molecules 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]. Molecules 2018, 23, 2834; doi:10.3390/molecules23112834 www.mdpi.com/journal/molecules Molecules 2018, 23, 2834 2 of 39 MoleculesMolecules 2018 ,2018 23, x, 23FOR, x FORPEER PEER REVIEW REVIEW 2 of 382 of 38 Molecules 2018, 23, x FOR PEER REVIEW 2 of 38 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° afor60° 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. Molecules 2018, 23, 2834 3 of 39 Molecules 2018, 23, x FOR PEER REVIEW 3 of 38 125.0 ) -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