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

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 2834 ◽  
Author(s):  
Stephen Glover ◽  
Adam Rosser
Keyword(s):  
Amide Bond ◽  
Anomeric Effect ◽  
Amide Nitrogen ◽  
Carbonyl Carbon ◽  
Heteroatom Substitution ◽  
Electronegative Atom ◽  
Anomeric Effects ◽  
Acyl Derivatives

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.

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

2018 ◽  
Author(s):  
Stephen A. Glover ◽  
Adam A. Rosser
Keyword(s):  
Amide Bond ◽  
Anomeric Effect ◽  
Amide Nitrogen ◽  
Carbonyl Carbon ◽  
Heteroatom Substitution ◽  
Electronegative Atom ◽  
Anomeric Effects ◽  
Acyl Derivatives

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.

scholarly journals The role of substituents in the HERON reaction of anomeric amides

2016 ◽  
Vol 94 (12) ◽  
pp. 1169-1180 ◽  
Author(s):  
Stephen A. Glover ◽  
Adam A. Rosser
Keyword(s):  
Molecular Conformation ◽  
Minor Role ◽  
Amide Nitrogen ◽  
Carbonyl Carbon ◽  
Activation Barriers ◽  
Resonance Energies ◽  
Electronegative Atom ◽  
A Minor ◽  
Bound Electron

Anomeric amides, RCON(X)(Y), have two electronegative atoms at the amide nitrogen, a configuration that results in greatly reduced amide resonance and strongly pyramidal nitrogen atoms. This, combined with facilitation of anomeric interactions, can result in the HERON reaction, an intramolecular migration of the more electronegative atom, X, from nitrogen to the carbonyl with production of a Y-stabilised nitrene. We have modelled, at the B3LYP/6-31G(d) level, a variety of anomeric amides that undergo the HERON reaction to determine factors that underpin the process. The overriding driving force is anomeric destabilisation of the bond to the migrating group. Rotated transition states show loss of residual resonance and this is a component of the overall activation energies. However, the reduced resonance in these systems plays only a minor role. We have determined the resonance energies (RE) and HERON activation barriers (EA) of five anomeric systems. REs for the amides have been calculated isodesmically using our calibrated trans amidation method and COSNAR calculations. Reduction of their overall EAs by the corresponding RE gives rearrangement energies (Erearr.), a measure of relative impact on rearrangement of substituents on nitrogen. In CH3CON(OMe)(Y) systems producing (CH3CO2Me + NY), a loosely bound electron pair on the donor atom, Y, in nY–σ*NOMe anomeric interactions drives the reaction. Erearr. increases in the sequence Y = N(nitrene) < O−(oxide) ≪ NMe2 < SMe ≪ OMe. For the same systems, RE increases in the order Y = N < O− ≪ OMe ≪ NMe2 ∼ SMe. Other effects such as molecular conformation, nature of the migrating group, X, and acyl substituents at the carbonyl carbon are discussed.

Studies of the Structure, Amidicity, and Reactivity of N-Chlorohydroxamic Esters and N-Chloro-β,β-dialkylhydrazides: Anomeric Amides with Low Resonance Energies

2014 ◽  
Vol 67 (9) ◽  
pp. 1344 ◽  
Author(s):  
Stephen A. Glover ◽  
Adam A. Rosser ◽  
Robert M. Spence
Keyword(s):  
Density Functional ◽  
Resonance Effect ◽  
Amide Bond ◽  
Basis Set ◽  
Anomeric Effect ◽  
Amide Nitrogen ◽  
Density Functional Methods ◽  
Functional Methods ◽  
Resonance Energies ◽  
Chlorine Substituent

Density functional calculations have been carried out to determine the properties of the title anomeric amides. At the B3LYP/6-31G(d) level, N-chloro-N-methoxyacetamide 8a is computed to be strongly pyramidal at nitrogen with a long amide bond that is untwisted. N-Chloro-N-dimethylaminoacetamide 9a is completely planar, but its amide bond is still much longer than that in N,N-dimethylacetamide 4. This is a steric, rather than a resonance, effect. COSNAR and a trans-amidation method calculate low resonance energies for both model amides, which is attributed to the combined electronegativity of the heteroatoms at the amide nitrogen and the strong anomeric effect when there is a chlorine substituent on nitrogen. When M06 and ωB97X-D dispersion-corrected density functional methods are used with the expanded 6-311++G(d,p) basis set, the resonance energies of 8a (–34 kJ mol–1) and 9a (–49 kJ mol–1) are in line with the gross electronegativity of the substituent atoms. Unlike other anomeric amides, 8a and 9a are not predicted to undergo HERON reactivity.

scholarly journals Unexpected Resistance to Base-Catalyzed Hydrolysis of Nitrogen Pyramidal Amides Based on the 7-Azabicyclic[2.2.1]heptane Scaffold

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2363 ◽  
Author(s):  
Diego Ocampo Gutiérrez de Velasco ◽  
Aoze Su ◽  
Luhan Zhai ◽  
Satowa Kinoshita ◽  
Yuko Otani ◽  
...  
Keyword(s):  
Nitrogen Atom ◽  
Amide Bond ◽  
Free Energies ◽  
Amide Nitrogen ◽  
Bond Rotation ◽  
Entropy Term ◽  
And Inversion ◽  
Kinetics Of ◽  
Hydrolysis Of ◽  
Amide Nitrogen Atom

Non-planar amides are usually transitional structures, that are involved in amide bond rotation and inversion of the nitrogen atom, but some ground-minimum non-planar amides have been reported. Non-planar amides are generally sensitive to water or other nucleophiles, so that the amide bond is readily cleaved. In this article, we examine the reactivity profile of the base-catalyzed hydrolysis of 7-azabicyclo[2.2.1]heptane amides, which show pyramidalization of the amide nitrogen atom, and we compare the kinetics of the base-catalyzed hydrolysis of the benzamides of 7-azabicyclo[2.2.1]heptane and related monocyclic compounds. Unexpectedly, non-planar amides based on the 7-azabicyclo[2.2.1]heptane scaffold were found to be resistant to base-catalyzed hydrolysis. The calculated Gibbs free energies were consistent with this experimental finding. The contribution of thermal corrections (entropy term, –TΔS‡) was large; the entropy term (ΔS‡) took a large negative value, indicating significant order in the transition structure, which includes solvating water molecules.

scholarly journals An efficient computational model to predict protonation at the amide nitrogen and reactivity along the C–N rotational pathway

2015 ◽  
Vol 51 (29) ◽  
pp. 6395-6398 ◽  
Author(s):  
Roman Szostak ◽  
Jeffrey Aubé ◽  
Michal Szostak
Keyword(s):  
Nitrogen Atom ◽  
Computational Model ◽  
Amide Bond ◽  
Amide Nitrogen

A computational model enabling prediction of protonation at the amide bond nitrogen atom along the C–N rotational pathway is reported.

Configuration and conformation of alkoxyalkyl and hydroxyalkyl trifluoromethyl nitroxides. Anomeric effects and nitroxide conformations

1981 ◽  
Vol 59 (12) ◽  
pp. 1745-1752 ◽  
Author(s):  
C. Chatgilialoglu ◽  
K. U. Ingold
Keyword(s):  
Anomeric Effect ◽  
Conformational Preference ◽  
Nodal Plane ◽  
Spectral Parameters ◽  
Small Magnitude ◽  
Or Groups ◽  
Steric Factors ◽  
Hyperfine Splittings ◽  
Anomeric Effects ◽  
Configuration And Conformation

The epr spectral parameters for some [Formula: see text] radicals have been measured over a range of temperatures. These radicals are probably non-planar at nitrogen. Their OR groups are in the eclipsed position with respect to the N 2pz orbital, a conformational preference which is attributed to a combination of steric factors and the anomeric effect. For [Formula: see text] the H hyperfine splittings (hfs) are of unusually small magnitude. It is pointed out that all other known [Formula: see text] also have anomalously low H hfs. It is suggested that this is due to the anomeric effect which not only promotes the eclipsed conformation but also causes the OR group to bend towards the semioccupied orbital, thereby moving H and R2 towards the nodal plane of this orbital.

scholarly journals Mechanism of acyl transfer by the class A serine β-lactamase of Streptomyces albus G

1991 ◽  
Vol 279 (1) ◽  
pp. 213-221 ◽  
Author(s):  
J Lamotte-Brasseur ◽  
G Dive ◽  
O Dideberg ◽  
P Charlier ◽  
J M Frère ◽  
...  
Keyword(s):  
Carbon Atom ◽  
Amide Bond ◽  
Carbonyl Carbon Atom ◽  
Cephalosporin C ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Carbonyl Carbon ◽  
Class A ◽  
Streptomyces Albus ◽  
Hydrolysis Of

Optimization by energy minimization of stable complexes occurring along the pathway of hydrolysis of benzylpenicillin and cephalosporin C by the Streptomyces albus G beta-lactamase has highlighted a proton shuttle that may explain the catalytic mechanism of the beta-lactamases of class A. Five residues, S70, S130, N132, T235 and A237, are involved in ligand binding. The gamma-OH group of T235 and, in the case of benzylpenicillin, the gamma-OH group of S130 interact with the carboxylate group, on one side of the ligand molecule. The side-chain NH2 group of N132 and the carbonyl backbone of A237 interact with the exocyclic CONH amide bond, on the other side of the ligand. The backbone NH groups of S70 and A237 polarize the carbonyl group of the scissile beta-lactam amide bond. Four residues, S70, K73, S130 and E166, and two water molecules, W1 and W2, perform hydrolysis of the bound beta-lactam compound. E166, via W1, abstracts the proton from the gamma-OH group of S70. While losing its proton, the O-gamma atom of S70 attacks the carbonyl carbon atom of the beta-lactam ring and, concomitantly, the proton is delivered back to the adjacent nitrogen atom via W2, K73 and S130, thus achieving formation of the acyl-enzyme. Subsequently, E166 abstracts a proton from W1. While losing its proton, W1 attacks the carbonyl carbon atom of the S70 ester-linked acyl-enzyme and, concomitantly, re-entry of a water molecule W'1 replacing W1 allows E166 to deliver the proton back to the same carbonyl carbon atom, thus achieving hydrolysis of the beta-lactam compound and enzyme recovery. The model well explains the differences found in the kcat. values for hydrolysis of benzylpenicillin and cephalosporin C by the Streptomyces albus G beta-lactamase. It also explains the effects caused by site-directed mutagenesis of the Bacillus cereus beta-lactamase I [Gibson, Christensen & Waley (1990) Biochem J. 272, 613-619].

The HERON reaction — Origin, theoretical background, and prevalence

2005 ◽  
Vol 83 (9) ◽  
pp. 1492-1509 ◽  
Author(s):  
Stephen A Glover ◽  
Arvi Rauk ◽  
Jeanne M Buccigross ◽  
John J Campbell ◽  
Gerard P Hammond ◽  
...  
Keyword(s):  
Gas Phase ◽  
Theoretical Basis ◽  
Historical Perspective ◽  
Theoretical Background ◽  
Amide Bond ◽  
Chemical Transformations ◽  
Amide Nitrogen ◽  
Gas Phase Reactions ◽  
Physical Organic ◽  
Computational Work

The origin of the HERON reaction is reviewed from a historical perspective and shown to have its foundation in the unusual properties of bisheteroatom-substituted amides, so-called anomeric amides. The reaction involves migration of anomerically destabilized oxo-substituents on an amide nitrogen to the amide carbon and dissociation of the amide bond. Computational work providing a theoretical basis for the reaction is presented, together with physical organic measurements that support results therefrom. The rearrangement has been observed in a number of chemical transformations of N-alkoxy-N-aminoamides, reactions of 1-acyloxy-1-alkoxydiazenes, N-alkoxy-N-aminocarbamates, N-alkoxyhydroxamic acids, as well as in the gas-phase reactions of N-acyloxy-N-alkoxyamides.Key words: HERON reaction, anomeric amides, rearrangements, hindered esters, concerted reactions.

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