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Stereoelectronic effects are crucial in governing the conformational behaviour of small molecules bearing heterocyclic rings adjacent to amides. It dictates the antagonist and agonist activity for G-protein coupled receptor (C3aR) of inflammatory protein complement C3a on human macrophages. We have examined the role of non-covalent attractive interactions of heteroatoms of heterocycles adjacent to amides in the antagonists of C3a receptor (C3aR) using the CBS-QB3 and M06-2X/aug-cc-pVDZ levels of theory. The contribution of orbital interaction (n → σ* delocalization) towards the stability of antagonist has been examined and the systems were designed for the clear preference of such molecules to bind with C3aR protein. The molecular electrostatic potential (MESP) analysis also revealed the presence of Sigma-holes (σ-holes) in such systems interacting with the amide oxygen and contributed to the stability of the cis-conformation responsible for the antagonist behavior of such molecules. The –CF3 substituted electron-withdrawing group attached to the carbon atom of the –C–X bond enhanced the attractive non-covalent interaction between X(heterocycle) and O(amide) and electrostatic interactions that contribute to the stability of the cis-conformation of the antagonists. The –CF3 substituted selenazole ring (6Se-a) was stabilized by ∼4.0 kcal mol−1 than the other corresponding possible conformations. The non-covalent interaction (NCI) plot corroborates the non-covalent interactions between the heteroatoms in such molecules. The docking study performed with ligands L-1 and L-2 showed improved interaction with C3aR compared to those with the reported SB290157. Importantly, the cis-conformation of the ligands L-1 and L-2 persisted in the C3aR environment. The influence of the stereoelectronic effect on conformations of small ligands acting as antagonists towards G-protein coupled C3aR has been highlighted to design new candidates with better efficacy.

l-Rhamnose forms the key components of important antigenic oligo- and polysaccharides of a variety of pathogens. Obtaining 1,2-cis stereoselectivity in the glycosylation of l-rhamnoside is quite challenging due to the unavailability of neighboring group participation and disfavoring of the anomeric effect and stereoelectronic effect of the substituents on the C-2 axial position. Nevertheless, various methodologies have been developed exploiting diverse pathways for obtaining β-stereoselectivity in the glycosylation of l-rhamnose. This review describes the recent advances in β-l-rhamnosylation and its applications in the total synthesis of β-l-rhamnose-containing biologically important oligosaccharides.

How far can we push the limits in removing stereoelectronic protection from an unstable intermediate? We address this question by exploring the interplay between the primary and secondary stereoelectronic effects in the Baeyer–Villiger (BV) rearrangement by experimental and computational studies of γ-OR-substituted γ-peroxylactones, the previously elusive non-strained Criegee intermediates (CI). These new cyclic peroxides were synthesized by the peroxidation of γ-ketoesters followed by in situ cyclization using a BF3·Et2O/H2O2 system. Although the primary effect (alignment of the migrating C–Rm bond with the breaking O–O bond) is active in the 6-membered ring, weakening of the secondary effect (donation from the OR lone pair to the breaking C–Rm bond) provides sufficient kinetic stabilization to allow the formation and isolation of stable γ-hydroperoxy-γ-peroxylactones with a methyl-substituent in the C6-position. Furthermore, supplementary protection is also provided by reactant stabilization originating from two new stereoelectronic factors, both identified and quantified for the first time in the present work. First, an unexpected boat preference in the γ-hydroperoxy-γ-peroxylactones weakens the primary stereoelectronic effects and introduces a ∼2 kcal mol−1 Curtin–Hammett penalty for reacquiring the more reactive chair conformation. Second, activation of the secondary stereoelectronic effect in the TS comes with a ∼2–3 kcal mol−1 penalty for giving up the exo-anomeric stabilization in the 6-membered Criegee intermediate. Together, the three new stereoelectronic factors (inverse α-effect, misalignment of reacting bonds in the boat conformation, and the exo-anomeric effect) illustrate the richness of stereoelectronic patterns in peroxide chemistry and provide experimentally significant kinetic stabilization to this new class of bisperoxides. Furthermore, mild reduction of γ-hydroperoxy-γ-peroxylactone with Ph3P produced an isolable γ-hydroxy-γ-peroxylactone, the first example of a structurally unencumbered CI where neither the primary nor the secondary stereoelectronic effect are impeded. Although this compound is relatively unstable, it does not undergo the BV reaction and instead follows a new mode of reactivity for the CI – a ring-opening process., Protecting stereoelectronic effects prevent Baeyer–Villiger rearrangement and stabilize γ-OX-γ-peroxylactones (X = H, OH), the previously elusive non-strained Criegee intermediates.

The influence of diarylamino (Ar2N–) substituents on the oxidation potential of 3,7-bis(diarylamino)phenothiazines (Ar2N)2–PTZ (1a–f, a: carbazolyl; b: dihydrodibenzoazepinyl; c: dibenzoazepinyl; d: diphenylamino; e: phenothiazinyl; and f: phenoxazinyl) is investigated, where the Ar2N-substituent sequence a→f is aligned in the increasing order of their electron-donating ability. Interestingly, a different sequence of electron-donating ability for Ar2N-substituents was observed for the oxidation potentials of (Ar2N)2–PTZ: 1a (Eox1 = +0.35 V vs. Fc/Fc+) > 1f (+0.30 V) > 1e (+0.15 V) > 1d (−0.05 V) > 1c (−0.19 V) > 1b (−0.22 V). The observed sequence can be explained by the stereoelectronic effect of the Ar2N-substituents to stabilize (Ar2N)2–PTZ˙+. Clear-cut examples are observed in the crystal structure of 1c˙+ and 1e˙+, for which coplanar conformation is observed between the PTZ˙+-plane and the planes of the sp2-hybridized nitrogen atoms in Ar2N-substituents through a large conformational change during the oxidation process of (Ar2N)2–PTZ.

A series of benzene derivatives with different substituents adsorbed on graphene was investigated using a density-functional tight-binding method with a dispersion correction. Compared to benzene, the derivative with either an electron-withdrawing or -donating substituent exhibits stronger physisorption. Moreover, the steric size of the substituent is important in determining the adsorption strength, while the direction and the number of H atoms in the substituent affect the electron transfer from graphene. NBO analysis reveals that the stereoelectronic effect of the conjugation between the substituent and the benzene ring strongly influences the π···π interaction region between the molecule and graphene. The findings can deepen the understanding of the interaction between an aromatic molecule and graphene as well as the corresponding adsorption mechanism.

The unusual stability of bis- and tris-peroxides contradicts the conventional wisdom – some of them can melt without decomposition at temperatures exceeding 100 °C. In this work, we disclose a stabilizing stereoelectronic effect that two peroxide groups can exert on each other. This stabilization originates from strong anomeric nO → σ*CO interactions that are absent in mono-peroxides but reintroduced in molecules where two peroxide moieties are separated by a CH2 group. Furthermore, such effects can be induced by other σ-acceptors and amplified by structural constraints imposed by cyclic and bicyclic frameworks.

The reduction of (E)-1,2-dimesityl-2-phenylvinyl bromide (E-4-Br) to the corresponding ethene (4-H) under radical conditions (Bu3SnH–AIBN–benzene–hν) proceeds with predominant inversion of configuration to give an E-4-H/Z-4-H ratio of ≥9∶1. This suggests that the intermediate 1,2-dimesityl-2-phenylvinyl radical (3) is captured preferentially from the mesityl face. The reason for this is clarified by theoretical calculations which show that in the conformation of 3 the β-mesityl ring is close to perpendicular to (78.2°) and the β-phenyl ring is nearly coplanar (12.0°) to the plane of the double bond (at BLYP/6-31G*). The calculated transition state energy for hydrogen transfer from the model hydrogen donor SiH4 is 5.7 kcal mol–1 lower from the mesityl than from the phenyl face.Comparison with the analogous ketene MesC(Ph)CO and the vinyl cation MesC(Ph)C+–Mes systems shows the same preference for reaction from the formally bulkier, but in fact easier to approach mesityl face, which is likewise governed by steric effects.

A variety of 2,6-di-tert-butyl-4-(N,N-disubstituted aminomethyl)phenoxyl radicals have been studied with respect to the para substituents’ and meta protons’ coupling constants observed in EPR and ENDOR experiments. For all molecules considered, restricted rotation dominates the spectroscopic features of the β-nuclei, and this plays a key role throughout the investigation. Based on the well-known McConnell–Heller equation, an empirical formula is proposed for analyzing the conformation at the α-carbon atom relative to the aroxyl plane. The results obtained reveal a strong stereoelectronic interaction between the β-nitrogen atom and the aromatic π-system. Hence, sterically unfavorable orientations are found to be preferred. The stereoelectronic interdependence is finally interpreted in terms of the generalized anomeric effect.

The opening of a model aziridinimine has been studied by ab initio molecular orbital methods. Geometries of stationary points were optimized at the MP2/6-31G(d,p) level, while relative energies were estimated using configuration interaction (CISDQ) and quadratic configuration interaction [QCISD(T)] methods with the 6-311G(d,p) basis set and corrected for zero-point energies. The [2 + 1] cycloreversion of aziridinimine giving an imine plus an isocyanide is consistently favoured over its isomerization yielding other alternative rings. The calculated enthalpy of activation for cycloreversion of the unsubstituted molecule amounts to ΔH‡= 150 kJ mol–1 at 0 K. While methyl substitution at the exocyclic nitrogen activates this fragmentation, methyl substitution at the ring nitrogen atom slightly deactivates it. For trimethylaziridimmine, we estimate a value of ΔH‡= 120 kJ mol–1. While the latter can be compared with the experimental values of 112–128 kJ mol–1 measured for alkyl substituted species, the entropy of activation for alkylated aziridinimines is calculated to be positive, ΔS‡(calc)≃ 10 J mol–1 K–1, in conflict with available experimental results, ΔS‡(exptl)=–13 to –24 J mol–1 K–1. The energy barrier for ring–ring rearrangement giving an alternative ring with an exocyclic CC bond amounts to ca. 160–170 kJ mol–1. The stereochemistry of the [2 + 1 ] cycloreversion can be rationalized by a stereoelectronic effect. Protonation occurs at the exocyclic nitrogen. The aziridinimine radical cation ion still has a cyclic structure; the adiabatic ionization energy is estimated to be Ei,a(aziridinimine)= 9.4 ± 0.3 eV. The cyclic ion easily undergoes ring-opening yielding a more stable open distonic radical cation, H2C˙–NH–CNH+, which lies 128 kJ mol–1 below the cyclic ion.

Hydroxide-dependent hydrolysis of triesters of phosphonoformic acid (PFA)via P–O bond cleavage proceeds at rates 103–106 times greater than hydrolysis of simple phosphonates. The means by which an α-carbonyl substituent elicits such a rate enhancement has been examined using ab initio calculations. Model compounds have been derived, from full geometry optimization at the RHF/6-31G*//6-31G* level, of (a) the tetracoordinate ground state PFA triesters (4, RPO3Me2; R = CHO) and simple phosphonate esters (4, R = CF2H, CH3), and (b) pentacoordinate intermediates for hydrolysis of these triesters (5, RPO4H3–; 6, RPO4HMe2–, R = CHO, CO2H and 5, 6, R = CF2H, CH3, respectively). Intramolecular charge-transfer interactions have been quantified employing natural bond orbital analysis, including calculation of molecular energies on deletion of each individual interaction. These molecular orbital calculations demonstrate significant stabilizing, intra-molecular charge-transfer interactions, including internal hydrogen bonding and np(O)→π*(CO) charge transfer in the pentacoordinate state. The n→π* stabilization contributes 4–10 kcal mol–1 to the stabilization of these intermediates in the gas phase. It is suggested that such charge-transfer stabilization in the pentacoordinate intermediates and transition states for hydrolysis of PFA triesters contributes to the observed rate enhancement. In contrast, these calculations show no evidence for the stereoelectronic effect (akin to the generalized anomeric effect) proposed by Gorenstein and Taira for pentacoordinate phosphoranes and suggested also to lead to large rate enhancements for nucleophilic substitution at phosphorus. Calculations on models [7, RC(O)CO3HMe–, R = H, OH] for tetrahedral intermediates in oxalate ester hydrolysis demonstrate a greatly diminished intramolecular np(O)→π*(CO) charge-transfer stabilization. This is in accord with rate data on carboxylate ester hydrolysis.

1,1,3,3-Tetramethyl-2,3-dihydro-1H-isoindol-2-yloxyl has been used as a radical trap to investigate the pattern of hydrogen abstraction reactions occurring in a range of acyclic ethers by tert-butoxyl radicals. The results confirm the high degree of selectivity for abstraction at C atoms adjacent to ethereal O. The presence of two α ethereal O atoms is less effective in enhancing abstraction than one. This is possibly due to a stereoelectronic effect whereby the 1,3-oxygen orbital interactions reduce the ability of either oxygen to interact effectively with the developing radical centre. Whereas the presence of an α-oxygen enhances the rate of hydrogen abstraction, the presence of a β-oxygen retards the rate of hydrogen abstraction. Abstraction at a methine C atom adjacent to ethereal O occurs at about the same rate or a little faster than at a methylene C atom, whereas abstraction at methyl groups is much slower. A temperature study of the abstraction from methyl and methylene sites in dimethoxymethane shows that the difference in abstraction rates at these sites is predominantly an entropy effect. A lower entropy of activation due to the loss of the internal rotational mode of the methyl group in the formation of the transition state is the probable reason. Ethers appear to be less reactive than alcohols in hydrogen abstraction reactions.

The isopropyl group has no significant Stereoelectronic effect on inter- and intra-molecular competition in deprotonation from alkylbenzene radical cations in the photoaddition of alkylbenzene derivatives with 10-methylacridinium ion viaphotoinduced electron transfer from alkylbenzene derivatives to the singlet excited state of 10-methylacridinium ion, followed by the deprotonation of alkylbenzene radical cations.

Two diastereoisomeric phenylselenoesters of 4,5-dihydroxyhept-6-enoic acid were prepared as their acetonide derivatives from the chiral pool. On treatment with tributyltin hydride and azoisobutyronitrile the erythro isomer cyclized to give meso-4,5-dihydroxycycloheptanone, as its acetonide, in moderate yield whereas under the same conditions the threo-isomer gave a much lower yield of the corresponding C2-symmetric ketone. In the erythro-series an alkyl group at C-7 of the heptenoyl system was found to retard significantly the direct endo-mode cyclisation; however, the cycloheptanone could still be obtained by a rearrangement when the tin hydride concentration was kept to a minimum. A tandem 7-endo/5-exo cyclization system was then constructed and tested, resulting in the formation of all four possible diastereoisomeric bicyclo[5.3.0]decanones. Further model studies were conducted on the effect of alkyl and alkoxy substituents at C-5 of the heptenoyl radical system on the mode of cyclisation. Alkyl substituents exert a steric effect whilst alkoxy substituents also have a stereoelectronic effect.

The structures of 2-(pyrimidin-2-yl)(1c), 2-methoxycarbonylisatogen (1d), and 2-(1-ethyl-benzimidazol-2-yl)isatogen (1e) have been determined by X-ray crystallography. The dihedral angle between the isatogen ring and the plane of the 2-substituent varies as 43°(1c), 15°(1d), and 48°(1e). The transoid arrangement of the isatogen O(1) atom and the pyridine-type nitrogen atom N (1 5), previously reported in (1b), is preserved in (1e) despite the increased steric effects arising from the ethyl group in this molecule. There are surprising variations in the lengths of the O(1)–N(1)–C(2)–C(3)–O(3) bonds in the isatogen moiety and the C(2)–C(10) bond, this last having very little double bond character. MNDO calculations using the experimental geometries show, as before, that the C(2) atom carries a negative charge and indicate that there is a strong stereoelectronic effect arising from the centres of highest electron density in the isatogen ring O(1) and the nitrogen atoms, N(11) and N(18) in (1c) and (1e), which are remote from each other. The energies of the LUMO and HOMO orbitals indicate that the reaction between these isatogens and dipolarophiles shows the same regioselectivity reported in an earlier paper. Natural abundance 15N NMR spectra of isatogens are reported for the first time. The chemical shifts of the N(1) atom in the isatogens (1a-e) correlate negatively (r=–0.96) with 13C shifts of the C(3) atom, providing further evidence of the highly polarizable nature of the five-membered ring in the isatogen system.

5-Deuteriated 5-deazaflavinophanes (dFI(n)D) were synthesized in which N-3 in the isoalloxazine group and O-2′ in the 10-(2-hydroxyphenyl) group were linked by a –(CH2)n– chain (n= 8 and 10). 1H NMR studies established that NaBH4 reduction of dFI(8)D to the reduced form dFlred(8)D, in which ring inversion is inhibited because of a short (CH2)8 strap, gives an axial C-5 proton (Hax). This indicates that hydrogen is exclusively incorporated into the axial C-5 position. In contrast, NaBH4 reduction of dFI(10)D to dFlred(10)D, in which ring inversion is allowed because of a long (CH2)10 strap, gave an axial and an equatorial proton (Hax and Heq) in the ratio 1 : 1. This indicates that hydrogen is primarily incorporated into the axial C-5 position but is rapidly exchanged through ring inversion. Oxidation of alcohols and amines by dFI(n)D gave 1H NMR spectra similar to those obtained after NaBH4 reduction. Therefore we conclude that hydrogen from these substrates is also transferred to the axial C-5 position. The ‘axial preference’, which is generally observed for 5-deazaflavin-mediated redox reactions, was rationalized in terms of the stereoelectronic effect.

The preparation and acid catalysed hydrolysis of a number of isoxazolinyldioxepins is reported. Individual diastereoisomer pairs were isolated by column chromatography and shown to differ significantly in their hydrolytic stability at acidic pH. The crystal structures of one diastereoisomer pair reveal that conformational differences induce a selective stereoelectronic effect at the acetal centre of the more hydrolytically labile isomer, while the less labile isomer shows no such selectivity.

The spontaneous, general acid and H3O+-catalysed hydrolyses of the bis-acetals (3) are unusual, semi-concerted fragmentations in which the rate of loss of the 4-nitrophenolate leaving group is controlled by the geometry at the remote acetal centre. The hydrolysis of the cis-axial compound (3ca), in which the remote oxygen atom can act as a π-donor, is up to 200 times faster than that of its trans-isomer (3ta), in which it cannot, but acts simply as a σ-acceptor to slow C–OAr cleavage. The magnitude of the stereoelectronic effect on ΔH‡ is of the order of 7 kcal (30 kJ) mol–1.

Cyclopropene formed the exo and endo Diels–Alder adducts in a 1 : 1 ratio with furan; only the endo-isomer readily rearranges to cycloheptadienones.

(E)-Benzohydroximoyl chlorides have been examined for the first time and are shown to react (as the conjugate ion) > 107-fold more slowly than the corresponding (Z)-benzohydroximoyl chloride anions. This large rate difference is attributed to the favourable antiperiplanar lone pair on the adjacent nitrogen which facilitates Cl– loss from the (Z)-substrate. The (Z)-benzohydroximoyl chlorides were formed by direct chlorination of (E)- or (Z)-benzaldoximes while the (E)-chlorides were formed by acylation of these (Z)-isomers, photoisomerisation and separation, and then subsequent deacylation in situ.

Free-radical additions of cyclic ethers to various fluorinated alkenes have been studied and a clear stereoelectronic effect has been established. The order of reactivity is oxolane > oxepane > oxane and increasing substitution at the double bond leads to lower reactivity of the fluorinated alkene with oxolane.

The reactivity sequence tetralin-1-ol > indan-1-ol tetrahydrobenzocyclohepten-1-ol is observed in the dehydrogenation of these benzyl alcohols to the corresponding ketones by dichlorodicyanobenzoquinone. There is a linear relationship between the angle of inclination of the tertiary benzylic C–H bond to the plane of the aromatic ring and log k, reflecting the degree of σ–π overlap in the transition state for the oxidation. Factors underlying the preferred pseudo-axial conformation of the benzylic hydroxy-groups in these benzocycloalkenols are discussed.

The geometries and enthalpies of formation of cyclopropyl, cyclopropylmethyl, cyclobut-2-enylmethyl, cyclobutylmethyl, the isomeric bicyclo[2.1.0]pentyl, bicyclo[1.1.1]pentyl, and spiropentyl radicals have been studied by the semi-empirical MINDO/3 method and compared with the calculated and experimental data for the corresponding cyclo- or bicyclo-alkanes. The ring fission reactions of the radicals have been investigated by calculating the energies for successive increments of a chosen reaction co-ordinate. For the cycloalkylmethyl radicals the calculated enthalpies of activation show the same trend as the experimental activation energies for β-scission. The MINDO/3 calculations for the bicycloalkyl radicals are also in agreement with such experimental evidence as is available. For the bicycloalkyl radicals which have not been examined by experiment MINDO/3 suggests that ring fission should be favoured for bicyclo[2.1.0]-pent-5-yl radicals. The calculations indicate that overlap of the SOMO with the bond to be broken is usually the most important factor in controlling which bond breaks and the rate of the process. Release of ring strain may, however, oppose and overrule the stereoelectronic effect, e.g. with bicyclo[2.1.0]pent-2-yl radicals. If overlap of the SOMO with the β,γ bond is prevented then ring fission is predicted to have a high energy barrier, e.g. in cyclopropyl and spiropentyl radicals.

In the Type II photochemical reactions of cis-2-propyl-4-t-butylcyclohexanone, the ratio of cyclobutanols to fragmentation products is 13 : 87 for the singlet-state reaction and 68 : 32 for the triplet-state reaction, showing that, in the latter state at least, there is a noticeable stereoelectronic effect on the fragmentation reaction.