap with the adjacent carbonyl C2pz orbital, as illustrated in Figure1, often results in observation of different chemical shifts of cis and trans conformers in their 1H NMR spectra, from which barriers to isomerisation can be deduced [83,84]. The computed surface for N,N-dimethylacetamide in Figure3 indicates that the barrier (difference between the completely planar and the fully rotated-pyramidal forms) is of the order of 71–75 kJ mol−1. Hydroxamic esters have slightly less resonance and amidicity, and the rotation barrier for N-methoxy-N-methylacetamide from Figure5a is approximately 67 kJ mol −1. Many hydroxamic esters have broadened 1H NMR signals at ambient temperatures. Anomeric amides with lower resonance should have lower cis–trans isomerisation barriers as exemplified in the model N,N-dimethoxyacetamide in Figure5b. Accordingly, the isomerisation barrier in bisoxyl-substituted amides 2b and 2c are too low to be measured by usual dynamic NMR methods. All proton signals 1 of N,N-dimethoxy-4-toluamide remained sharp down to 180 K (in d4-methanol) and the H NMR signals for N-acetoxy-N-benzyloxybenzamide remained isochronous down to 190 K (in d8-toluene) [26]. The barrier for N-benzyloxy-N-chlorobenzamide 18 could likewise not be determined by dynamic NMR [35]. Figure 11 illustrates the dramatic difference between 1H NMR spectra of N-butoxyacetamide and its N-chloro- or N-acetoxyl derivatives as a consequence of reduced resonance in the anomeric structures, which clearly have much lower isomerization barriers. At room temperature, the anomeric amides are in the fast exchange region as opposed to the slow exchange in the hydroxamic ester. Earlier theoretical studies by Glover and Rauk support this assertion [27,28]. For example, a comparison of formamide 17a, N-methoxyformamide 17b, and N-chloro-N-methoxyformamide 17d, calculated at the B3LYP/6-31G(d) level, showed little reduction in the cis–trans isomerisation barrier of 73.2 kJ mol−1 in formamide, to 67–75 kJ mol−1 in N-methoxyformamide. However, the introduction of a second electronegative heteroatom, Cl, reduced the barrier to only 32.2 kJ mol−1, indicating that monosubstitution alone is insufficient to impact upon the isomerisation barrier [27]. A theoretical isomerisation barrier for N-methoxy-N-(dimethylamino)formamide, which, by analogy with typical NNO systems, should retain ~70% the resonance in N,N-dimethylacetamide, was computed to be higher at 52.7 kJ mol−1 [28]. Such an amide isomerisation barrier in the hydrazine, 0 0 ‡ −1 N,N -diacetyl-N,N -di(4-chlorobenzyloxy)hydrazine 20d, was measurable at ∆G 278 = 54.0 kJ mol , in line with this theoretical barrier [27]. Molecules 2018, 23, 2834 16 of 39 Molecules 2018, 23, x FOR PEER REVIEW 16 of 38

11 3 Figure 11. 300300 MHz MHz 1HH NMR NMR spectra spectra (300K, (300K, CDCl CDCl3) 3of) ofN-butoxyacetamide,N-butoxyacetamide, and and anomeric anomeric amides amides N- butoxy-N-butoxy-N-chloroacetamideN-chloroacetamide and and N-acetoxy-N-acetoxy-N-butoxyacetamide.N-butoxyacetamide.

The intrinsic intrinsic barrier barrier to to inversion inversion at at nitrogen nitrogen in in bisheteroatom-substituted bisheteroatom-substituted amides amides is expected is expected to beto bemuch much lower lower than than those those of analogous of analogous amines. amines. The transition The transition state for state inversion for inversion in anomeric in anomeric amides amides is expected to be planar, where the nitrogen lone pair can interact with the carbonyl 2pzz orbital is expected to be planar, where the nitrogen lone pair can interact with the carbonyl 2pz orbital generating stabilisation [35]. [35]. For For N,,N-dimethoxyacetamide-dimethoxyacetamide (Figure (Figure 55b)b) thisthis barrierbarrier isis representedrepresented byby the energy energy of of structure structure (b), (b), while while the the difference difference in in energy energy between between fully fully twisted twisted structures structures (d) (d)and and (c) represents(c) represents the themuch much larger larger barrier barrier to to inversion inversion in in the the corresponding corresponding anomeric amine. Several −11 theoretical estimates put these barriers in anomeric amides atat aboutabout 1010 kJkJ molmol−1 [28].[28].

In anomeric systems, strong nYσ–σ*NX interactions should increase the bond order of the N–Y In anomericanomeric systems,systems, strong strong n Yn–Y–*σNX*NXinteractions interactions should should increase increase the the bond bond order order of the of N–Y the bond,N–Y bond,which shouldwhich imposeshould barriers impose to rotationbarriers aboutto rotation those bonds. about For thoseN-chloro- bonds.N-methoxyformamide For N-chloro-N- 17dmethoxyformamide, the N–O and N–C(O) 17d, the rotation N–O and barriers N–C(O) have rotation been estimated barriers have at the been B3LYP/6-31G(d) estimated at the level B3LYP/6- at 44.7 −1 −1 31G(d)and 29.2 level kJ molat 44.7, and respectively 29.2 kJ mol [27−1],, respectively while the theoretical [27], while barrier the theo toretical rotation barrier about to therotation N–N about bond −1 −1 thein N N–N-methoxy- bond Nin-dimethylaminoformamide N-methoxy-N-dimethylaminoformamide17e was computed 17e was at ~60 computed kJ mol at[ 28~60]. ExperimentalkJ mol−1 [28]. Experimentalmeasurements measurements for both anomerically for both induced anomerically barriers induced have been barriers made. Anhave N–O been anomeric made. rotationalAn N–O ‡ −1 ‡ −1 anomericbarrier of ∆rotationalG = 43 kJ molbarrierhas of been ∆G‡ determined = 43 kJ formolN−1-chloro- has beenN-benzloxybenzamide determined for 18N,-chloro- where theN- d 8 benzloxybenzamidebenzylic methylenes become18, where diastereotopic the benzylic atmethylenes 217 K in 8 be-toluene,come diastereotopic but as no amide at 217 isomerisation K in d8-toluene, could butbe detected, as no amide that barrierisomerisation must be could signiﬁcantly be detected, lower [th26at]. Anbarrier anomerically must be inducedsignificantly rotational lower barrier [26]. An for 0 anomericallyN–N bond in ainduced number ofrotationalN,N-diacyl- barrierN,N -dialkoxyhydrazinesfor N–N′ bond in19a a– enumberand 20a –eofhas N been,N-diacyl- measuredN,N- 1 0 1 0 dialkoxyhydrazinesin dynamic H NMR 19a studies–e and [ 3220a].– Methylenee has been measured signals of Nin, Ndynamic-diethoxy 1H NMR19a–e studiesand N, N[32].-dibenzyloxy Methylene signalsgroups 20aof N–e,N, which′-diethoxy were 19a diastereotopic–e and N,N′ at-dibenzyloxy room temperature, groups as20a a– consequencee, which were of restricteddiastereotopic rotation at room temperature, as a consequence of restricted rotation about the N–N′ bond, coalesced at higher

Molecules 2018, 23, 2834 17 of 39

0 about the N–N bond, coalesced at higher temperatures (Tc = 316–346 K) from which rotational free energy barriers of the order of 60−70 kJ mol−1 could be determined [32], which compare favourably with the theoretically calculated N–N0 rotational barrier for 17e of 60 kJ mol−1 [28].

3. Reactivity of Anomeric Amides The reduced resonance and attendant pyramidalisation at the amide nitrogen together with anomeric properties of these unusual molecules results in a plethora of amide reactivity, some known, and now better understood, and others that are unique to anomeric amides. The destabilisation of the amide bond, coupled with the substitution pattern, facilitates reactivity at the amide nitrogen in which the amides are usually transformed from one anomeric amide form to another. Moreover, it can induce a novel process, known as the HERON reaction (Named at the Third Heron Island Conference on Reactive Intermediates and Unusual Molecules, Heron Island 1994.), in which the amide bond is broken to form acyl derivatives and heteroatom-stabilised nitrenes. This reaction is facilitated by weakened amide resonance, but is driven by nY–σ*NX anomeric destabilisation of the N–X bond.

3.1. Reactivity at the Amide Nitrogen Due to their characteristic, diminished amide resonance and anomeric destabilisation, this class of amide has been shown to undergo SN2 reaction at nitrogen, and elimination of N-substituents leading to SN1-type processes. Several congeners undergo thermolytic homolysis to give alkoxyamidyl radicals.

3.1.1. SN2 Reactions

In XNY systems, a moderate nY–σ*NX negative hyperconjugation leads, through neighbouring group participation, to weakening of the N–X bond, which can encourage SN2 reactions at nitrogen [26,31,35]. The increased electrophilicity of nitrogen in N-acyloxy-N-alkoxyamides 21 leaves them vulnerable to attack by arylamines (Scheme1 i) [ 42,44,47,51], azide (Scheme1 ii) [ 54], hydroxide (Scheme1 iii) [ 45], and thiols (Scheme1 iv) [ 52], the outcomes from which are anomerically substituted intermediates 22–24 and 26 that ultimately may undergo HERON reactions. Furthermore, N-acyloxy-N-alkoxyamides 21 themselves may be synthesised in SN2 reactions between N-alkoxy-N-chloroamides 25 and sodium carboxylates (Scheme1 vi) [ 43,45,46,48,51,80,85]. N-alkoxy-N-chloroamides 25 also react bimolecularly with azide generating reactive N-alkoxy-N-azidoamides 26 (Scheme1 v) [54]. Reactions of 21 systems with amines and thiols have been modelled at the AM1, HF/6-31G(d), and pBP/DN* levels, which reveal signiﬁcant charge separation in the transition states and alkoxynitrenium ion character (Figure 12)[86]. These reactions should be favoured by electron-donor substituents on the nucleophile and electron-acceptor substituents on the acyloxyl group. The SN2 reaction of N-methylaniline with a wide range of N-acyloxy-N-alkoxyamides 21 has been studied (Scheme1 i), and relative rate constants, Arrhenius activation energies, and entropies of activation are in accord with a transition state with signiﬁcant charge separation [31,44,51,87]. EA’s are of the order of 40 to 60 kJ mol−1. Entropies of activation (−90–160 J K−1 mol−1) are more negative than found in SN2 reactions of alkyl halides, owing to a greater degree of solvation in the charge separated transition state [88]. In addition, the rates for reactions i, iii, and iv with a series of NAA’s bearing N-p-substituted benzoyloxyl leaving groups correlated with Hammett σ constants with positive slope (i, $ = 1.7, iii, $ = 0.6, and iv, $ = 1.1) [44,45,52]. In addition, a series of anilines reacted bimolecularly + and rate constants correlate with Hammett σ constants ($ = −0.9) [44]. In most respects, the SN2 reactions are electronically and geometrically reminiscent of those at carbon centres and are accelerated by electron-donor groups on the nucleophile and electron-withdrawing groups on the leaving group. The amide carbonyl facilitates SN2 reactivity in line with enhanced reactivity in phenacyl bromides [89]. In particular, bimolecular reaction rates are radically impeded with branching α to the carbonyl [50], which is analogous to the resistance to SN2 reactions of α-halo ketones bearing substituents at the α’ position [90,91]. Molecules 2018, 23, x FOR PEER REVIEW 18 of 38

Molecules 2018, 23, 2834 18 of 39 Molecules 2018, 23, x FOR PEER REVIEW 18 of 38

Scheme 1. SN2 reactions of N-acyloxy-N-alkoxyamides 21 with: (i) arylamines; (ii) azide; (iii) hydroxide; (iv) thiols; (vii) DNA and reaction of N-alkoxy-N-chloroamides 25 with (v) azide and (vi) sodium carboxylates.

Reactions of 21 systems with amines and thiols have been modelled at the AM1, HF/6-31G(d), and pBP/DN* levels, which reveal significant charge separation in the transition states and Scheme 1. N N 21 alkoxynitreniumScheme 1.S NS ion2N2 reactions reactionscharacter of of -acyloxy-(Figure N-acyloxy- 12)-alkoxyamides [86].N-alkoxyamides These reactionswith: 21 (i) arylamines;with: should (i) bearylamines; (ii) favoured azide; (iii) by(ii) hydroxide; electron-donorazide; (iii) (iv) substituentsthiols;hydroxide; (vii) on DNA (iv)the thiols;nucleophile and reaction (vii) DNA of andN -alkoxy-and electron-a reactionN-chloroamidescceptor of N-alkoxy- substituents25 Nwith-chloroamides (v) azide on the and 25acyloxyl (vi) with sodium (v) group. azide carboxylates. and (vi) sodium carboxylates.

Reactions of 21 systems with amines and thiols have been modelled at the AM1, HF/6-31G(d), and pBP/DN* levels, which reveal significant charge separation in the transition states and alkoxynitrenium ion character (Figure 12) [86]. These reactions should be favoured by electron-donor substituents on the nucleophile and electron-acceptor substituents on the acyloxyl group.

(a) (b)

FigureFigure 12. 12. HF/6-31G*HF/6-31G* predicted predicted charge charge separation separation in in transition transition states states for for reactions reactions of of NN-formyloxy--formyloxy-NN-- methoxyformamidemethoxyformamide with with ( (aa)) ammonia ammonia and and ( (b)) methanethiol. methanethiol.

TheAnomeric S 2 reaction substitution of N-methylaniline at nitrogen in N with-acyloxy- a wideN-alkoxyamides range of N-acyloxy-21 rendersN-alkoxyamides this class of amides 21 has as N S. typhimurium beendirect-acting studied mutagens.(Scheme 1 Mutagenicityi), and relative(a) towards rate constants, Arrheniusin the( bactivation Ames) reverse energies, mutation and assayentropies does ofnot activation require premetabolic are in accord activation with a transition [92,93]. Our state DNA with damage significant studies charge on plasmidseparation DNA [31,44,51,87]. at physiological EA’s Figure 12. HF/6-31G* predicted charge separation in transition states for reactions of N-formyloxy-N- arepH, of as the well order as extensive of 40 to structure–activity 60 kJ mol−1. Entropies relationships of activation [31,38 –(41−90–160,43,45, 46J K,48−1– mol50,79−1), 80are], pointmore tonegative binding methoxyformamide with (a) ammonia and (b) methanethiol. of NAA’s 21, intact, into the major groove of DNA, where an SN2 reaction occurs at the most nucleophilic than found in SN2 reactions of alkyl halides, owing to a greater degree of solvation in the charge centre, the electron-rich N7 in guanine (Scheme1 vii) [ 94–97]. All three side chains (R1,R2, and R3) of separatedThe Stransition2 reaction state of [88].N-methylaniline In addition, thewith rates a wide for reactionsrange of i,N iii,-acyloxy- and iv Nwith-alkoxyamides a series of NAA’s 21 has 21 have anN impact upon both DNA damage profiles as well as mutagenicity levels. An S 1 mechanism, bearing N-p-substituted benzoyloxyl leaving groups correlated with Hammett σ constantsN with yieldingbeen studied electrophilic (SchemeN-acyl- 1 i), Nand-alkoxynitrenium relative rate consta ions,nts, was Arrhenius ruled out since activation only R1 energies,and R2 would and entropies influence positive slope (i, ρ = 1.7, iii, ρ = 0.6, and iv, ρ = 1.1) [44,45,52]. In addition, a series of anilines reacted of activation are in accord with a transition state with significant charge separation [31,44,51,87]. EA’s binding and reactivity. Moreover, mutagenic activity is radically+ reduced when there is branching bimolecularly and rate constants correlate−1 with Hammett σ constants (ρ = −−10.9) [44].−1 In most respects, αareto of the the carbonyl order of in 40 parallel to 60 kJ with mol the. Entropies impaired of SN activation2 reactivity (−90–160[40,50,51 J ]K. Themol mutagenic) are more activity negative of Nthan-acyloxy- foundN -alkoxyamidesin SN2 reactions21 ofhas alkyl been halides, used recently owing to to show a greater how hydrophobicity degree of solvation and intercalating in the charge side chainsseparated impact transition upon DNA state binding[88]. In [addition,38,39]. the rates for reactions i, iii, and iv with a series of NAA’s bearing N-p-substituted benzoyloxyl leaving groups correlated with Hammett σ constants with positive slope (i, ρ = 1.7, iii, ρ = 0.6, and iv, ρ = 1.1) [44,45,52]. In addition, a series of anilines reacted bimolecularly and rate constants correlate with Hammett σ+ constants (ρ = −0.9) [44]. In most respects,

Molecules 2018, 23, x FOR PEER REVIEW 19 of 38 Molecules 2018, 23, x FOR PEER REVIEW 19 of 38 the SN2 reactions are electronically and geometrically reminiscent of those at carbon centres and are the SN2 reactions are electronically and geometrically reminiscent of those at carbon centres and are acceleratedaccelerated by electron-donor by electron-donor groups groups on the on nucl the eophilenucleophile and electron-withdrawingand electron-withdrawing groups groups on the on the leaving group. The amide carbonyl facilitates SN2 reactivity in line with enhanced reactivity in leaving group. The amide carbonyl facilitates SN2 reactivity in line with enhanced reactivity in phenacylphenacyl bromides bromides [89]. [89].In part In icular,particular, bimolecular bimolecular reaction reaction rates ratesare radicallyare radically impeded impeded with with branching α to the carbonyl [50], which is analogous to the resistance to SN2 reactions of α-halo branching α to the carbonyl [50], which is analogous to the resistance to SN2 reactions of α-halo ketonesketones bearing bearing substituents substituents at the at α the’ position α’ position [90,91]. [90,91]. AnomericAnomeric substitution substitution at nitrogen at nitrogen in N-acyloxy- in N-acyloxy-N-alkoxyamidesN-alkoxyamides 21 renders 21 renders this class this classof amides of amides as direct-actingas direct-acting mutagens. mutagens. Mutagenicity Mutagenicity towards towards S. typhimurium S. typhimurium in the in Ames the Ames reverse reverse mutation mutation assay assay does doesnot requirenot require premetabolic premetabolic activation activation [92,93]. [92,93]. Our DNAOur DNA damage damage studies studies on plasmid on plasmid DNA DNA at at physiologicalphysiological pH, as pH, well as aswell extensive as extensive structure–acti structure–activity relationshipsvity relationships [31,38–41,43,45,46,48–50,79,80], [31,38–41,43,45,46,48–50,79,80], point to binding of NAA’s 21, intact, into the major groove of DNA, where an SN2 reaction occurs at point to binding of NAA’s 21, intact, into the major groove of DNA, where an SN2 reaction occurs at the mostthe mostnucleophilic nucleophilic centre, centre, the electron-rich the electron-rich N7 in N7 guanine in guanine (Scheme (Scheme 1 vii) 1 [94–97]. vii) [94–97]. All three All three side side chains (R1, R2, and R3) of 21 have an impact upon both DNA damage profiles as well as mutagenicity chains (R1, R2, and R3) of 21 have an impact upon both DNA damage profiles as well as mutagenicity levels. An SN1 mechanism, yielding electrophilic N-acyl-N-alkoxynitrenium ions, was ruled out since levels. An SN1 mechanism, yielding electrophilic N-acyl-N-alkoxynitrenium ions, was ruled out since only R1 and R2 would influence binding and reactivity. Moreover, mutagenic activity is radically only R1 and R2 would influence binding and reactivity. Moreover, mutagenic activity is radically reduced when there is branching α to the carbonyl in parallel with the impaired SN2 reactivity reduced when there is branching α to the carbonyl in parallel with the impaired SN2 reactivity [40,50,51].[40,50,51]. The mutagenicThe mutagenic activity activity of N -acyloxy-of N-acyloxy-N-alkoxyamidesN-alkoxyamides 21 has 21 been has beenused usedrecently recently to show to show how hydrophobicity and intercalating side chains impact upon DNA binding [38,39]. Moleculeshow hydrophobicity2018, 23, 2834 and intercalating side chains impact upon DNA binding [38,39]. 19 of 39

3.1.2. 3.1.2.Elimination Elimination Reactions Reactions

In3.1.2. an anomeric Elimination amide Reactions where nY–σ*NX is a strong interaction, where X has a high electron affinity In an anomeric amide where nY–σ*NX is a strong interaction, where X has a high electron affinity and Y is a strong electron donor, polarisation can lead to elimination of X−, leaving a Y-stabilised and InY is an a anomeric strong electron amide wheredonor, n polaY–σ*risationNX is a strong can lead interaction, to elimination where Xof hasX−, aleaving high electron a Y-stabilised affinity − nitreniumandnitrenium Y ion is a28 ion strong (Scheme 28 (Scheme electron 2) [98]. 2) donor, The[98]. stronger The polarisation stronger the anomeric canthe anomeric lead effect, to elimination effect, the more the ofmore readily X ,readily leaving the elimination the a Y-stabilisedelimination is expectednitreniumis expected to occur. ion to 28occur. In(Scheme the In case the2) [ofcase98 N]. -alkoxy-of The N-alkoxy- strongerN-chloroamidesN the-chloroamides anomeric 25, effect, elimination 25, elimination the more can readily becan facilitated be the facilitated elimination by by LewisisLewis acid expected complexationacid complexation to occur. with In thewithX and case X byand of theN by-alkoxy- use the of use polarN of-chloroamides polar solvents solvents [35].25 ,For[35]. elimination example, For example, cantreatment be treatment facilitated of N- of byN- chloro-Lewischloro-N-(2-phenylethyloxy)- acidN-(2-phenylethyloxy)- complexation 29a with and29a X and andN-chloro- by N the-chloro-N use-(3-phenylpropyloxy)amidesN of-(3-phenylpropyloxy)amides polar solvents [35]. For 29b example, 29bwith withsilver treatment silver tetrafluoroborateoftetrafluoroborateN-chloro- Nin-(2-phenylethyloxy)- ether, in ether, initiates initiates a 29aring a and ringclosingN closing-chloro- reaction Nreaction-(3-phenylpropyloxy)amides to form to formN-acyl-1 N-acyl-1H-3,4-dihydro-2,1-H-3,4-dihydro-2,1-29b with silver benzoxazinestetrafluoroboratebenzoxazines 30a and30a in ether,andN-acyl-1,3,4,5-tetrah initiatesN-acyl-1,3,4,5-tetrah a ring closingydrobenzoxazepinesydrobenzoxazepines reaction to form N30b-acyl-1 , 30brespectively,H,-3,4-dihydro-2,1-benzoxazines respectively, via chlorinevia chlorine elimination30aeliminationand toN form-acyl-1,3,4,5-tetrahydrobenzoxazepines to formnitrenium nitrenium ions (Scheme ions (Scheme 3). N -acyl-3). N-acyl-N30b-alkoxynitrenium,N respectively,-alkoxynitrenium via ions chlorine are ions strongly are elimination strongly stabilised stabilised to form by delocalisationnitreniumby delocalisation ions of (Schemethe of positive the3 ).positiveN charge-acyl- chargeN onto-alkoxynitrenium oxygeonto oxygen [98,99].n ions[98,99]. This are methodolog stronglyThis methodolog stabilisedy hasy been by has delocalisation beenused usedwidely widely of the sincepositive sinceits discovery its chargediscovery in onto 1984 in oxygen 1984by Glover by [98 Glover,99 [100,101]]. This [100,101] methodology and Kikugawa and Kikugawa has [102–108]. been [102–108]. used In widely addition, In sinceaddition, treatment its discovery treatment of N inof 1984 N- alkoxy-byalkoxy-N Glover-chloroamidesN-chloroamides [100,101] and25 with Kikugawa 25 withsilver silver [carboxylates102– 108carboxylates]. In addition, in diethyl in diethyl treatment ether, ether, allows of N allows-alkoxy- the nitrenium theN-chloroamides nitrenium ion to ion be25 towith be scavengedsilverscavenged carboxylatesby carboxylate by carboxylate in diethyl in a versatilein ether, a versatile allows reaction thereaction nitrenium which which has ion been has to be beenused scavenged usedto synthesise to by synthesise carboxylate a range a inrange of a versatileN -of N- acyloxy-reactionacyloxy-N-alkoxyamides whichN-alkoxyamides has been 21 [48,80]. used 21 [48,80]. to synthesise a range of N-acyloxy-N-alkoxyamides 21 [48,80]. O O O O O O C C C C R N C C R N R N YN Y R N YN Y Y Y R R X 28 X 28

Scheme 2. Nitrenium ion formation by elimination of X due to a strong nY–σ*NX interaction. SchemeScheme 2.2. NitreniumNitrenium ionion formationformation byby eliminationelimination ofof XX duedue toto aa strongstrongn nYY––σσ**NXNX interaction.

O O O O O O O O (CH ) R N (CH2O)n AgBF4 R N (CH2O)n O O2 n(CH ) R N (CH2)n AgBF4 +R N (CH2)n N 2 n Cl Et O + N Cl 2 Et O R 2 R

29 30 a: n=2 29 a: n=2 30 b: n=3 a: n=2 b: n=3 a: n=2 b: n=3 b: n=3 Molecules 2018, 23, Schemex FOR PEER 3. Cyclisation REVIEW by silver ion catalysed elimination reactions. 20 of 38 Scheme 3. Cyclisation by silver ion catalysed elimination reactions.reactions. Elimination ofof chloride chloride in in the the alcoholysis alcoholysis of 25 ofto 25 give to nitreniumgive nitrenium ion provided ion provided a synthetic a synthetic pathway pathwayN N to N,N-dialkoxyamides5 5 (Scheme 4) [55,56]. We recently reported a more versatile synthesis to , -dialkoxyamides (Scheme4)[ 55,56]. We recently reported a more versatile synthesis effected effectedby PIFA by oxidation PIFA oxidation of hydroxamic of hydroxamic esters 31 inesters appropriate 31 in appropriate alcohol, which alcohol, proceeds which throughproceeds a through reactive phenylbistriﬂuoroacetatea reactive phenylbistrifluoroacetate derivative derivative32 [30,55]. 32 Similar [30,55]. hypervalent Similar hypervalent iodine oxidations iodine oxidations have been have used beenin nitrenium used in ionnitrenium cyclisations ion cyclisations onto aromatic onto rings aromatic [105]. rings [105].

O O O R1OH R1OH OR2 OR2 OR2 R3 N R3 N R3 N Cl OR1 25 5

O O 2 PIFA 2 OR 3 OR R3 N R N H 1 R OH I(Ph)(OCOCF3)2 31 32 Scheme 4. N-Acyl--Acyl-N-alkoxynitrenium-alkoxynitrenium ion ion mediated mediated syntheses of N,N-dialkoxyamides 5.

N N N-Alkoxy-N-benzoylnitrenium-benzoylnitrenium ions 34 are generated through AAA1A111 acid-catalysed solvolysis of N-acetoxy-N-alkoxybenzamides 33 (Scheme5 5))[ [46,48,49].46,48,49]. Acetoxyl, Acetoxyl, upon protonation with a catalytic amount of mineral acid, is eliminated from N-acetoxy-N-alkoxybenzamides 33 and the nitrenium ions are trapped by water to form N-alkoxyhydroxamic acids 35. The anomeric 35 undergoes secondary reactions to form a range of products.

Scheme 5. Acid catalysed hydrolysis of N-acetoxy-N-butoxybenzamides.

The elimination reactions of N-alkoxy-N-chloroamides 25 and the acid-catalysed solvolysis reactions of 33, both of which proceed through intermediacy of N-acyl-N-alkoxynitrenium ions, can better be re-evaluated in terms of anomeric destabilisation in combination with their reduced amidicities.

3.2. The HERON Reaction

3.2.1. HERON Reactions of N-Amino-N-Alkoxymides A novel reaction of suitably constituted anomeric amides is the HERON (Heteroatom Rearrangement On Nitrogen) reaction [56,109–113]. In such amides, when the X heteroatom of an anomerically destabilised N–X bond is a poor leaving group, the amide can undergo a concerted rearrangement involving the migration of X to the carbonyl carbon and the ejection of a Y-stabilised nitrene (Scheme 6).

O O C N Y C N Y N Y R R X X Scheme 6. The heteroatom rearrangement on nitrogen (HERON) reaction of an anomeric amide.

Molecules 2018,, 23,, xx FORFOR PEERPEER REVIEWREVIEW 20 of 38

Elimination of chloride in the alcoholysis of 25 toto givegive nitreniumnitrenium ionion provided a synthetic pathway to N,,N-dialkoxyamides-dialkoxyamides 5 (Scheme(Scheme 4)4) [55,56].[55,56]. WeWe recentlyrecently rereported a more versatile synthesis effected by PIFA oxidation of hydroxamic esters 31 inin appropriateappropriate alcohol,alcohol, whichwhich proceedsproceeds throughthrough a reactive phenylbistrifluoroacetate derivative 32 [30,55].[30,55]. SimilarSimilar hypervalenthypervalent iodineiodine oxidationsoxidations havehave been used in nitrenium ion cyclisations onto aromatic rings [105].

O O O R1 OH R1 OH 2R OH 2 R OH 2 3 OR 3 OR 3 OR R3 N R3 N R3 N 1 Cl OR1 25 5

O O O PIFA 2 2 OR2 3 OR R3 N R3 N R N H R1 OH I(Ph)(OCOCF ) R OH I(Ph)(OCOCF3)2 31 32 Scheme 4. N-Acyl--Acyl-N-alkoxynitrenium-alkoxynitrenium ionion mediatedmediated synthesessyntheses ofof N,,N-dialkoxyamides-dialkoxyamides 5.. Molecules 2018, 23, 2834 20 of 39 N-Alkoxy--Alkoxy-N-benzoylnitrenium-benzoylnitrenium ionsions 34 areare generatedgenerated throughthrough AAA11 acid-catalysed solvolysis of N-acetoxy--acetoxy-N-alkoxybenzamides-alkoxybenzamides 33 (Scheme(Scheme 5)5) [46,48,49].[46,48,49]. Acetoxyl,Acetoxyl, upon protonation with a catalytic amount ofof mineralmineral acid, acid, is is eliminated eliminated from fromN-acetoxy- N-acetoxy--acetoxy-N-alkoxybenzamidesN-alkoxybenzamides-alkoxybenzamides33 and33 andand the nitreniumthethe nitreniumnitrenium ions ionsareions trapped areare trappedtrapped by water byby towaterwater form totoN- formformalkoxyhydroxamic N-alkoxyhydroxamic acids 35 .acids The anomeric 35.. TheThe anomeric35anomericundergoes 35 undergoes secondary secondaryreactions to reactions form a range to form of products.a range of products.

Scheme 5. AcidAcid catalysed catalysed hydrolysis hydrolysis of N-acetoxy--acetoxy-N-butoxybenzamides.-butoxybenzamides.

The eliminationelimination reactionsreactions ofof NN-alkoxy--alkoxy-N-chloroamides-chloroamides 25 and thethe acid-catalysedacid-catalysedacid-catalysed solvolysissolvolysis reactions of of 3333,, bothboth, both ofof whichwhich of which proceedproceed proceed throughthrough through intermediacyintermediacy intermediacy ofof N-acyl--acyl- ofNN-alkoxynitrenium-alkoxynitrenium-acyl-N-alkoxynitrenium ions,ions, cancan betterions, canbe betterre-evaluated be re-evaluated in terms of in termsanomeric of anomericdestabilisation destabilisation in combination in combination with their with reduced their amidicities.reduced amidicities.

3.2. The HERON Reaction 3.2.1. HERON Reactions of N-Amino-N-Alkoxymides 3.2.1. HERON Reactions of N-Amino--Amino-N-Alkoxymides-Alkoxymides A novel reaction of suitably constituted anomeric amides is the HERON (Heteroatom A novel reaction of suitably constituted anomeric amides is the HERON (Heteroatom Rearrangement On Nitrogen) reaction [56,109–113]. In such amides, when the X heteroatom of Rearrangement On Nitrogen) reaction [56,109–113]. InIn suchsuch amides,amides, whenwhen thethe XX heteroatomheteroatom ofof anan an anomerically destabilised N–X bond is a poor leaving group, the amide can undergo a concerted anomerically destabilised N–X bond is a poor leavingleaving group,group, thethe amideamide cancan undergoundergo aa concertedconcerted rearrangement involving the migration of X to the carbonyl carbon and the ejection of a Y-stabilised rearrangement involving the migration of X to the carbonyl carbon and the ejection of a Y-stabilised nitrene (Scheme6). nitrene (Scheme 6).

O O C N N Y N Y C N Y C N Y N Y R R X X Scheme 6. TheThe heteroatomheteroatom rearrangement rearrangement on on nitrogen nitrogen (HERON) (HERON) reaction ofof anan anomericanomeric amide.amide.

The HERON reaction was discovered by Glover and Campbell during research into SN2 reactivity of N-acyloxy-N-alkoxyamides 21, speciﬁcally the reaction between N-acetoxy-N-butoxybenzamide and N-methylaniline according to Scheme1i[ 47,111]. In a polar solvent such as methanol, N-methylaniline attacks the amide nitrogen, replacing the acetoxyl side chain to form an unstable intermediate, N-butoxy-N-(N0-methylanilino)benzamide 36, which undergoes the HERON reaction to form butyl benzoate 37, and an aminonitrene, 1-methyl-1-phenyldiazene 38 (Scheme7 i). Aminonitrenes are highly reactive intermediates with a singlet ground state, which persist long enough under reaction conditions to dimerise to tetrazenes [114–117], in this case, 39 (Scheme7 ii) [ 44,47]. N,N0-Diacyl-N,N0-dialkoxyhydrazines 40, the only forms of N-alkoxy-N-aminoamides 2d to have been isolated, undergo tandem HERON reactions to form two equivalents of ester 41 and a molecule of nitrogen; the N-acyl-N-alkoxyaminonitrenes 42, formed in this HERON reaction, rapidly undergo a second rearrangement to form a molecule of nitrogen and ester before dimerisation of the N-acyl-N-alkoxyaminonitrene can occur (Scheme8)[ 56,76]. Step ii can also be regarded as a HERON process, driven by a high energy electron pair on 1,1-diazene, a charge separated form of aminonitrene. Barton and coworkers studied the decomposition at about the same time, and both groups established the operation of three-centre mechanisms using asymmetric hydrazines [77]. In addition, Barton found its concerted nature facilitated the formation of a range of highly hindered esters and, recently, Molecules 2018, 23, x FOR PEER REVIEW 21 of 38

The HERON reaction was discovered by Glover and Campbell during research into SN2 reactivity of N-acyloxy-N-alkoxyamides 21, specifically the reaction between N-acetoxy-N- butoxybenzamide and N-methylaniline according to Scheme 1 i [47,111]. In a polar solvent such as methanol, N-methylaniline attacks the amide nitrogen, replacing the acetoxyl side chain to form an unstable intermediate, N-butoxy-N-(N′-methylanilino)benzamide 36, which undergoes the HERON reaction to form butyl benzoate 37, and an aminonitrene, 1-methyl-1-phenyldiazene 38 (Scheme 7 i). Aminonitrenes are highly reactive intermediates with a singlet ground state, which persist long enough under reaction conditions to dimerise to tetrazenes [114–117], in this case, 39 (Scheme 7 ii) [44,47]. N,N′-Diacyl-N,N′-dialkoxyhydrazines 40, the only forms of N-alkoxy-N-aminoamides 2d to have been isolated, undergo tandem HERON reactions to form two equivalents of ester 41 and a molecule of nitrogen; the N-acyl-N-alkoxyaminonitrenes 42, formed in this HERON reaction, rapidly undergo a second rearrangement to form a molecule of nitrogen and ester before dimerisation of the N-acyl-N-alkoxyaminonitrene can occur (Scheme 8) [56,76]. Step ii can also be regarded as a HERON process, driven by a high energy electron pair on 1,1-diazene, a charge separated form of aminonitrene. Barton and coworkers studied the decomposition at about the same time, and both groupsMolecules established2018, 23, 2834 the operation of three-centre mechanisms using asymmetric hydrazines [77].21 of In 39 addition, Barton found its concerted nature facilitated the formation of a range of highly hindered esters and, recently, Zhang has utilised the reaction to generate hindered esters from N,N′-dialkoxy- N N0 N N0 NZhang,N′-diacylhydrazines, has utilised the reaction synthesised to generate through hindered N-bromosuccinimide esters from , -dialkoxy-(NBS) oxidation, -diacylhydrazines, of hydroxamic N esterssynthesised [118]. through -bromosuccinimide (NBS) oxidation of hydroxamic esters [118].

O Me O Me Me C N i Bu N ii N N Ph O + N Ph Ph N N Ph N O Bu Me 36 37 38 39 Scheme 7. The first ﬁrst HERON reaction of N-butoxy--butoxy-N-(N′0-methylanilino)benzamide-methylanilino)benzamide 36.

O OR3 R3 O 4 O O N R HERON 4 HERON 1 ++N R4 N2 R N i N R ii 2 R1 OR2 N R4 OR3 OR2 O O 40 41 43 R3 O N R4 N O 42 Scheme 8. Tandem HERON reactions ofof NN,,NN0′-diacyl-N,,N0′-dialkoxyhydrazines 40.

3.2.2. Theoretical and Experimental Validation ofof thethe HERONHERON ReactionReaction The HERON reaction of 22 andand 4040 hashas been been modelled modelled and and validated validated computationally. computationally. Initially, Initially, AM1 modelling predicted that the three-centre reactionreaction inin thethe firstfirst HERONHERON (Scheme(Scheme7 7i) i) hadhad anan −1 −1 energy barrierbarrier ofof 184184 kJkJ molmol−1,, while while that of thethe secondsecond stepstep waswas veryvery lowlow (25(25 kJ kJ mol mol−1)[) [56,77].56,77]. An extensive AM1AM1 study study of of HERON HERON reactions reactions of N of-amino- N-amino-N-alkoxyacetamidesN-alkoxyacetamides predicted predicted a similar a similar barrier −1 −1 barrierof 159 kJ of mol 159 kJin mol the−1 gasin the phase, gas phase, but a lower but a barrierlower barrier of 126 kJof mol126 kJ inmol solution−1 in solution [111]. The[111]. same The studysame studyalso predicted also predicted lower barrierslower barriers with electron-donor with electron-d groupsonor ongroups the amino on the nitrogen. amino nitrogen. In a more In rigorous a more rigorousstudy at thestudy B3LYP/6-31G(d) at the B3LYP/6-31G(d) level [76], level Glover [76], et al.Glover modelled et al. themodelled HERON the reaction HERON of Nreaction-methoxy- of NN-- 0 methoxy-dimethylaminoformamideN-dimethylaminoformamide17e, a model representative17e, a model of Nrepresentative-(N -methylanilino)- of NN-(-butoxybenzamideN′-methylanilino)-N36-, 0 0 butoxybenzamideand N,N - diacyl-N 36,N, and-dialkoxyhydrazines N,N′-diacyl-N,N′-dialkoxyhydrazines40, for which HERON 40 reactions, for which had HERON been experimentally reactions had observed. It was confirmed that the nN–σ*NO anomeric destabilisation resulted in migration of the methoxyl group with an activation barrier of 90 kJ mol−1 and the reaction was exothermic by 23 kJ mol−1. Similar diasteromeric transition states were located, but the transition state accessible from the lowest energy (syn) conformer of 17e was found to be that depicted in Figure 13a. Importantly, modelling showed that amide resonance in the transition state was largely lost, as migration occurs in a plane perpendicular to the carbonyl, twisting the nitrogen lone pair away from alignment with the π*C=O orbital. Anomeric destabilisation, however, remained along the reaction coordinate, driving the reaction forward. The N–C(O) bond is largely intact at the transition state but breaks as the O2–C1 bond forms in an internal, SN2-like reaction at the amide carbon. Significantly, a tetrahedral intermediate is avoided by this process. Subsequent high level calculations on the decomposition of anomeric hydrazines by Tomson and Hall, yielded similar energetics for the HERON process [119]. Molecules 2018, 23, x FOR PEER REVIEW 22 of 38

been experimentally observed. It was confirmed that the nN–σ*NO anomeric destabilisation resulted in migration of the methoxyl group with an activation barrier of 90 kJ mol−1 and the reaction was exothermic by 23 kJ mol−1. Similar diasteromeric transition states were located, but the transition state accessible from the lowest energy (syn) conformer of 17e was found to be that depicted in Figure 13a. Importantly, modelling showed that amide resonance in the transition state was largely lost, as migration occurs in a plane perpendicular to the carbonyl, twisting the nitrogen lone pair away from alignment with the π*C=O orbital. Anomeric destabilisation, however, remained along the reaction coordinate, driving the reaction forward. The N–C(O) bond is largely intact at the transition state but breaks as the O2–C1 bond forms in an internal, SN2-like reaction at the amide carbon. Significantly, a tetrahedral intermediate is avoided by this process. Subsequent high level calculations on the Moleculesdecomposition2018, 23, 2834of anomeric hydrazines by Tomson and Hall, yielded similar energetics for22 ofthe 39 HERON process [119].

O1 1.51Å O2 N2 N1 1.23Å 2.15Å b C1 1.19Å 1.27Å a C2 1.71Å b c 1.88Å 2.04Å a O1 O2 1.52Å 1.14Å N1

N2 O1C2N1O2=120.7° O1C2N1N2=-28.2°

a =56.2°, b=76.6°, c=47.2° a =78°, b=59°,

(a) (b) Figure 13. Twisted HERON transition states of ((aa)) NN-methoxy--methoxy-N-dimethylaminoformamide 17e and (b) 1-formyl-1-methoxydiazene 44 (R(R11 == H, H, R R22 == Me) Me) at at B3LYP/6-31G(d) B3LYP/6-31G(d) level level [53,76]. [53,76 ].

Analysis of charge separation in the B3LYP/6-31G(d)B3LYP/6-31G(d) transition state revealed a partial positive charge of of +0.5 +0.5 on on amino amino group, group, partial partial negative negative charge charge of of−0.3− 0.3on the on themigrating migrating methoxyl methoxyl group group and andlittlelittle change change in charge in charge at the at carbonyl. the carbonyl. This This indicated indicated that that HERON HERON in these in these NNO NNO systems systems could could be beassisted assisted by bypolar polar solvents, solvents, electron-donating electron-donating gr groupsoups on on the the stationary stationary amino amino substituent, and electron-withdrawing groupsgroups on on the the migrating migrating oxygen oxygen substituent. substituent. The activationThe activation barriers barriers and charge and separationcharge separation in the transition in the transition state were state validated were validated experimentally experimentally by Arrhenius by Arrhenius studies and studies Hammett and correlationsHammett correlations from thermal from decomposition thermal decomposit of a rangeion of of a substitutedrange of substituted hydrazines hydrazines19a–e and 19a20a–e– eandin mesitylene20a–e in mesitylene (Table6)[ (Table76]. In 6)19 [76]., the In donor 19, the ability donor of ability nN is increasedof nN is increased by electron-rich by electron-rich aroyl groups, aroyl + 2 leadinggroups, toleading enhanced to enhanced reaction reaction rates and rates a negative and a negative Hammett Hammettσ correlation σ+ correlation ($ = −0.35, (ρ = R−0.35,= 0.978) R2 = (Figure0.978) (Figure 14a). However,14a). However, acceptor acceptor benzyloxy benzyloxy substituents substituents in 20 infacilitate 20 facilitate the migration, the migration, leading leading to a 2 positiveto a positive Hammett Hammettσ-correlation σ-correlation ($ = ( 1.02,ρ = 1.02, R = R 0.911)2 = 0.911) (Figure (Figure 14b). 14b). Rate Rate constants constants were were lower lower in 20in on20 on account account of of anegative a negative impact impact at at the the donor donor nitrogen. nitrogen. Donor Donor groups, groups, on onthe the otherother hand,hand, havehave little impact on the carbonyl in 19..

Table 6. Hammett reaction constants, Arrhenius activation energies, entropies of activation, and rate constants for HERON decomposition of 19a–e and 20a–e [76].

−1 ‡ −1 −1 6. −1 Series System EA/kJ mol ∆S /J K mol 10 k298/s 19a 99.2 (4.3) −21.2 (13) 5.56 19b 100.7 (8.2) −19.6 (25) 3.72 Series 19: σ+ reaction constant $ = −0.35 1 19c 100.4 (5.1) −23.8 (15) 2.52 19d 107.7 (1.7) 0.9 (5) 2.50 19e 104.0 (1.7) −15.4 (5) 1.57 8. −1 10 k298/s 20a 111.4 (0.9) −21.1 (2) 4.02 20b 125.9 (1.0) 24.5 (3) 2.76 Series 20: σ reaction constant $ = +1.02 1 20c 114.1 (3.9) −8.7 (11) 6.21 20d 125.1 (8.5) 27.4 (24) 5.44 20e 98.8 (0.3) −46.4 (1) 31.9 1 Hammett correlations using k298K. Molecules 2018, 23, x FOR PEER REVIEW 23 of 38

Table 6. Hammett reaction constants, Arrhenius activation energies, entropies of activation, and rate constants for HERON decomposition of 19a–e and 20a–e [76].

−1 ‡ −1 −1 6. −1 Series System EA/kJ mol ΔS /J K mol 10 k298/s 19a 99.2 (4.3) −21.2 (13) 5.56 19b 100.7 (8.2) −19.6 (25) 3.72 Series 19: σ+ reaction constant ρ = −0.35 1 19c 100.4 (5.1) −23.8 (15) 2.52 19d 107.7 (1.7) 0.9 (5) 2.50 19e 104.0 (1.7) −15.4 (5) 1.57 108.k298/s−1 20a 111.4 (0.9) −21.1 (2) 4.02 20b 125.9 (1.0) 24.5 (3) 2.76 Series 20: σ reaction constant ρ = +1.02 1 20c 114.1 (3.9) −8.7 (11) 6.21 20d 125.1 (8.5) 27.4 (24) 5.44 Molecules 2018, 23, 2834 20e 98.8 (0.3) −46.4 (1) 31.9 23 of 39 1 Hammett correlations using k298K.

Figure 14. InfluenceInﬂuence on on the the HERON HERON transition transition state state of of(a) ( aelectron-rich) electron-rich benzoyl benzoyl groups groups in 19 in and19 and (b) (electron-deficientb) electron-deﬁcient benzyloxy benzyloxy groups groups in 20 in. 20.

3.2.3. HERON Reaction of 1-Acyl-1-Alkoxydiazenes 0 0 The second second step step in in the the thermal thermal decomposition decomposition of ofN,NN′,-dialkoxy-N -dialkoxy-N,NN′-diacylhydrazines,N -diacylhydrazines 40, 1940,, 19and, and20 has20 alsohas been also beenmodelled modelled at both at B3LYP/6-31G(d) both B3LYP/6-31G(d) and CCSD(T)//B3P86 and CCSD(T)//B3P86 level using level N-formyl- using N-formyl-N-methoxydiazene, and was found to have an extremely small E of between 5−1 and N-methoxydiazene, and was found to have an extremely small EA of between 5A and 12 kJ mol and 12 kJ mol−1 and to be highly exothermic (∆E = −400 kJ mol−1)[53,119]. We encountered this process to be highly exothermic (ΔE = −400 kJ mol−1) [53,119]. We encountered this process from the reaction N N fromof N-acyloxy- the reactionN-alkoxyamides of -acyloxy- 21 with-alkoxyamides azide (Scheme21 with 1 ii), azide which (Scheme generates1 ii), ester which and generates two molecules ester N N andof nitrogen two molecules [54]. The ofreaction nitrogen of N [54-acyloxy-]. The reactionN-alkoxyamides of -acyloxy- with azide-alkoxyamides was originally with conceived azide was in originallyan attempt conceived to trap and in andetermine attempt the to trap lifetimes and determine of N-acyl- theN-alkoxynitrenium lifetimes of N-acyl- ions,N-alkoxynitrenium by analogy with ions,the determination by analogy withof lifetimes the determination of arylnitrenium of lifetimes ions in of water arylnitrenium [120,121]. ionsHowever, in water N-Alkoxy- [120,121N].- However,azidoamidesN-Alkoxy- 26 areN -azidoamideshighly unstable26 are intermediates, highly unstable losing intermediates, nitrogen losing to nitrogengenerate to 1-acyl-1- generate 1-acyl-1-alkoxydiazenesalkoxydiazenes 44, which44 react, which further react to furthernitrogen to and nitrogen ester Scheme and ester 9. The Scheme transition9. The state transition for this statereaction for of this N-formyl- reactionN of-methoxydiazene,N-formyl-N-methoxydiazene, modelled at the modelledB3LYP/6-31G(d) at the level, B3LYP/6-31G(d) is depicted in level, Figure is depicted13b. Once in again, Figure the 13 methoxylb. Once group again, migrates the methoxyl in a plane group orthogonal migrates into athe plane N1-C2-O1 orthogonal plane toin thean N1-C2-O1earlier transition plane state in an with earlier little transition N–C(O) statebond withcleavage, little which N–C(O) occurs bond in cleavage, concert with which O2–C2 occurs bond in concertformation, with again O2–C2 avoiding bond formation,a tetrahedral again intermediate. avoiding a tetrahedralThe reaction intermediate. of azide with The N reaction-chloro-N of- azidealkoxyamides with N-chloro- 25 provedN-alkoxyamides to be an excellent25 proved means to ofbe gene anrating excellent highly means hindered of generating esters [54]—not highly hindered esters [54]—not surprisingly, in light of the very low EA and extreme exothermicity born surprisingly, in light of the very low EA and extreme exothermicity born out of the entropically out of the entropically favourable generation of two highly stable molecules (methyl formate and favourable generation of two highly stable molecules (methyl formate and nitrogen) [53,119]. Overall, nitrogen) [53,119]. Overall, the decomposition of N-azido-N-methoxyformamide to two molecules of the decomposition of N-azido-N-methoxyformamide to two molecules of nitrogen and nitrogen and methylformate was computed to be exothermic by some 575 kJ mol−1 [53]. Yields of methylformate was computed to be exothermic by some 575 kJ mol−1 [53]. Yields of esters prepared esters prepared by this method are given in Table7. Moleculesby this method 2018, 23, x are FOR given PEER inREVIEW Table 7. 24 of 38

O N O N O -N2 N HERON 1 N 1 N + R N R N 2 1 2 2 R OR OR2 OR 26 44 41 Scheme 9. Decomposition and HERON reaction of N-alkoxy-N-azidoamides 26.

Table 7. Ester 41 (R1COOR2) formation from the reaction of N-alkoxy-N-chloroamides 25 (R1CONClOR2) with sodium azide in aqueous acetonitrile.

R R′ Isolated Crude Yield/%

Ph (CH3)3C 87

(CH3)3C (CH3)3C 30

1-adamantyl (CH3)3C 82

(CH3)3C cyclohexyl 97

Ph (CH3)2CH 92

Ph PhCH2 93

CH3 PhCH2 92

p-NO2C6H4 Et 94 Ph Et 94

Both Barton and recently Zhang have shown that the thermal decomposition of N,N′-dialkoxy- N,N′-diacylhydrazines is a source of hindered esters. The avoidance of a tetrahedral intermediate in both HERON steps of these reactions, and which is a limiting structure in Fisher esterification, is critical. This, and the clear role of anomeric substitution at nitrogen in both reducing amidicity, as well as promoting the rearrangement, are paramount.

3.2.4. HERON Reactions of Anionic Systems Hydroxide substitution of the acyloxyl side chain from a range of N-acyloxy-N- alkoxybenzamides 21, at room temperature in aqueous acetonitrile, generated esters and their hydrolysis products [45]. Rate data and crossover experiments pointed to an SN2 reaction at nitrogen and the intramolecular nature of the reaction, implicating a HERON process. The hydroxamic acid intermediates 45 from initial attack (Scheme 1 iii) would be converted to their conjugate base 23 under basic reaction conditions, generating a strong nO−–σ*NO anomeric destabilisation of the N–O bond (Scheme 10). A HERON migration of the alkoxyl side chain to the carbonyl carbon results in the formation of alkyl benzoate and the ejection of the nitric oxide anion (Scheme 10, R1 = Ph). This route to esters from hydroxamic acids in equilibrium with 23 was earlier invoked to explain non-crossover ester formation in the AAl1 solvolysis of N-acyloxy-N-alkoxyamides at low acid concentrations (Scheme 5) [45,46,48,49].

O O HO – O OH O HERON R1 N R1 N NO + R1 OR2 OR2 OR2 45 23 41 NaOMe DMA O OR2 R1 N OAc 46 Scheme 10. HERON reaction of hydroxamate anion 23.

Molecules 2018, 23, x FOR PEER REVIEW 24 of 38

O N O N O -N2 N HERON 1 N 1 N + R N R N 2 1 2 2 R OR OR2 OR 26 44 41 Scheme 9. Decomposition and HERON reaction of N-alkoxy-N-azidoamides 26.

Table 7. Ester 41 (R1COOR2) formation from the reaction of N-alkoxy-N-chloroamides 25 Molecules 2018, 23, 2834 24 of 39 (R1CONClOR2) with sodium azide in aqueous acetonitrile.

R R′ Isolated Crude Yield/% Table 7. Ester 41 (R1COOR2) formation from the reaction of N-alkoxy-N-chloroamides 25 (R1CONClOR2) with sodium azide in aqueousPh acetonitrile.(CH3)3C 87 (CH3)3C (CH3)3C 30 RR0 Isolated Crude Yield/% 1-adamantyl (CH3)3C 82 Ph (CH3)3C 87 (CH3)3C cyclohexyl 97 (CH3)3C (CH3)3C 30 (CH ) CH 1-adamantylPh (CH3 2 3)3C92 82 (CHPh3) 3CPhCH cyclohexyl2 93 97 Ph (CH3)2CH 92 CH3 PhCH2 92 Ph PhCH2 93 p-NOCH2C36H4 PhCHEt 2 9492 p-NOPh2C 6H4 EtEt 94 94 Ph Et 94 Both Barton and recently Zhang have shown that the thermal decomposition of N,N′-dialkoxy- N,N′Both-diacylhydrazines Barton and recently is a source Zhang of hindered have shown esters. that The the avoidance thermal decomposition of a tetrahedral of intermediateN,N0-dialkoxy- in Nboth,N0 -diacylhydrazinesHERON steps of these is a source reactions, of hindered and which esters. is a Thelimiting avoidance structure of a in tetrahedral Fisher esterification, intermediate is incritical. both HERONThis, and steps the clear of these role reactions, of anomeric and substitution which is a limiting at nitrogen structure in both in Fisherreducing esteriﬁcation, amidicity, as is critical.well as promoting This, and the the clear rearrangement, role of anomeric are paramount. substitution at nitrogen in both reducing amidicity, as well as promoting the rearrangement, are paramount. 3.2.4. HERON Reactions of Anionic Systems 3.2.4.Hydroxide HERON Reactions substitution of Anionic of Systemsthe acyloxyl side chain from a range of N-acyloxy-N- alkoxybenzamidesHydroxide substitution 21, at room of the temperature acyloxyl side in chain aqueous from a acet rangeonitrile, of N-acyloxy- generatedN-alkoxybenzamides esters and their

21hydrolysis, at room products temperature [45]. in Rate aqueous data and acetonitrile, crossover generated experiments esters pointed and their to an hydrolysis SN2 reaction products at nitrogen [45]. Rateand the data intramolecular and crossover nature experiments of the reaction, pointed toimplicating an SN2 reaction a HERON at nitrogen process. and The the hydroxamic intramolecular acid natureintermediates of the reaction, 45 from implicating initial attack a HERON(Scheme process. 1 iii) woul Thed be hydroxamic converted acid to their intermediates conjugate 45basefrom 23 under initial attackbasic reaction (Scheme conditions1 iii) would, generating be converted a strong to their nO conjugate−–σ*NO anomeric base 23 destabilisationunder basic reaction of the conditions,N–O bond generating(Scheme 10). a strongA HERON nO−– σmigration*NO anomeric of the destabilisation alkoxyl side chain of the to N–O the bondcarbonyl (Scheme carbon 10 ).results A HERON in the migrationformation ofof thealkyl alkoxyl benzoate side and chain the to ejection the carbonyl of the nitric carbon oxide results anion in the(Scheme formation 10, R of1 = alkylPh). This benzoate route 1 andto esters the ejection from hydroxamic of the nitric acids oxide in anionequilibrium (Scheme with 10,R 23 was= Ph). earlier This invoked route to to esters explain from non-crossover hydroxamic acidsester information equilibrium in the with A23Al1was solvolysis earlier invokedof N-acyloxy- to explainN-alkoxyamides non-crossover at ester low formation acid concentrations in the AAl1 solvolysis(Scheme 5) of [45,46,48,49].N-acyloxy-N -alkoxyamides at low acid concentrations (Scheme5)[45,46,48,49].

O O HO – O OH O HERON R1 N R1 N NO + R1 OR2 OR2 OR2 45 23 41 NaOMe DMA O OR2 R1 N OAc 46 Scheme 10.10. HERON reaction of hydroxamatehydroxamate anionanion 2323..

The HERON reaction was also invoked by Shtamburg and coworkers to account for formation of ethyl benzoate 41 (R1 = Ph, R2 = Et) when N-acetoxy-N-ethoxybenzamide 46 (R1 = Ph, R2 = Et) was treated with methoxide in aprotic media. Anion 23 (R1 = Ph, R2 = Et) leading to the HERON reaction was generated by methoxide addition at the ester carbonyl (Scheme 10), while methoxide attack at the amide carbonyl lead to the formation of methyl benzoate [122]. Dialkyl azadicarboxylates, widely used in the Mitsonobu reaction, decompose vigorously with methoxide in methanol [123,124]. 47a afforded methyl isopropyl carbonate 49a and isopropyl formate 50a in a 1:1 ratio by 1H NMR, and diethyl azadicarboxylate 47b behaved similarly, though volatile ethyl formate 50b was less prevalent in the reaction mixture (Scheme 11)[112,125]. Since the nitrogens Molecules 2018,, 23,, xx FORFOR PEERPEER REVIEWREVIEW 25 of 38

The HERON reaction was also invoked by Shtamburg and coworkers to account for formation of ethyl benzoate 41 (R(R11 = Ph, R22 = Et) when N-acetoxy--acetoxy-N-ethoxybenzamide-ethoxybenzamide 46 (R(R11 = Ph, R22 = Et) was treatedtreated withwith methoxidemethoxide inin aproticaprotic media.media. AnionAnion 23 (R(R11 = Ph, R22 = Et) leading to the HERON reaction was generated by methoxide addition at the ester carbonyl (Scheme 10), while methoxide attack at thethe amideamide carbonylcarbonyl leadlead toto thethe formationformation ofof methylmethyl benzoatebenzoate [122].[122]. Dialkyl azadicarboxylates, widely usedused inin thethe MitsonobuMitsonobu reaction,reaction, decomposedecompose vigorouslyvigorously withwith methoxideMolecules 2018 in, 23 methanol, 2834 [123,124]. 47a affordedafforded methylmethyl isopropylisopropyl carbonatecarbonate 49a49a and isopropyl formate25 of 39 50a inin aa 1:11:1 ratioratio byby 11H NMR, and diethyl azadicarboxylate 47b behavedbehaved similarly,similarly, thoughthough volatilevolatile ethyl formate 50b waswas lessless prevalentprevalent inin thethe reactionreaction mixturmixture (Scheme 11) [112,125]. Since the nitrogens inin 4747 areare the the overwhelming overwhelming contributorscontributors toto thethe LUMOLUMO of azadicarboxylates [112], [112], the the most most probable probable routeroute to to these these products products is is methoxide methoxide addition addition at at ni nitrogentrogentrogen andand aa facilefacile HERONHERON reactionreaction ofof thethe anionicanionic adducts 48. Calculations based on the HERON reaction of dimethyl azodicarboxylate 5c, gave an EA adducts 48.. CalculationsCalculations basedbased onon thethe HERONHERON reactionreaction ofof dimethyldimethyl azodicarboxylateazodicarboxylate 5c,, gave an EEA of 27 kJ mol−1 and exothermicity of 59 kJ mol−1, at the B3LYP/6-31G*//HF/6-31G(d) level [112]. of 27 kJ mol−−11 andand exothermicityexothermicity ofof 5959 kJkJ molmol−−11,, atat thethe B3LYP/6-31G*//HF/6-31G(d)B3LYP/6-31G*//HF/6-31G(d) levellevel [112].[112].

SchemeScheme 11. 11. AmideAmide anion anion induced induced HERON HERON reaction reaction in in reac reactionstionstions ofof of azadicarboxylatazadicarboxylat azadicarboxylateses with with methoxide. methoxide.

3.2.5.3.2.5. HERON HERON Reactions Reactions of of NN-Alkoxy--Alkoxy--Alkoxy-NN-Aminocarbamates-Aminocarbamates-Aminocarbamates ByBy analogy with the HERON reactions of N-acyloxy--acyloxy-N-alkoxyamides,-alkoxyamides, severalseveral carbamatescarbamates havehave beenbeen shown to undergo aa similarsimilar reactionreaction (Scheme(Scheme 1212).). NN-Acetoxy--Acetoxy--Acetoxy-OO-alkyl--alkyl-N-benzyloxycarbamates-benzyloxycarbamates 51a51a––cc and N-methylaniline-methylaniline reacted reacted bimolecularly bimolecularly in in [D [D44]-methanol]-methanol]-methanol toto to produceproduce the the corresponding corresponding carbonatescarbonates 5353 and tetrazene 39,, presumably presumably through through HERON HERON reaction reaction of of the the NN-methylanilino-methylanilino intermediateintermediate 52 [126].[[126].126].

SchemeScheme 12. HERONHERON reactionsreactions ofof N-alkoxy--alkoxy-NN-aminocarbamates.-aminocarbamates.

3.2.6. HERON Reactions of N-Acyloxy-N-Alkoxyamides 3.2.6. HERON Reactions of N-Acyloxy--Acyloxy-N-Alkoxyamides-Alkoxyamides Based on RE’s of models 15c and 16a in Table4, the amidicity of NNO systems such as Based on RE’s of models 15c andand 16a inin TableTable 4,4, thethe amidicityamidicity ofof NNONNO systemssystems suchsuch asas N-alkoxy--alkoxy- N-alkoxy-N-aminoamides 2d or N-alkoxy-N-aminocarbamates such as 52, is likely to be reduced N-aminoamides-aminoamides 2d or N-alkoxy--alkoxy-N-aminocarbamates-aminocarbamates suchsuch asas 52,, isis likelylikely toto bebe reducedreduced byby modestmodest by modest amounts (60–70% that of N,N-dimethylacetamide), yet these systems undergo HERON amounts (60–70% that of N,,N-dimethylacetamide),-dimethylacetamide), yetyet thesethese systemssystems undergoundergo HERONHERON reactionsreactions atat reactions at room temperature, as do the 1,1-diazenes 2h and hydroxamates 2g. However, all room temperature, as do the 1,1-diazenes 2h andand hydroxamateshydroxamates 2g.. However,However, allall havehave inin commoncommon aa have in common a strong anomeric destabilisation of the N–O bond through high energy electron strong anomeric destabilisation of the N–O bond throughthrough highhigh energyenergy electronelectron pairspairs onon thethe donordonor pairs on the donor atom, nY, and high electronegativity of oxygen. nO–σ*NO systems such as atom, nY,, andand highhigh electronegativityelectronegativity ofof oxygen.oxygen. nnO–σ**NO systemssystems suchsuch asas N-acyloxy--acyloxy-N-alkoxyamides-alkoxyamides N-acyloxy-N-alkoxyamides 2b and N,N-dialkoxyamides 2c, on the other hand, should have lower 2b andand N,,N-dialkoxyamides-dialkoxyamides 2c,, onon thethe otherother hand,hand, shouldshould hahave lower RE’s (amidicities(amidicities RE’s (amidicities approximately 50% that of N,N-dimethylacetamide), yet they are thermally stable approximately 50% that of N,,N-dimethylacetamide),-dimethylacetamide), yetyet theythey areare thermallythermally stablestable atat roomroom at room temperature on account of a weaker nO–σ*NO anomeric interaction. However, at elevated temperatures, N-acyloxy-N-alkoxyamides 2b also undergo HERON reactivity [85]. A tandem mass spectrometric analysis by electrospray ionisation, used in characterising mutagenic N-acyloxy-N-alkoxyamides 21 (Scheme 13), produced, in addition to sodiated parent compound 54, three characteristic sodiated ions, a sodiated alkoxyamidyl radical, 55, which was generally most prevalent, a sodiated anhydride, 56, and a minor cation due to sodiated ester, 57, which was absent in the ionisation of aliphatic amides. While the fragments formed in parallel Molecules 2018, 23, x FOR PEER REVIEW 26 of 38

temperature on account of a weaker nO–σ*NO anomeric interaction. However, at elevated temperatures, N-acyloxy-N-alkoxyamides 2b also undergo HERON reactivity [85]. A tandem mass spectrometric analysis by electrospray ionisation, used in characterising mutagenic N-acyloxy-N-alkoxyamides 21 (Scheme 13), produced, in addition to sodiated parent compoundMolecules 2018 ,5423, 2834three characteristic sodiated ions, a sodiated alkoxyamidyl radical, 55, which26 was of 39 generally most prevalent, a sodiated anhydride, 56, and a minor cation due to sodiated ester, 57, withwhich each was productabsent in ion, the58 ionisation–60, were of undetectable, aliphatic amides. under While these the conditions fragments the formed source in of parallel anhydrides with eachmust product be an intramolecular ion, 58–60, were process undetectable, and the under HERON these rearrangement conditions the atsource elevated of anhydrides temperature must was be animplicated. intramolecular Furthermore, process the and relative the HERON amounts rearrang of sodiatedement anhydride at elevated and temperature ester reﬂected was the implicated. expected Furthermore, the relative amounts of sodiated anhydride and ester reflected the expected bias bias towards an nO–σ*NOAc anomeric stabilisation with attendant weakening of the N–OAc, rather towardsthan the an N–OR, nO–σ*NOAc bond anomeric [112]. stabilisation A B3LYP/6-31G(d) with attendant computational weakening study of the of N–OAc, migration rather tendencies than the N–OR,in N-formyloxy- bond [112].N -methoxyformamideA B3LYP/6-31G(d) computat predictedional high studyEA ’sof formigration migration tendencies of both in formyloxyl N-formyloxy- and −1 Nmethoxyl-methoxyformamide in the gas phase predicted (162 andhigh 182 EA’s kJ for mol migration, respectively) of both formyloxyl [112]. While and acyloxyl, methoxyl rather in the than gas phasealkoxyl, (162 migration and 182 kJ would mol−1, be respectively) energetically [112]. more While favourable, acyloxyl, in rather solution than atalkoxyl, room temperaturemigration would and particularlybe energetically in polar more media, favourable, the HERON in solution reaction at wouldroom temperature not be competitive and particularly with SN2 and in SpolarN1 reactions media, theat nitrogen. HERON reaction would not be competitive with SN2 and SN1 reactions at nitrogen.

Scheme 13. Fragments from collision induced electrospr electrosprayay ionisation-mass spectrometric (ES-MS) analysis of N-acyloxy-N-alkoxyamides 21.

However, in toluene at 90 ◦°C,C, HERON reactions of 21 have been detected in competition with a homolytic decomposition pathway, pathway, and analysis of the complex reaction mixtures provides further support for the driving force behind the HERON pr processocess (Scheme 1414))[ [85].85]. Homolysis of the N–OAc bond in 61 gave relatively long-lived alkoxyamidyl radicals 62, which in solvent cage reactions with product radicals ge generatednerated di dioxazoleoxazole 63,, or upon escaping the solvent cage dimerise to hydrazineshydrazines leading toto the the expected expected thermal thermal decomposition decomposition esters. esters. The HERON The HERON reaction ofreaction61 generates of 61 anhydrides generates anhydrides65 and alkoxynitrenes 65 and alkoxynitrenes66. Anhydrides, 66. whichAnhydrides, in the casewhich of symmetricalin the case benzoicof symmetrical anhydride benzoic from anhydride61a and mixed from benzoyl61a and heptanoylmixed benzoyl anhydride heptanoyl from anhydride61b were relativelyfrom 61b were stable, relatively react further stable, to react give furtheresters 68 to andgive 69esterswith 68 alcohols and 69 with67 generated alcohols 67 in generated the reaction in the mixture, reaction the mixture, source the of source which of was which the wasalkoxynitrenes, the alkoxynitrenes, the other the HERON other HERON product. product. Critical Critical evidence evidence for the for HERON the HERON process process derived derived from productsfrom products of alkoxynitrenes of alkoxynitrenes66, which 66 (1), which could be(1) trapped could bybe oxygen;trapped (2) by dimerised oxygen; to(2) hyponitrites; dimerised or,to (3)hyponitrites; underwent or, characteristic (3) underwent rearrangements characteristic leading rearrangements aldehydes, nitriles,leading and aldehydes, alcohols. Competitionnitriles, and alcohols.between theCompetition HERON and between homolytic the reactionHERON pathways and homolytic was evident reaction in a comparisonpathways was of products evident fromin a comparison61c–e. The polarity of products of these from HERON 61c–e. The transition polarity states of these would HERON require tr aansition build-up states of positive would chargerequire on a build-upthe donor of alkoxyl positive oxygen, charge nonO. the This donor would alkoxyl be stabilised oxygen, by nO electron-donor. This would bepara stabilisedsubstituents by electron- on the donorbenzyloxy para group, substituents but destabilised on the benzyl by electron-withdrawingoxy group, but destabilisedpara substituents. by electron-withdrawing In accord with this, para61c substituents.and 61e generated In accord dioxazole with andthis, esters.61c and Little 61e dioxazolegenerated was dioxazole formed and from esters.61d in Little which dioxazole the methoxyl was formedgroup would from 61d lower in thewhich energy the methoxyl of the HERON group transition would lower state, the but energy would of have the littleHERON impact transition on the state,non-polar but would transition have state little for impact homolysis on the of non-polar the N–OAc transition bond (Figure state for 15 homolysis). of the N–OAc bond (Figure 15).

Molecules 2018, 23, 2834x FOR PEER REVIEW 27 of 38 39 Molecules 2018, 23, x FOR PEER REVIEW 27 of 38

Scheme 14. HERON and radical decomposition pathways for N-acyloxy-N-alkoxyamides in toluene SchemeatScheme 90 °C. 14. 14.HERON HERON and and radical radical decomposition decomposition pathways pathways for N for-acyloxy- N-acyloxy-N-alkoxyamidesN-alkoxyamides in toluene in toluene at 90 ◦ C. at 90 °C.

Figure 15. ((aa)) Stabilisation of of the HERON transition state forfor NN-acyloxy--acyloxy-N-alkoxyamides by para methoxylFigure 15. group (a) Stabilisation and (b) destabilisation of the HERON by aa paratransition nitro group.state for N-acyloxy-N-alkoxyamides by para methoxyl group and (b) destabilisation by a para nitro group. 3.2.7. HERON Reactions of N,N-Dialkoxyamides 3.2.7. HERON Reactions of N,N-Dialkoxyamides Like NN-acyloxy--acyloxy-NN-alkoxyamides-alkoxyamides 2b2b, N, N,N,N-dialkoxyamides-dialkoxyamides 2c2c possesspossess low low amidicity amidicity and and they they are ◦ thermallyare thermallyLike Nunstable,-acyloxy- unstable, butN-alkoxyamides require but require higher higher 2b temperatures, N, temperaturesN-dialkoxyamides (typically (typically 1552c possess °C 155 in mesitylene).C low in mesitylene).amidicity However, and However, they their are reactionthermallytheir reaction proceeds unstable, proceeds exclusively but require exclusively by higher homolysis. by temperatures homolysis. Secondary Secondary (typically products products155 from °C in alkoxynitrenes, frommesitylene). alkoxynitrenes, However, which would which their wouldbereaction produced be proceeds produced by the exclusively HERON by the HERON pathway,by homolysis. pathway, were Seco not were ndaryobserved not products observed for acyclic from for Nalkoxynitrenes, acyclic,N-dialkoxyamides.N,N-dialkoxyamides. which Rather, would 0 0 theybeRather, produced produce they produce by alkoxyamidyl the HERON alkoxyamidyl radicals,pathway, radicals, which were which dimerisenot observed dimerise to N for, toN′ -dialkoxy-Nacyclic,N -dialkoxy- N,NN,-dialkoxyamides.N′-diacylhydrazinesN,N -diacylhydrazines Rather, and ultimatelytheyand ultimatelyproduce esters. alkoxyamidyl esters. In addition, In addition, radicals, they can they which be cantrappe dimerise bed trapped by hydrogen to byN,N hydrogen′-dialkoxy- donors donorsandN,N solvent′-diacylhydrazines and derived solvent derivedradicals and [55].ultimatelyradicals [55 esters.]. In addition, they can be trapped by hydrogen donors and solvent derived radicals [55]. On the other hand, room room temperature temperature HERON reactivity was found to occur exclusively in severalOn alicyclic the other ONO hand, systems systems room [30]. [ 30temperature]. Cyclic Cyclic NN,N, NHERON-dialkoxyamides,-dialkoxyamides, reactivity N Nwas-butoxy-3(-butoxy-3( found2H 2Hto)-benzisoxazolone )-benzisoxazoloneoccur exclusively 7373in,, Nseveral-butoxyisoxazolidin-3-one alicyclic ONO systems 74 [30].,, and Cyclic N-butoxytetrahydro--butoxytetrahydro- N,N-dialkoxyamides,2H-1,2-oxazin-3-one N-butoxy-3(2H 75,75,)-benzisoxazolone can be synthesised 73, − byN-butoxyisoxazolidin-3-one PIFA oxidation of the salicamide 74, and 70N-butoxytetrahydro-,, β− andand γγ-hydroxyhydroxamic-hydroxyhydroxamic2H-1,2-oxazin-3-one esters, esters, 71 7175, andand can 7272 be, ,respectively, respectively,synthesised by analogyPIFA oxidation with the of synthesis the salicamide of acyclic 70, βN− ,,andN-dialkoxyamides-dialkoxyamides γ-hydroxyhydroxamic (Scheme 4esters,4)) [[55].55]. 71 Only Only and N N72-butoxy-3(2-butoxy-3(2, respectively,HH)-)- benzisoxazoloneby analogy with73 the73is is synthesis stable; stable;N N-butoxyisoxazolidin-3-one of-butoxyisoxazolidin-3-one acyclic N,N-dialkoxyamides74 and74 and N(Scheme-butoxytetrahydro-2 N-butoxytetrahydro-2 4) [55]. OnlyH N-1,2-oxazin-3-one-butoxy-3(2H-1,2-oxazin-H)- 1 3-onebenzisoxazolone75 both 75 react both at react room 73 atis temperature stable;room temperatureN-butoxyisoxazolidin-3-one and the reactions and the canreactions be monitored 74 can and be N by-butoxytetrahydro-2monitoredH NMR by and 1H mass NMRH spectrometry-1,2-oxazin- and mass (Schemespectrometry3-one 75 15both). The react(Schemeγ-oxazinolactam at room 15). temperature The undergoesγ-oxazinolactam and quantitative the reactions undergoes ring can opening be quantitative monitored to a diastereomeric by ring 1H NMRopening mixtureand massto ofa diastereomericspectrometrythe stable hyponitrite (Schememixture76 , which15).of theThe must stable γ-oxazinolactam arise hyponitrite from dimerization 76undergoes, which of alkoxynitrene mustquantitative arise 77from ,ring a known dimerization opening reaction to of a alkoxynitrenediastereomericalkoxynitrenes. 77 Themixture, aδ -oxazinolactam,known of thereaction stable on of the hyponitritealkoxynitrenes. other hand, 76 undergoes, Thewhich δ-oxazinolactam, must a quantitative arise from ring on contractiondimerizationthe other hand, to theof undergoesalkoxynitreneγ-valerolactone a quantitative 7778, witha known production ring reaction contraction of butoxynitreneof alkoxynitrenes. to the γ-valerolactone79. Both The are δ clearly -oxazinolactam,78 with HERON production reactions on ofthe butoxynitrene other [30]. hand, 79undergoes. BothThe areEA a forclearlyquantitative both HERON HERON ring reactions reactions contraction must[30]. to be the radically γ-valerolactone lower than 78 that with for production acyclic N,N of-dialkoxyamides. butoxynitrene Analysis of the B3LYP/6-31G(d) optimised ground state structures of N-methoxy-γ-oxazinolactam 81 79. BothThe areEA clearly for both HERON HERON reactions reactions [30]. must be radically lower than that for acyclic N,N- (Figure 16b) and N-methoxy-δ-oxazinolactam 82 (Figure 16c) provide insight into this unusual difference dialkoxyamides.The EA for Analysisboth HERON of the B3LYP/6-31G(reactions mustd) optimisedbe radically ground lower state than structures that for of Nacyclic-methoxy- N,Nγ- oxazinolactamdialkoxyamides. 81 Analysis (Figure 16b)of the and B3LYP/6-31G( N-methoxy-d)δ-oxazinolactam optimised ground 82 (Figurestate structures 16c) provide of N-methoxy- insight intoγ- oxazinolactam 81 (Figure 16b) and N-methoxy-δ-oxazinolactam 82 (Figure 16c) provide insight into

Molecules 2018, 23, 2834 28 of 39 MoleculesMolecules 2018 2018, ,23 23, ,x x FOR FOR PEER PEER REVIEW REVIEW 2828 of of 38 38 thisthis unusualunusual differencedifference inin reactivity.reactivity. Firstly,Firstly, thethe modelmodel γγ-oxazinolactam-oxazinolactam isis stronglystrongly pyramidalpyramidal◦ atat in reactivity. Firstly, the model γ-oxazinolactam is strongly pyramidal at nitrogen (χN = 64.6 ) and χχ ◦ significantlynitrogennitrogen ( ( NN twisted= = 64.6°) 64.6°) (and τand= −significantly significantly36 ), with attendant twisted twisted ( lossτ(τ = = − of−36°),36°), amide with with character. a attttendantendant The loss loss N–C(O) of of amide amide bond character. character. is very longThe The comparedN–C(O)N–C(O) bond bond to N,N is is very very-dimethoxyacetamide long long compared compared to to 4bN,N N,N(1.417-dimethoxyacetamide-dimethoxyacetamide Å, Table3). The COSNAR 4b 4b (1.417 (1.417 and Å, Å, Table TATable resonance 3). 3). The The COSNAR COSNAR energies −1 forandand81 TA TAare resonance resonance−20 and −energies energies19 kJ mol for for 81 81, respectively, are are − −2020 and and translating− −1919 kJ kJ mol mol− to1−,1 ,respectively, amidicitiesrespectively, of translating onlytranslating 26% and to to amidicities 25%.amidicities Torsion of of ◦ anglesonlyonly 26% 26% close and and to 25%. 9025%.indicate Torsion Torsion that angles angles the close endoclose andto to 90° 90°exo indicate indicateoxygen that lonethat the pairsthe endo endo are and and ideally exo exo alignedoxygenoxygen lone forlone maximum pairs pairs are are σ nideallyideallyO– *NO aligned alignedstabilisation. for for maximum maximum Low amidicity n nOO––σσ**NONO andstabilisation. stabilisation. a strong stereoelectronic Low Low amidicity amidicity andeffect and a a strongwould strong stereoelectronic favourstereoelectronic either reaction effect effect but,wouldwould clearly, favourfavour ring either openingeither reactionreaction would but, bebut, more clearly,clearly, favourable ringring openingopening than ring wouldwould contraction, bebe moremore which favourablefavourable would give thanthan a highly ringring strainedcontraction,contraction,β-lactone. which which would would give give a a highly highly strained strained β β-lactone.-lactone.

SchemeScheme 15. 15. HERON HERON reactions reactions of of γ γ-oxazinolactam-oxazinolactam 71 71 and and δ δ-oxazinolactam-oxazinolactam 72 72.. .

NN NN NN NN O1O1 O2O2 O1O1 O2 O1O1 O2 O1 O1 O2O2 O2O2 χ χ χ χ = = 61° 61° χ= = 65° 65° χ= = 61° 61° χχ = = 54° 54° τ τ τ τ =-18° =-18° τ = = –37° –37° τ = = 13° 13° τ τ = = –10° –10° N–CN–C = = 1.461Å 1.461Å N–CN–C = = 1.465Å 1.465Å N–CN–C = = 1.427Å 1.427Å N–CN–C = = 1.425Å 1.425Å N–O1N–O1 = = 1.477Å 1.477Å N–O1N–O1 = = 1.419Å 1.419Å N–O1N–O1 = = 1.46Å 1.46Å N–O1N–O1 = = 1.413Å 1.413Å N–O2N–O2 = = 1.373Å 1.373Å N–O2N–O2 = = 1.428Å 1.428Å N–O2N–O2 = = 1.379Å 1.379Å N–O2N–O2 = = 1.401Å 1.401Å C-O1-N-O2C-O1-N-O2 = = –135° –135° C-O1-N-O2C-O1-N-O2 = = –86° –86° C-O1-N-O2C-O1-N-O2 = = 171° 171° C-O1-N-O2C-O1-N-O2 = = 79.4° 79.4° C-O2-N-O1C-O2-N-O1 = = –97° –97° C-O2-N-O1C-O2-N-O1 = = –95° –95° C-O2-N-O1C-O2-N-O1 = = –92° –92° C-O2-N-O1C-O2-N-O1 = = –90.4° –90.4° (a)(a) (b) (b) (c) (c) (d)(d) FigureFigure 16. 16. Ground GroundGround state state state structures structures structures of of models models ( a( a) )N NN-methoxybenzisoxazolone-methoxybenzisoxazolone-methoxybenzisoxazolone 80 8080,,( ,( b(bb)) )N N-methoxy--methoxy--methoxy-γγγ--- oxazinolactamoxazinolactam81 81 81,, and ,and and ( c( )c(c chair) )chair chair and and and (d () d( boatd) )boat boatN-methoxy- N N-methoxy--methoxy-δ-oxazinolactamδδ-oxazinolactam-oxazinolactam82. 82 82. .

Molecules 2018, 23, x FOR PEER REVIEW 29 of 38

Molecules 2018, 23, 2834 χ 29 of 39 The B3LYP/6-31G(d) structure of the model δ-oxazinolactam 82 ( N = 61° and τ = 13°) matches the experimental (1H NMR) chair conformation of 75 which has a chiral nitrogen. It is also more ◦ ◦ The B3LYP/6-31G(d) structure of the model δ-oxazinolactam 82 (χN = 61 and τ = 13 ) matchesχ the pyramidal at nitrogen and slightly more twisted than the alicyclic N,N-dimethoxyacetamide 4b ( N = 1 75 experimental ( H NMR) chair conformation of which has a chiral nitrogen. It is also more−1 pyramidal 48° and τ = 9°, Figure 7c, Table 3), but its resonance and amidicity (RECOSNAR = −38 kJ mol , amidicity◦ at nitrogen and slightly more twisted than the alicyclic N,N-dimethoxyacetamide 4b (χN = 48 and −1 49%, ◦and RETA = −37 kJ mol , amidicity 47%) is almost identical to the open chain− 1form. However, τ = 9 , Figure7c, Table3), but its resonance and amidicity (RE COSNAR = −38 kJ mol , amidicity 49%, only an n –σ* anomeric−1 alignment is evident; with a torsion angle of 171°, the n –σ* and RETAO(=exo−) 37NO( kJendo mol) , amidicity 47%) is almost identical to the open chain form. However,O(endo) NO( onlyexo) ◦ interactionan nO(exo)–σ is*NO( completelyendo) anomeric switched alignment off. The is evident;endo N–O with bond a torsion is nearly angle 0.1 of Å 171 longer, the than nO(endo the)– exoσ*NO( N–Oexo) bondinteraction (the endo is completely bond is marginally switched shorter off. The thanendo theN–O exo bondbond isby nearly 0.01 Å 0.1 in Åγ-oxazinolactam longer than the andexo N–O bondsbond (the differendo bybond 0.02 is marginallyÅ in N,N-dimethoxyacetamide). shorter than the exo bond Ring by 0.01open Åing in γand-oxazinolactam ring contraction and N–O are ‡ computedbonds differ to by have 0.02 about Å in N the,N-dimethoxyacetamide). same EA and ΔH at B3LYP/6-31G(d) Ring opening and [30]. ring It contraction is evident arethat computed the ring ‡ contractionto have about of the the δ same-oxazinolactamEA and ∆H to γat-butyrolactone B3LYP/6-31G(d) is largely [30]. It driven is evident by a strong, that the conformationally ring contraction imposedof the δ-oxazinolactam anomeric effect, to aγ -butyrolactoneremarkable impact is largely of anomeric driven bysubstitution a strong, conformationallyat an amide nitrogen imposed [30]. Whileanomeric the effect,computed a remarkable transition impact state for of anomericring opening substitution of model at anN-methoxyamide nitrogenδ-oxazinolactam [30]. While is marginallythe computed lower transition in energy, state the for required ring opening nO(endo)– ofσ*NO( modelexo) is Nonly-methoxy- accessibleδ-oxazinolactam from the boat conformation is marginally oflower the δ in-oxazinolactam energy, the required (Figure 16d). nO(endo Experimentally,)–σ*NO(exo) is only accessing accessible this fromconformation the boat in conformation 75 by nitrogen of inversionthe δ-oxazinolactam could be energetically (Figure 16 d).unfavourable, Experimentally, owing accessing to steric hindrance this conformation between the in 75 axialby 4-methyl nitrogen andinversion N-butoxy could groups. be energetically However, unfavourable, even in the boat owing conformation, to steric hindrance the strong between nO(exo) the–σ* axialNO(endo 4-methyl), which favoursand N-butoxy ring contraction groups. However, is still evident. even in the boat conformation, the strong nO(exo)–σ*NO(endo), which favoursThe ring γ-lactam contraction in benzisoxazolone is still evident. is stable at room temperature, though model 80 has a The γ-lactam in benzisoxazolone is stable at room temperature, though model 80 has a moderately moderately suitable anomeric alignment for migration of O2. However, the nO(endo)–σ*NO(exo) interaction suitable anomeric alignment for migration of O2. However, the nO(endo)–σ*NO(exo) interaction is probably is probably weakened by conjugation of the Oendo p-type lone pair onto the aromatic ring. Ring weakened by conjugation of the Oendo p-type lone pair onto the aromatic ring. Ring contraction driven contraction driven by a favourable nO(exo)–σ*NO(endo) interaction would be disfavoured. by a favourable nO(exo)–σ*NO(endo) interaction would be disfavoured.

3.2.8. NN-Alkoxy--Alkoxy-NN-Alkylthiylamides-Alkylthiylamides The combination of sulphur and oxygen attachment to to amide nitrogen in N-methoxy--methoxy-NN-- methylthiylacetamide 15d15d resultsresults in in a a similar similar reduction reduction in in amide amide resonance resonance to to that that of of NN-methoxy--methoxy-NN-- dimethylaminoacetamide 15c15c,, namely namely about about 64% 64% vs. vs. 67% 67% (Table (Table 4).4). However, However, the the reaction reaction of ofN- acyloxy-N-acyloxy-N-alkoxyamidesN-alkoxyamides 21 21withwith biological biological thiols, thiols, glutathione, glutathione, and and methyl methyl and and ethyl ethyl esters esters of cysteine, which resulted in SN2 displacement of carboxylate, produced exclusively hydroxamic esters cysteine, which resulted in SN2 displacement of carboxylate, produced exclusively hydroxamic 83esters and 83disulphidesand disulphides 84 [52] (Scheme84 [52] (Scheme16). The driving16). The force driving for HERON force forreactivity HERON is not reactivity only reduced is not resonance,only reduced but resonance, the anomeric but theeffect. anomeric Instead effect. of HERON Instead reactions, of HERON the reactions,intermediate the intermediateN-alkoxy-N- alkylthiylamides 24 undergo an S 2 reaction at sulphur by thiol. The distinction between reactivity N-alkoxy-N-alkylthiylamides 24 undergoN an SN2 reaction at sulphur by thiol. The distinction between modesreactivity for modes NNO forand NNO SNO andsystems SNO lies systems in the lies nS– inσ* theNO nanomericS–σ*NO anomeric interaction, interaction, which is whichmuch isweaker much thanweaker the than nN–σ the*NOn ofN –Nσ-alkoxy-*NO of NN-alkoxy--aminoamides.N-aminoamides.

Scheme 16. Reaction of N-acyloxy--acyloxy-N-alkoxyamides-alkoxyamides with with alkylthiols. alkylthiols.

3.3. Driving Driving Force Force for the HERON Reaction The most most accessible accessible transition transition states states for forHERON HERON migration migration of methoxyl of methoxyl in a number in a number of model of anomericmodel anomeric amides, amides, N-methoxy-N-methoxy-N-dimethylaminoacetamideN-dimethylaminoacetamide 15c, N15c,N,-dimethoxyacetamideN,N-dimethoxyacetamide 4b, 4bN-, acetoxy-N-acetoxy-N-methoxyacetamideN-methoxyacetamide 15b15b, and, and OO-methyl--methyl-NN-methoxy--methoxy-NN-dimethylaminocarbamate-dimethylaminocarbamate 16a16a,, ring ring opening of of NN-methoxy--methoxy-γγ-oxazinolactam-oxazinolactam 8181, and, and ring ring contracting contracting of N of-methoxy-N-methoxy-δ-oxazinolactamδ-oxazinolactam 82, each82, each of which of which represents represents a class aof classneutral of anomeric neutral anomericamides known amides to undergo known toHERON undergo reactions, HERON as wellreactions, as asfor wellmethoxyl as for methoxylmigration migrationin N-methoxy- in N-methoxy-N-methylthiylacetamideN-methylthiylacetamide 15d, 15dN-, methoxyacetohydroxamateN-methoxyacetohydroxamate 15f15f, and, and 1-acetyl-1-methoxydiazene 1-acetyl-1-methoxydiazene 15g15g, have, have been been derived derived at at the

Molecules 2018, 23, 2834 30 of 39 Molecules 2018, 23, x FOR PEER REVIEW 30 of 38

B3LYP/6-31G(d)B3LYP/6-31G(d) levellevel as part of several studies studies [30,61,62]. [30,61,62 ].Transition Transition state state geometries geometries of 4b of,4b15b,15b–d,f– d,f andandg ,g16a, 16a, 81, 81,, and and82 82are are presentedpresented in Figure 17.17.

C2 O1 O1 C1 O3 N2 1.519Å 1.860Å O1 N1 C2 1.199Å C1 1.875Å C1 θ O3 N1 1.263Å θ θ 1.583Å N1 1.546Å 1.348Å 2.012Å O2 1.747Å 1.981Å O2 O2 C4 C3 C5

θ = 57.3° θ = 48.2° θ = 48.4° O1-C1-N1-O2 = 107.4° O1-C1-N1-O2 = –112.7° O1-C1-N1-O2 = –114.9° O4 O1-C1-N1-N2 = 11.8° O1-C1-N1-O3 = 157.8° O1-C1-N1-O3 = 159.6° (a) (b) (c)

C2 C7 O1 C1 1.210Å S1 1.74Å θ O3 1.727Å O1 C1 O3 θ 1.383Å 1.222Å θ N1 C1 1.606Å 1.607Å 1.50Å C6 O1 N1 N2 1.483Å 2.10Å N1 1.926Å θ C4 O2 O2 1.269Å 1.744Å 2.003Å C5 O2 C3

θ = 57.8° θ = 51.9° θ = 44.6° O1-C1-N1-O2 = –111.6° O1-C1-N1-O2 = –113.2° O1-C1-N1-O2 = –119.5° O1-C1-N1-N2 = 154.5° O1-C1-N1-O3 = 154.3° O1-C1-N1-O3 = 152.0° (e) (f) (d)

C2 O1 N1 O3 C1 1.187Å O3 1.195Å C1 1.433Å 1.560Å 1.80Å O1 C4 θ 1.271Å N1 1.136Å C1 N1 θ N2 1.21Å 2.188Å 2.207Å θ 1.96Å 1.655Å 1.87Å 1.54Å O1θ O2 O2 O2 (b)

C3 C3

θ θ = 48.0° θ = 89.6° = 79.0° O1-C1-N1-O2 = –112.8° O1-C1-N1-O2 = –103.4° O1-C1-N1-O2 = –111.1° O1-C1-N1-O3 = –21.9° O1-C1-N1-O3 = 145.8° O1-C1-N1-N2 = 36.5°

(g) (h) (i)

FigureFigure 17.17. B3LYP/6-31G(d)B3LYP/6-31G(d) optimised optimised transition transition states of statesfavoured of HERON favoured reactions HERON of ( reactionsa) N- ofmethoxy- (a) N-dimethylaminoacetamide-methoxy-N-dimethylaminoacetamide 15c, (b) N,N-dimethoxyacetamide15c,(b) N,N-dimethoxyacetamide 4b, (c) N-acetoxy-N- 4b, (cmethoxyamide) N-acetoxy- N15b-methoxyamide, (d) O-methyl-N15b-methoxy-,(d) N-dimethylaminocarbamateO-methyl-N-methoxy-N-dimethylaminocarbamate 16a, (e) N-methoxy-N- 16amethylthiylacetamide,(e) N-methoxy-N-methylthiylacetamide 15d, (f) N-methoxy-γ-oxazinolactam15d,(f) N-methoxy- 81 (ringγ-oxazinolactam opening), (g) 81N-methoxy-(ring opening),δ- (goxazinolactam) N-methoxy- δ-oxazinolactam82 (ring contraction),82 (ring (h contraction),) N-methoxyacetohydroxamate (h) N-methoxyacetohydroxamate 15f and (i) 1-acetyl-1-15f and (i) methoxydiazene 15g. 1-acetyl-1-methoxydiazene 15g.

InIn all all the the transition transition statestate complexes,complexes, the the migrating migrating oxygen oxygen does does so so in ina plane a plane largely largely orthogonal orthogonal to the N1–C1–O1 plane and the donor atom nY, driving the migration, is largely in the N1–C1–O1 to the N1–C1–O1 plane and the donor atom nY, driving the migration, is largely in the N1–C1–O1 plane. As a consequence, the amide nitrogen lone pair lies close to the plane and amide resonance is plane. As a consequence, the amide nitrogen lone pair lies close to the plane and amide resonance is largely lost in the transition state. The resonance energy, RE is therefore a component of the overall largely lost in the transition state. The resonance energy, RE is therefore a component of the overall EA, the balance being the energy required for the rearrangment under anomeric assistance, Erearr, and EA, the balance being the energy required for the rearrangment under anomeric assistance, Erearr, and must reflect the relative nature of the nX–σ*NO driving force. It is therefore possible to approximate must reﬂect the relative nature of the nX–σ*NO driving force. It is therefore possible to approximate

Molecules 2018, 23, x FOR PEER REVIEW 32 of 38

Table 8. B3LYP/6-31G(d) activation energies (EA), resonance energies (RETA), and rearrangement

energies (Erearr) for HERON reactions of model anomeric amides and tricyclic anomeric amides; all values in kJ mol−1.

1 2 Migratory Mode EA XNY RETA Erearr MeO from anti 15c 95.0 ONN −51.5 43.5 MeO from 4b 156.5 ONO −35.9 120.5 MeO from syn 16a 92.4 ONN −50.7 41.8 AcO from syn 15b 181.0 AcONO −40.5 140.5 MeO from syn 15b 207.9 ONOAc −40.5 167.4 AcO from anti 15b 181.5 AcONO −40.5 141.0 MeO from anti 15b 182.8 ONOAc −40.5 142.3 MeO from anti 15d 174.1 ONS −48.6 125.4 MeO from 15f 3 48.0 ONO– −32.4 15.6 MeO from 15g 8.8 ONNitrene −14.8 −6.0 Ring opening 81 113.0 ONO −19.2 93.8 Ring contraction 82 145.2 ONO −36.7 108.4 Ring opening of 82 136.4 ONO −36.7 99.7 Scheme 17 i X=NMe 59.0 ONN 0.0 59.0 Scheme 17 i X=O 146.9 ONO 0.0 146.9 Molecules 2018, 23,Scheme 2834 17 i X=S 152.7 ONS 0.0 152.7 31 of 39

Scheme 17 ii X=CH2 242.7 ONCH2 0.0 242.7

Molecules 2018, 23, x FORScheme PEER 18 REVIEW i 133.5 AcONO 0.0 133.5 32 of 38 the inﬂuence of theScheme anomeric 18 ii substituents 161.5 on the resonance ONOAc interaction on the 0.0 one hand, 161.5 and on the migration1 process,Y on theNX other.2 Table8 gives the EA, RETA, and net Erearr data3 for these transition states. Tablen 8. donor B3LYP/6-31G(d) to σ* ; Transamidation activation energies data (COSNAR (EA), resonance data very energies similar); (RE HF/6-31G(d)TA), and rearrangement values.

energies (Erearr) for HERON reactions of model anomeric amides and tricyclic anomeric amides; all values in kJ mol−1.

1 2 Migratory Mode EA XNY RETA Erearr MeO from anti 15c 95.0 ONN −51.5 43.5 MeO from 4b 156.5 ONO −35.9 120.5 MeO from syn 16a 92.4 ONN −50.7 41.8

AcO from syn 15b 181.0 AcONO −40.5 140.5 MeOScheme from syn 17. 15b HERON migrations 207.9 of alkoxyl inONOAc the absence of resonance. −40.5 167.4 AcO from anti 15b 181.5 AcONO −40.5 141.0 Table 8. B3LYP/6-31G(d) activation energies (E ), resonance energies (RE ), and rearrangement MeO from anti 15b 182.8 A ONOAc TA−40.5 142.3 E energies ( MeOrearr) from for HERON anti 15d reactions of model174.1 anomeric amidesONS and tricyclic−48.6 anomeric amides;125.4 all −1. values in kJMeO mol from 15f 3 48.0 ONO– −32.4 15.6

MeO from 15g 8.8 ONNitrene1 2 −14.8 −6.0 Migratory Mode EA XNY RE Erearr Ring opening 81 113.0 ONO TA −19.2 93.8 MeORing from contractionanti 15c 82 95.0145.2 ONN ONO −51.5−36.7 43.5108.4 MeO from 4b 156.5 ONO −35.9 120.5 SchemeRing opening 18. HERON of 82 reactions of N136.4-acyloxy- N-alkoxyamideONO in absence− 36.7of resonance. 99.7 MeO from syn 16a 92.4 ONN −50.7 41.8 Scheme 17 i X=NMe 59.0 ONN 0.0 59.0 AcO from syn 15b 181.0 AcONO −40.5 140.5 Scheme 17 i X=O 146.9 ONO 0.0 146.9 4. ConclusionsMeO from syn 15b 207.9 ONOAc −40.5 167.4 AcOScheme from anti 1715b i X=S 181.5 152.7 AcONO ONS −40.5 0.0 141.0 152.7 In this review we have outlined the theoretical and structural properties and the reactivity of the MeOScheme from anti 17 ii15b X=CH2 182.8242.7 ONOAcONCH2 −40.50.0 142.3242.7 class of anomericMeO fromScheme amides.anti 15d18 Much i of the174.1 data 133.5 from this, ONS and AcONO several other−48.6 groups, 0.0 is 125.4 relatively 133.5 recent – and, while MeOseveralScheme from compilations15f 183 ii on 48.0the subject 161.5 ha ONOve appeared ONOAc in− 32.4the literature, 0.0 15.6 a 161.5focus on the MeO from 15g 8.8 ONNitrene −14.8 −6.0 perturbation1 nY donor of the to σamide*NX; 2 Transamidation structure is befittingdata (COSNAR this special data very edition. similar); The 3 HF/6-31G(d) fairly recent values. accrual of − structural dataRing from opening our 81laboratory and113.0 that of Shtamburg ONO has provided19.2 experimental 93.8 verification of Ring contraction 82 145.2 ONO −36.7 108.4 the unusualRing properties opening of 82bisheteroatom-substituted136.4 ONOamides. Coupled−36.7 with extensive 99.7 computational results, theScheme effect 17 of i X=NMeheteroatoms at 59.0nitrogen on amide ONN resonance and 0.0 conformation 59.0 at the amide nitrogen canScheme be better 17 i understood X=O and 146.9 predicted, in particular ONO the role 0.0 played by electronegativity 146.9 of the bonded Schemeatoms and17 i X=Sorbital interactions. 152.7 Ensuing from ONS the work is 0.0 a clearer understanding 152.7 of the Scheme 17 ii X=CH 242.7 ONCH 0.0 242.7 energetic consequences of distortion2 of the amide linkage.2 It is clear that spectroscopic properties of Scheme 18 i 133.5 AcONO 0.0 133.5 various congenersScheme are 18 dictatedii by two 161.5 principle co ONOAcncepts: the first is 0.0 impaired resonance 161.5 owing to change in hybridisation1 bought2 about by orbital interactions that have 3their foundation in Bent’s, and nY donorScheme to σ*NX 17.; TransamidationHERON migrations data (COSNAR of alkoxyl data invery the absence similar); ofHF/6-31G(d) resonance. values.

Scheme 18. HERON reactions of N-acyloxy-N-alkoxyamide in absence ofof resonance.resonance.

−1 4. ConclusionsMethoxyl migration in the NNO systems 15c and 16a (EA’s 95 and 92 kJ mol respectively) have similar RE’s of around −50 kJ mol−1, and therefore E of approximately 40 kJ mol−1. The change In this review we have outlined the theoretical anrearrd structural properties and the reactivity of the in charge on the carbonyl carbon in the HERON transition state is negligible [76], so replacement of class of anomeric amides. Much of the data from this, and several other groups, is relatively recent methyl by methoxyl has little bearing on the rearragement energies. ONO in 4b and ONOAc in 15b and, while several compilations on the subject have appeared in the literature, a focus on the migrations have much higher E ’s despite the lower amide resonance energy. The large difference perturbation of the amide structureA is befitting this special edition. The fairly recent accrual of lies in the E which is nearly 100 kJ mol−1 less favourable and a reﬂection of the relative efﬁcacy structural datarearr from our laboratory and that of Shtamburg has provided experimental verification of of the n –σ* vs. the weaker n –σ* anomeric interaction. The difference of about 80 kJ mol−1 the unusualN propertiesNO of bisheteroatom-substitutedO NO amides. Coupled with extensive computational between methoxy migration in the ONS 15d and ONN acetamides 15c lies, again, in the much weaker results, the effect of heteroatoms at nitrogen on amide resonance and conformation at the amide n –σ* anomeric effect. This can be accounted for by size mismatch due the larger 3p orbitals nitrogenNO can be better understood and predicted, in particular the role played by electronegativity of of the sulphur. Both HERON reactions of the cyclic forms of N,N-dialkoxyamides 81 and 82 have the bonded atoms and orbital interactions. Ensuing from the work is a clearer understanding of the energetic consequences of distortion of the amide linkage. It is clear that spectroscopic properties of various congeners are dictated by two principle concepts: the first is impaired resonance owing to change in hybridisation bought about by orbital interactions that have their foundation in Bent’s, and

Molecules 2018, 23, 2834 32 of 39

substantially lower overall EA’s than N,N-dimethoxyacetamide 4b. After RE has been taken into account, Erearr values indicate that in the cyclic forms, reorganisation to the HERON transition state is easier. Better stereoelectronic control in the cyclic system accounts for this. The RE of the 1,1-diazene 15g, is computed to be about the same as the overall EA for its HERON reaction. This is a very early transition state in keeping with the exothermicity of the process. Erearr is essentially zero on account of the high energy electron-pair on the amino nitrene and the EA is essentially equivalent to the RE that must be sacriﬁced. Likewise, the hydroxamate 15f bears a very high energy electron pair on the anomeric donor oxygen. While the resonance energy is similar to that of N,N-dimethoxyacetamide, the Erearr is small. This too is a very early transition state. Overall, the decreasing order of Erearr of XNY systems based on the deconvolution in Table8, which can be regarded as the order of decreasing effectiveness of an nY–σ*NX interaction and destabilisation of the N–OMe bond, is AcONO > ONS ~ONO > ONN > ONO− > ONNitrene. − The order of RETA is ONN > ONS > AcONO > ONO > ONO > ONNitrene and the overall activation energies decrease in the order AcONO > ONS > ONO > ONN > ONO− > ONNitrene. Clearly, the dominant inﬂuence in HERON reactivity is the strength of the anomeric effect rather than the decrease in amidicity. Rearrangement energies, Erearr’s, obtained by the deconvolution method represent activation energies in the absence of resonance. Relative Erearr’s can be compared to relative EA’s for intramolecular rearrangement in fully twisted amides, heteroatom-substituted 1-aza-2-adamantanones 85 (Scheme 17) and 2-quinuclidone 88 (Scheme 18) and the EA’s are also presented in Table8. ∆EA’s relative to migration of oxygen (Scheme 17i) in 85b, for 85a, and 85c are −88 and 5.8 kJ mol−1, respectively, which correlate well with the respective differences in Erearr of the respective acetamides, namely −77 and 5 kJ mol−1. Similarly, the difference in the ease of migration of alkoxyl to form 90 and acyloxyl to form 89 in 88 (Scheme 18i,ii) is 28 kJ mol−1 and the difference between the corresponding −1 Erearr form the syn conformer of 15b is 27 kJ mol . No transition state can be found for migration of alkoxyl group in hydroxamic ester 3b. However, 85d can be rearranged to lactone 87 (Scheme 17ii) with concomitant rearrangement of the nitrene product to the imine. The difference between EA for this process and the −1 rearrangement of 85a is 184 kJ mol . If this translates to the difference in Erearr between twisted N-methoxy-N-methylacetamide 3b and N-methoxy-N-dimethylaminoacetamide 15c, for which Erearr is 43.5 kJ mol−1, the rearrangement of 3 to methyl acetate and methylnitrene would have an activation energy of about 233 kJ mol−1 from twisted 3b or, adding in the RE for 3b of 62 kJ mol−1, 295 kJ mol−1 from conjugated 3. It is clear that hydroxamic esters do not rearrange to esters and alkylnitrenes and the role of anomeric (bisheteroatom) substitution in the HERON reaction is vital.

4. Conclusions In this review we have outlined the theoretical and structural properties and the reactivity of the class of anomeric amides. Much of the data from this, and several other groups, is relatively recent and, while several compilations on the subject have appeared in the literature, a focus on the perturbation of the amide structure is befitting this special edition. The fairly recent accrual of structural data from our laboratory and that of Shtamburg has provided experimental verification of the unusual properties of bisheteroatom-substituted amides. Coupled with extensive computational results, the effect of heteroatoms at nitrogen on amide resonance and conformation at the amide nitrogen can be better understood and predicted, in particular the role played by electronegativity of the bonded atoms and orbital interactions. Ensuing from the work is a clearer understanding of the energetic consequences of distortion of the amide linkage. It is clear that spectroscopic properties of various congeners are dictated by two principle concepts: the first is impaired resonance owing to change in hybridisation bought about by orbital interactions that have their foundation in Bent’s, and more recently Alabugin’s theories of orbital interactions. Of particular importance is the reassignment of 2s character to the amide nitrogen lone pair orbital, as consequence of both electronegativity and Molecules 2018, 23, 2834 33 of 39 orbital overlap considerations. Secondly, the participating atoms in this purturbation of regular amide bonding possess intrinsic orbital interactions by virtue of both their electronegativity and their lone pairs. The anomeric interaction bought about by nY–σ*NX overlap is pronounced in anomeric amides. What is clear is that the electronegativity induces a shift to less resonance through pyramidalisation and lowering the energy of the amide nitrogen lone pair and the anomeric interaction is better served by this shift to sp3 character. Stronger electronegativity serves to reduce resonance as well as to promote the anomeric interaction. Regarding reactivity, it is abundantly clear that both resonance impairment and strength of the anomeric effect are definitive, but the anomeric effect dominates in promoting both SN2 and elimination reactions at the amide nitrogen. Most significant is the anomeric driving force for the HERON reaction, notably in systems such as N-amino-N-alkoxyamides (NNO systems) where the energetics for anomeric weakening of the N–O bond are optimised, and in cyclic systems such as the N-alkoxy-γ- and δ-oxazinolactams where conformation and configuration appear to favour and enhance anomeric overlap. The HERON reaction is unique to this class of amides and has no equivalence in the literature. It operates in the opposite sense to the well-known Curtius, Hoffman, and Lossen rearrangements in which an acyl substituent migrates from the carbonyl to the nitrogen. Finally our studies of the HERON and those of Barton and coworkers, shed light on the well-known decomposition reactions of N,N0-dialkoxy-N,N0-diacylhydrazines. The HERON mechanism that operates in these decompositions and in those of the 1-acyl-1-alkoxydizenes is critical to the synthesis of highly hindered esters.

Conﬂicts of Interest: The authors declare no conﬂict of interest.

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