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The cyclopropane ring-opening reaction of riolozatrione, a natural product obtained from Jatropha dioica, afforded a 2,2-disubstituted 1,3-cyclohexandione displaying an alkyl methyl ether group at position 5. The conformational analysis of this product showed a high preference for the trans-diaxial conformation in both solution and solid state. Such conformation was possible from the noncovalent intramolecular nX → π*C═O interactions (X = an element having an unshared electron pair), allowing the determination of the interaction energies. Since the nX → π*C═O interactions can be regarded as additive, the energy values ranged from 4.52 to 6.51 kcal mol-1 for each carbonyl group with a strong dependency on the interatomic distances. The rigorous analysis of the electron density in the topological theory of atoms in molecules framework clearly shows that the origin of O-C═O interactions are through the nO → π*C═O electron transfer mechanism. Such interactions are slightly weaker than a canonical hydrogen bond but seemingly stronger than a van der Waals interaction. This interaction must be considered as a stereoelectronic effect due the electronic transfer between the interacting groups, which are limited by their relative stereochemistry and can be represented by a bond-no bond interaction, causing the pyramidalization of the carbonyl, which is the charge acceptor group.

In an effort to develop efficient Ru(II)–NHC-based catalyst considering their stereoelectronic effect for hydride-transfer reaction, we found that the ancillary NHC ligand can play a significant role in its catalytic performance. This effect is demonstrated by comparing the activity of two different types of orthometalated precatalysts of general formula [(p-cymene)(NHC)RuII(X)] (NHC = an imidazolylidene-based ImNHC, compound 2a–c, or a mesoionic triazolylidene-based tzNHC, compound 4) in transfer hydrogenation of carbonyl substrates. The electron-rich precatalyst, 2c, containing p-OMe-substituted NHC ligand performed significantly better than both unsubstituted complex 2a and p-CF3 substituted electron-poor complex 2b in ketone reduction. Whereas bulky mesoionic triazolylidene ligand containing complex 4 was found to be superior catalyst for aldehyde reduction and the precatalyst 2a is more suitable for the selective transfer hydrogenation of a wide range of aromatic aldimines to amines. To the best of o...

The triple-helical structure of collagen, the most abundant protein in animal bodies, owes its stability to post-translationally installed hydroxyl groups at position 4 of prolyl residues. To shed light on the nature of this phenomenon, we have examined the influence of the 4-substituent on the amide isomerism in peptidyl-prolyl analogues. The rigid bicyclic skeleton of 2,4-methanoprolines allowed us to follow the through-bond impact of the substituent group (electronic effect) without the side-chain conformation being affected by a stereoelectronic effect. These proline analogues were prepared by [2 + 2] photocycloaddition of (2-allylamino)acrylic acid derivatives. Subsequent pKa studies demonstrated a remarkable electronic effect of the 4-fluorine substitution, while the effect of the 4-methyl group was negligible. The trans/cis amide ratio was measured in model compounds under low temperature conditions. The observed prevalence for a trans-amide is extraordinary, and in this regard, 2,4-methanoproline ...

Biphenyl, as the elementary unit of organic functional materials, has been widely used in electronic and optoelectronic devices. However, over decades little has been fundamentally understood regarding how the intramolecular conformation of biphenyl dynamically affects its transport properties at the single-molecule level. Here, we establish the stereoelectronic effect of biphenyl on its electrical conductance based on the platform of graphene-molecule single-molecule junctions, where a specifically designed hexaphenyl aromatic chain molecule is covalently sandwiched between nanogapped graphene point contacts to create stable single-molecule junctions. Both theoretical and temperature-dependent experimental results consistently demonstrate that phenyl twisting in the aromatic chain molecule produces different microstates with different degrees of conjugation, thus leading to stochastic switching between high- and low-conductance states. These investigations offer new molecular design insights into building functional single-molecule electrical devices.

A ruthenium catalyzed intramolecular C-S coupling reaction of N-arylthioureas for the synthesis of 2-aminobenzothiazoles has been developed. Kinetic, isotope labeling, and computational studies reveal the involvement of an electrophilic ruthenation pathway instead of a direct C-H activation. Stereoelectronic effect of meta-substituents on the N-arylthiourea dictates the final regioselective outcome of the reaction.

Hsung et al. have reported a series of torquoselective electrocyclizations of chiral 1-azahexa-1,3,5-trienes that yield functionalized dihydropyridines. To understand the origins of the torquoselectivities of these azaelectrocyclizations, we modeled these electrocyclic ring closures using the M06-2X density functional. A new stereochemical model that rationalizes the observed 1,2 stereoinduction emerges from these computations. This model is an improvement and generalization of the “inside-alkoxy” model used to rationalize stereoselectivities of 1,3-dipolar cycloaddition of chiral allyl ethers and emphasizes a stabilizing hyperconjugative effect, which we have termed a transition state gauche effect. This stereoelectronic effect controls the conformational preferences at the electrocyclization transition states, and only in one of the allowed, disrotatory electrocyclization transition states is the ideal stereoelectronic arrangement of substituent achieved without the introduction of a steric clash. Computational experiments confirm the role of this effect as a stereodeterminant, since substrates with electropositive groups like a silyl substituent and electronegative groups have different conformational preferences at the transition state and undergo ring closure with divergent stereochemical outcomes. This predicted reversal of stereoselectivity for the ring closure of a silyl-substituted azatriene has been demonstrated experimentally.

A stereoselective N-iminium ion cyclization with allylsilane to construct vicinal quaternary-tertiary carbon centers was developed for the concise synthesis of (±)-cephalotaxine. The current strategy features a TiCl4-promoted cyclization and ring-closure metathesis to furnish the spiro-ring system. The stereochemical outcome in the N-acyliminium ion cyclization was rationalized by the stereoelectronic effect of the Z- or E-allylsilane. Two diastereomers arising from the cyclization were merged into the formal synthesis of (±)-cephalotaxine.

The anionic complex [Ir(2-phenylpyridine)2(benzene-1,2-dithiolate)](-) ([IrSS](-)) is a nucleophile and metalloligand that reacts with methyl iodide and AuPR3(+) (R = Ph or Et) to form S-methylated complexes (thiother-thiolate and dithiother complexes) and S-aurated complexes, respectively. The reactions are completely diastereselective, producing only the enantiomers ΛS and ΔR or ΛSS and ΔRR. The diastereoselectivity is stereoelectronically controlled by the orientation of the highest occupied molecular orbital (HOMO) of [IrSS](-) arising from filled dπ-pπ antibonding interactions, and the chirality of the iridium ion. Methylation or auration removes the high-energy lone pair of the thiolate S atom, leading to low-lying HOMOs composed mainly of the Ir d-orbital and the 2-phenylpyridine π (ppyπ) orbital. The methylated and aurated complexes can be oxidized by H2O2 or peracid to give sulfinate-thiother, disulfoxide, and sulfinate-sulfoxide complexes, and the oxygenation further stabilizes the HOMO. All the complexes are luminescent, and their electronic spectra are interpreted with the aid of time-dependent density functional theory calculations. The thiother-thiolate complex exhibits ligand(S)-to-ligand(π* of ppy)-charge-transfer/metal-to-ligand-charge-transfer absorption (LLCT/MLCT) and a relatively low-energy (3)LLCT/MLCT emission, while the other complexes display (3)ππ*/MLCT emissions.

A time-resolved kinetic study of the hydrogen atom transfer (HAT) reactions from a series of alkanamides to the cumyloxyl radical (CumO(•)) was carried out. With N,N-dialkylformamides HAT preferentially occurs from the formyl C-H bond, while in N-formylpyrrolidine HAT mostly occurs from the ring α-C-H bonds. With the acetamides and the alkanamides almost exclusive HAT from the C-H bonds that are α to nitrogen was observed. The results obtained show that alignment between the C-H bond being broken and the amide π-system can lead to significant increases in the HAT rate constant (kH). This finding points toward the important role of stereoelectronic effects on the HAT reactivity and selectivity. The highest kH values were measured for the reactions of CumO(•) with N-acylpyrrolidines. These substrates have ring α-C-H bonds that are held in a conformation that is optimally aligned with the amide π-system, thus allowing for the relatively facile HAT reaction. The lowest kH value was measured for the reaction of N,N-diisobutylacetamide, wherein the steric bulk associated with the N-isobutyl groups increases the energy barrier required to reach the most suitable conformation for HAT. The experimental results are well supported by the computed BDEs for the C-H bonds of the most representative substrates.

The combination of experiments and computations reveals unusual features of stereoselective Rh(I)-catalyzed transformation of propargyl vinyl ethers into (E,Z)-dienals. The first step, the conversion of propargyl vinyl ethers into allene aldehydes, proceeds under homogeneous conditions via a "cyclization-mediated" mechanism initiated by Rh(I) coordination at the alkyne. This path agrees well with the small experimental effects of substituents on the carbinol carbon. The key feature revealed by the computational study is the stereoelectronic effect of the ligand arrangement at the catalytic center. The rearrangement barriers significantly decrease due to the greater transfer of electron density from the catalytic metal center to the CO ligand oriented trans to the alkyne. This effect increases electrophilicity of the metal and lowers the calculated barriers by 9.0 kcal/mol. Subsequent evolution of the catalyst leads to the in situ formation of Rh(I) nanoclusters that catalyze stereoselective tautomerization. The intermediacy of heterogeneous catalysis by nanoclusters was confirmed by mercury poisoning, temperature-dependent sigmoidal kinetic curves, and dynamic light scattering. The combination of experiments and computations suggests that the initially formed allene-aldehyde product assists in the transformation of a homogeneous catalyst (or "a cocktail of catalysts") into nanoclusters, which in turn catalyze and control the stereochemistry of subsequent transformations.

Switching of the magnetic exchange coupling from ferro- to antiferromagnetic or vice versa in a single molecule is an appealing but rarely occurring phenomenon in molecular magnetism. Here, we report this for an unprecedented pure organic system, computationally designed by tailoring a conformationally restricted, known nitroxide-diradical (Rajca et al. J. Am. Chem. Soc. 2007, 129, 10159). This ferro- to antiferromagnetic coupling switching of an "m-phenylene" based diradical is governed by a stereoelectronic effect and controlled by a redox-driven chemical reaction.

The effect of a peripheral disulfide bridge substituent on the phenolic O-H bond dissociation energy (BDE) and the ionization potential (IP) of naphthyridine diol has been studied by density functional theory (DFT) calculation. Compared with naphthalene diol, the substituent of a peripheral disulfide bridge group is very efficient in reducing the BDE, whereas the insertion of nitrogen atoms into the naphthalenic ring only slightly changes the BDE of O-H bond but dramatically enhances the IP. It is similar with the stereoelectronic effect of the heterocyclic ring for the well-known alpha-tocopherol antioxidant and leads to a highly delocalized spin distribution. With the incorporation of these two aspects, a potential antioxidant is expected to be more active and more stable than alpha-tocopherol.

The addition of singly and doubly activated dienophiles to TpW(NO)(PMe3)(5,6-η2-anisole) and TpW(NO)(PMe3)(5,6-η2-1,3-dimethoxybenzene) to generate dihapto-coordinated [2.2.2]bicyclooctadienes and -trienes is explored. The highly functionalized bicyclic scaffolds are isolated from the metal fragment intact. Although moderate yields hinder their synthetic application, a unique stereoelectronic effect is uncovered. Coordination diastereomers of anisoles with the methoxy substituent distal to the PMe3 ligand have faster reaction rates relative to the proximal diastereomer. DFT calculations reveal the metal fragment possesses a dipole that directs positive charge away from the PMe3 ligand, and a polarized cycloaddition transition state is invoked to explain this observation.

Anomeric O-alkylation/arylation is applied to the synthesis of 2-deoxy-beta-glycosides. Treatment of lactols with NaH in dioxane followed by the addition of electrophiles leads to the formation of 2-deoxy-beta-glycosides in high yield and high selectivity. The high beta-selectivity observed here demonstrates a powerful stereoelectronic effect for the stereoselective formation of acetals under kinetic control.

In the synthesis of vinyl sulfone-modified hex-5-enofuranosides, the E/Z ratios of the products are influenced by the stereoelectronic property of a group present at the C-3 position. This observation has been utilized to influence the diastereoselectivity of addition of amines to C-5 of vinyl sulfone- modified hex-5-enofuranosides, which are efficient Michael acceptors. The stereoelectronic effect of OMe attached to the beta-face of C-3 (gluco derivative) is sufficient to impose diastereoselectivity overwhelmingly in favor of l-ido-aminosugars when the Michael acceptor is reacted with both primary and secondary amines. 3-O-Benzylated gluco derivative is also effective in producing l-ido-aminosugars but only in reactions with primary amines. The selectivity is lost when an allo derivative with OBn at the alpha-face of C-3 is used. Selected products were desulfonated to establish this new approach as a general and versatile strategy for accessing 5-amino-5-deoxysugars.

[reaction: see text] Deprotonation of the radical cations of aromatic amines, such as anilines, generally occurs much more slowly than other fragmentation reactions. Here we report a stereoelectronic effect involving twisting of the anilino group out of the plane of the benzene ring that results in a significantly increased rate of reactivity toward deprotonation. Quantitative studies of the rate constants for deprotonation as a function of aniline radical cation pKa (Brønsted plots) demonstrate that the effect is not simply due to a change in the reaction thermodynamics. By combining this stereoelectronic effect with covalent attachment of carboxylate as a base, aniline radical cations that undergo unimolecular deprotonation with rate constants as high as 10(8) s(-1), even in unfavorable protic media, are described.

To estimate the antimicrobial effect of p-hydroxyphenyl acrylate (H5) derivatives on the basis of their molecular structure, the hydroxy and acryl groups of p-hydroxyphenyl acrylate were modified. The antimicrobial activity of the resulting compounds was assessed against a Gram-positive bacterium (Staphylococcus aureus), a Gram-negative bacterium (Pseudomonas aeruginosa), and fungi (Aspergillus fumigatus and Penicillium pinphilum) by the halo zone and the shake flask test. The antimicrobial activity of H5 was ascribed mainly to the acryl group. Compounds with acryl or acryloxy groups bound to the phenyl moiety were found to exhibit particularly high antimicrobial activities. The activities of phenyl acrylate and phenyl vinyl ketone were excellent as compared to aliphatic acrylates such as cyclohexyl acrylate and hexyl acrylate, indicating that the stereoelectronic effect of the phenyl group was important to the antimicrobial activity.

A systematic density functional theory (DFT) study of free and Cr- and W-coordinated alkoxy-carbenes has been carried out. The structure of the free carbenes and their relative energies remains unaltered by coordination to the metal. A clear bias for the anti-isomer is observed in both the free and coordinated carbenes. The exception is complexes having alkynyl substituents. In this case, the metal complex prefers the syn-disposition. The theoretical model explains the observed bias for the anti-isomer by the stabilizing contribution of a stereoelectronic effect due to the two-electron donation from the σCH orbital of the O-Me group to the π*CO orbital of the CO ligand and feedback donation of the πCO orbital to the σ*CH orbital and the destabilizing repulsion between the groups linked to the carbene carbon. This last factor is the determinant one since the linear triple bond produces a clear bias for the syn-isomer only in the coordinated carbene, showing that the steric contribution rather than the elec...

The anomeric effect in the phosphodiester backbone of nucleic acids is a stereoelectronic effect that has conventionally been linked to interactions between lone pairs on the O(ester) atoms and P-O(ester) antibonding orbitals. The present study demonstrates that the anomeric effect in the phosphodiester backbone is significantly more complex than portrayed by this description. The presence of multiple lone pairs and antibonding orbitals around the phosphorus atom leads to additional contributions to the anomeric effect, especially involving the anionic oxygen lone pairs. On the basis of the structural changes and Natural Bond Orbital analysis it is shown that a complex balance between stereoelectronic effects involving both the ester and anionic oxygen lone pairs governs the conformational properties of the phosphodiester backbone. The N3'-phosphoramidate DNA backbone differs from the phosphodiester backbone due to the N3'-H moiety having only a single lone pair instead of the two lone pairs present on the O3' atom substituted. The present study uses N3'-phosphoramidate as a control to understand the changes in stereoelectronic effects as a result of changes in the structure and conformation. Two previously uncharacterized properties of the N3'-phosphoramidate backbone are also observed and explained through the complex balance of the postulated electronic delocalizations. The first observation is that the N3'-H moiety in N3'-phosphoramidate is a flexible moiety that can change the orientation of its hydrogen through inversion without a significant energetic penalty in both the gas phase and the aqueous phase. The second observation is that the stabilization of the C3'-endo conformation in N3'-phosphoramidate is primarily due to aqueous solvation rather than intrinsic gas-phase effects involving the reduced electronegativity of the 3'-substituent.

The fluorescence quenching of two azoalkanes, the weak acceptor 2,3-diazabicyclo[2.2.2]oct-2-ene and its less reactive derivative 4-methyl-1-isopropyl-2,3-diazabicyclo[2.2.2]oct-2-ene, by a series of aliphatic amine donors was examined by time-resolved spectroscopy in benzene. The fluorescence quenching rate constants ranged from 0.13 × 107 to 25 × 107 M-1 s-1, while the activation energies were found to be 1.3 and 3.0 kcal mol-1 for the best (N-ethyldicyclohexylamine) and the poorest (N,N-diisopropyl-3-pentylamine) donor. The oxidation potentials of the amines and the reduction potentials of the azoalkanes were measured. Deviations from the expected dependence of the quenching rate constants on the energetics of electron transfer were observed. Steric effects on the kinetics of quenching, namely a reduction by up to a factor of 50, became significant for amines with three secondary alkyl substituents, triisopropylamine, and N,N-diisopropyl-3-pentylamine, while a stereoelectronic effect was found for 1,4-...

The catalytic asymmetric intermolecular Stetter reaction of heterocyclic aldehydes and nitroalkenes has been developed. We have identified a strong stereoelectronic effect on catalyst structure when a fluorine substituent is placed in the backbone. X-ray structure analysis provides evidence that hyperconjugative effects are responsible for a change in conformation in the azolium precatalyst. This new N-heterocyclic carbene precursor bearing fluorine substitution in the backbone results in significantly improved enantioselectivities across a range of substrates.

A systematic study of C-H insertion reactions with variously substituted and conformationally constrained substrates was carried out. High selectivity in the insertion between two competing C-H bonds caused by a strong stereoelectronic effect of an oxygen substituent was achieved. This regioselective C-H insertion reaction was employed as a platform to develop a concise asymmetric synthesis of platensimycin.

The conformational behavior of different aza-C-glycosides synthesized as glycosidase inhibitors has been studied using a combination of NMR spectroscopy (J and NOE data) and time-averaged restrained molecular dynamics calculations. The obtained results show that the population distribution of conformers around their pseudoglycosidic linkages is mainly controlled by 1,3-syn-diaxial interactions. Electrostatic effects slightly modulate the conformational equilibrium. This result is in contrast with that observed for O-glycosides. For these natural compounds, the conformational behavior around the glycosidic linkage Φ is mainly governed by the exo-anomeric effect. Experimentally based energy values for both the 1,3-syn-diaxial interactions and the stereoelectronic effect have been deduced. Finally, the inhibitory activity of these compounds has been tested again a variety of glycosidase enzymes.

The structure of phenylcyclopropane radical cation (1•+, R = H) is derived from CIDNP effects observed during the electron transfer reaction of 1 with chloranil. This species is an example of an elusive structure type. The secondary cyclopropane protons show significantly divergent hyperfine coupling constants due to an unprecedented stereoelectronic effect. Incorporation into a redox-active pentasil zeolite (Na−ZSM-5) converts 1 or its p-methoxy derivative (1, R = OCH3) to trans-propenylarene radical cations (2•+, R = H, OCH3).

Ion/molecule reactions performed by pentaquadrupole mass spectrometry are used to generate cluster ions in which neutral pyridines are bound to the polyatomic cation SF3 +. The dimeric ions Py1SF3 +Py2, where Py1 and Py2 represent substituted pyridines, are shown to have loosely bound structures by collision-induced dissociation (MS3) experiments and by semiempirical AMI and ab initio RHF/6-31G(d, p) molecular orbital calculations. In the case of dimers comprised of meta- and/or para-substituted pyridines (unhindered pyridines), there is an excellent linear correlation between the logarithm of the fragment ion abundance ratio ln[Py1(SF3 +)]/[Py(SF3 +)] and the proton affinities (PA) of the constituent pyridines. Semiempirical calculations are used to estimate the SF3 + affinities of pyridines which are found to be in the range of 25–31 kcal/mol. The SF3 + affinities show an excellent linear correlation with the proton affinities of the pyridines, and the relationship SF3 + affinity (kcal/mol) = 0. 73PA — 135. 8 between the two affinities is derived. The effective temperature of the dimeric ions is determined to be 595 ± 69 K, which is in good agreement with values of around 600 K obtained experimentally in studies on many other systems activated under similar conditions. Ortho-substituted pyridines show lower than expected affinities due to stereoelectronic effects that decrease the cation affinities. Gas-phase Stereoelectronic parameters (Sk) are measured from the deviation from the PA correlation and are ordered as 2-MePy (−1.09) < 2,6-diMePy (−1.11) < 2-EtPy (−1.91) < 2,3-diMePy (−2. 15) < 2,5-diMePy (− 2. 25) < 2,4-diMePy (− 2. 40). Overall, the steric effects are larger than those in the corresponding Cl+-bound dimers but smaller than those in the bulky [OCNCO+] system. Calculations show evidence for agostic bonding that offsets the steric effects in some cases. The eclipsed conformation of 2-methylpyridine/SF3 + adduct is found to be more stable than the staggered form by 0. 8 kcal/mol, due to auxiliary agostic bonding between the hydrogen of the ortho methyl substituent and the sulfur atom. Calculations on atomic charge distribution reveal that the positive charge is mainly on the sulfur atom (+1. 99) and the charge on the bonding hydrogen S-H-C (+ 0. 07) is considerably lower than that on the other two methyl hydrogens ( + 0. 14), which appears to be a good indication of agostic binding. The most stable form of the 2-ethylpyridine/SF3 + adduct is found when the N-C1-Cα-Cβ dihedral angle is approximately 60 °, where the ethyl hydrogen is directed toward the SF3 group via an interesting six-membered ring alignment. The experiments show a remarkably small steric effect in 2,6-dimethylpyridine, probably due to strong agostic bonding enhanced by the buttressing effect that shortens the S-H distance. In addition, the face-to-face interactions of the F atoms and the H atoms further stabilize this form.

Synthesis of the title compound 2 was accomplished in a multistep sequence starting from hypophosphorous acid. In strong base, the bicyclic phosphinate 2 hydrolyzes 2 orders of magnitude faster than the bicyclic phosphate OP(OCH2)3CCH3 (1a) and the acceleration is entirely enthalpic. This rate enhancement is attributed to the greater ease with which 2 achieves the five-coordinate transition state. The molecular structure of 2, determined by X-ray means, compared with that of 1a reveals no evidence of strain within either bicyclic framework. The observed acceleration does not support the contribution of a stereoelectronic effect in the hydrolysis of six-membered ring phosphates.

Properties of various oxyphosphoranes such as neutral pentahydroxyphosphorane (doubly protonated 3b) and dianionic trihydroxyphosphorane (3b) and trimethoxyphosphorane (3a) were examined by ab initio molecular orbital calculations. The energies of the stationary points were evaluated at the MP2 level of theory with the 6-31+G * basis. The analysis of the oxyphosphorane species indicates that the orientation of the equatorial methoxyl group determines the mode of formation/cleavage of the axial P-O 2 /P-O 5 bond. This dependence of the reactivity on the conformation of the equatorial P-O 3 bond is in accord with the prediction that is based on the stereoelectronic effect

3-[4-[(3-Chlorophenyl)methoxy]phenyl]-5-[(methylamino)methyl]- 2-oxazolidinone (1) is a secondary amine known to be a potent time-dependent irreversible inactivator of monoamine oxidase B (MAO-B). The primary amine analogues of derivatives of 1, as well as of the corresponding dihydrofuranone and pyrrolidinone, had been shown to be time-dependent, but reversible, inhibitors of MAO-B. Here it is shown that the primary amine analogue of 1 is a time-dependent reversible inhibitor of MAO-B and that the secondary and tertiary amine analogues of the corresponding oxazolidinone, dihydrofuranone, and pyrrolidinone are time-dependent irreversible inhibitors of MAO-B. The reaction leading to the irreversible enzyme adduct formation with 1 can be reversed by increasing the temperature. These results are consistent with a stabilizing stereoelectronic effect on the enzyme adduct caused by N-methylation which hinders free rotation and prevents the sp3-orbital containing the nitrogen nonbonded electrons from being trans to the active site amino acid leaving group.

A family of N-methylated and N,N-dimethylated alkyl and arylalkylamines was prepared and more than half of the analogues were shown to be time-dependent pseudo-first-order inhibitors of monoamine oxidase-B. Some of the time-dependent inactivators were reversible and others were irreversible with respect to prolonged dialysis following inactivation. Partition ratios ranged from zero to 11,000. These results are rationalized in terms of a combination of an inductive effect and a stereoelectronic effect as a result of hindered rotation of an active site covalent adduct. A molecular mechanics calculation indicates that there is at least 10 kcal/mol of torsional energy to be overcome in order for the enzyme adduct to be released. These findings show that tertiary amine homologues of primary amine substrates of monoamine oxidase are time-dependent inhibitors, and this should be useful in the design of new inactivators of this enzyme.

Results of low-temperature (130 K) crystal structure analyses for seven β-trimethylsilyl-substituted cyclo hexylnitrobenzoate esters are reported. For those molecules (three) with the Si-C and C-O bonds antiperiplanar the C-O bond lenghts are increased by 0.014 A av (Δ/σ min=2.9) compared with that in the silicon-free analogue. For those molecules (four) with the Si-C and C-O bonds gauche no such systematic lengthening of the C-O bonds is observed

The preference for chair- and boatlike transition-state geometries in the ester enolate Claisen rearrangement of straight chain, carbocyclic, and heterocyclic propanoates was investigated. A novel stereoelectronic effect in pyranoid and furanoid glycal systems leads to a significant relative stabilization of the boatlike vs the chairlike TS : . The preferred transition state in six- and five-membered carbocyclic systems is highly dependent on steric factors, as the energy difference between chair- and boatlike TS : tends to be small. With straight-chain substrates, a significant contribution of the boatlike TS : to the rearrangement product mixture is only expected in bis-donor substituted allylic esters

The mechanism we propose for the cyclopentane annulation is the following one. The allylic reagent (5D) attacks the siloxypyrylium salts (2a,b) at the C2 position, giving the intermediate carbocation (B) which is stabilized by the trimethylsilyl and the methyl group. Attack by the emerging enolate at C 3 , forms the five-membered ring compound (8a,b). Generally, electrophiles attack allylic silanes anti to the silyl group. Since there is undoubtedly interaction with the silicon in the transition state, the stereochemistry of the bridged intermediate (B) should be trans geometry due to stereoelectronic effect and allylic 1,3-strain. In the reaction of 2a, the favored pathway is cyclization. However, competition between cyclization and desilylation was observed in 2b due to steric hindrance between the two methyl groups at the step of cyclization

Elimination of trimethylamine from hydrazonium salts is promoted by base (methoxide ion in methanol). The mechanism is characterized as E2 as shown by substituent effects (ρ=+2.57), Bronsted coefficients, a primary kinetic isotope effect (k H /k D =2.10), and solvent effects. Variation in the leaving group shows that N-N bond cleavage is less well advanced in the transition state than C-H bond breaking

A polypeptide chain can adopt many conformations. Yet, the sequence of its amino acid residues directs folding to a particular native state.1 The loss of conformational entropy associated with folding destabilizes the native state. This destabilization is overcome by the hydrophobic effect, hydrogen bonds, other noncovalent interactions, and disulfide bonds.2 We have identified another force that can contribute to the conformational stability of a protein. The structure and reactivity of an organic molecule can rely on the stereochemistry of its electron pairs, bonded or nonbonded.3 Such stereoelectronic effects, which arise from the mixing of an electron pair with the antibonding σ* of an adjacent polar bond (C-X, where X ) N or O), endow nucleic acids and carbohydrates with conformational stability.4 For example, the multiple gauche effects (X-C-C-X) arising from a 2′ oxygen distinguish RNA‚RNA and RNA‚DNA duplexes from DNA‚DNA duplexes.5 The anomeric effect (X-C-X) enhances the stability of the R anomer of glycosides.6 Here, we demonstrate for the first time that a stereoelectronic effect is critical for the conformational stability of a protein. Collagen is the most abundant protein in animals.7 For example, collagen comprises one-third of the protein in humans and threefourths of the weight of human skin. The polypeptide chains of collagen are composed of approximately 300 repeats of the sequence XaaYaaGly, where Xaa is often an L-proline (Pro) residue and Yaa is often a 4(R)-hydroxy-L-proline (Hyp) residue. These chains are wound in tight triple helices, which are organized into fibrils of great tensile strength. Pro and Hyp comprise nearly one-fourth of the residues in common types of collagen.8 This prevalence of tertiary amides has dichotomous consequences for conformational stability. Pro and Hyp residues are constrained by their pyrrolidine rings, and this rigidity stabilizes triple-helical collagen.9 Yet, the trans and cis conformations of the peptide bonds to Pro and Hyp residues are of nearly equal free energy, which destabilizes collagen because all peptide bonds in triple-helical collagen are in the trans conformation (Figure 1).10 The 4(R)-hydroxyl group of the prevalent Hyp residues increases dramatically the conformational stability of collagen.11 We had shown previously that this increase arises from inductive effects.12 Can a stereoelectronic effect influence Ktrans/cis? To answer this question, we synthesized residue mimics of the form AcYaaOMe, where Yaa is Pro, Hyp, 4(S)-hydroxy-L-proline (hyp), 4(R)-fluoroL-proline (Flp), or 4(S)-fluoro-L-proline (flp).13 We chose Flp and flp because fluorine is small and electronegative and forms only weak hydrogen bonds when bound to carbon.14,15 We chose a methyl ester rather than an amide to prevent γ-turn formation, as had been observed in AcProNHMe.16 We find that the electronegativity and stereochemistry of the 4-substituent in the Yaa mimics has a significant effect on Ktrans/cis (Table 1). Compared to a flp residue, a Pro residue is twice as likely and a Flp residue is 3 times as likely to have a trans peptide bond. Does the value of Ktrans/cis have an impact on collagen stability? To answer this question, we synthesized (ProYaaGly)7 strands containing Flp or flp residues in the Yaa position.19 These strands are diastereomeric, differing only in the stereochemistry at Cγ of the Yaa residues. We found that a (ProFlpGly)7 triple helix has a Tm of 45 °C.20 In contrast, a (ProflpGly)7 triple helix has a Tm of

Le phosphite de triethyle reagit avec le benzenesulfenate d'ethyle ou le peroxyde d'ethyle pour donner le pentaethoxyphosphorane. Par contre, le methyl-1 trioxa-3,5,8 phospha-4 bicyclo [2.2.2] octane (I) ne reagit pas avec ces electrophiles pour donner le phosphorane bicyclique attendu (II). La faible reactivite du phosphite I est due a une barriere cinetique plutot que thermodynamique car le phosphorane II est forme a partir d'un melange equimolaire de P(OEt) 5 et de tris(hydroxymethyl)-1,1,1 ethane

The role of stereoelectronic effects in controlhg the reaction specificity of biological reactions involving pyri- doxal phosphate-amino acid Schiff's bases was tested with nonenzymatic models. The rates of racemization and H,, ex- change of a series of pyridoxal-amino acid Schiff's bases were determined. The order of these rates does not parallel the predictions based solely on electronic or steric effect, but parallels the proportions of the reactive conformers (e.g., conformers with the C,-H, bond orthogonal to the a system) estimated by CPK models. The special reactivity of the phe- nylalanine Schiff' s base was consistent with a special confor- mation in which some type of a--a interaction increases the Pyridoxal phosphate--amino acid Schiff s bases are key in- termediates in many important biological reactions catalyzed by enzymes which require pyridoxal phosphate as a cofactor. These include transaminases, decarboxylases, synthetases, racemases, etc. (Snell & Dimari, 1970). All of these reactions are believed to proceed via cleavage of one of three bonds to C, of the amino acid. Dunathan (1966, 1971) postulated that these enzymes control the reaction specificity by controlling the conformation about the N-C, bond of the Schiff's base (SB)' intermediate. He suggested that the bond orthogonal to the a system of the SB is most easily broken due to the maximum 6-a overlap, and therefore in the enzyme active site the bond to be broken is aligned orthogonal to the P plane. Although this model was used to relate the N-C, bond conformation of the SB inter- mediates to the reaction specificity of a number of enzymes (Dunathan, 1966, 1971), it has not been adequately tested in nonenzymatic systems. However, the principle that bonds parallel to a orbitals are more labile than bonds not aligned with the a orbitals has been used to explain the 12-fold dif- ference in the rates of exchange of the axial and equatorial protons LY to a ketone group in 3/3-acetoxycholestan-7-one in the process of enolization (Corey & Sneen, 1956). This effect was attributed to stereoelectronic factors since the u electrons of the axial bond are more favorably located for overlap with the a orbital of the carbonyl group. This stereoelectronic effect has also been invoked by other workers (Hine et al., 1965) and is supported by calculations which predict maximum 6-a proportion of exchangeable conformers, thus further sub- stantiating the role of conformation in governing the reactivity of the C,,-H, bond. Furthermore, semiempirical calculations of the conformation about the C,-N bond were performed using the CAMSEA conformational analysis program. The results of conformational calculations are consistent with the results of conformational analysis by nuclear magnetic reso- nance. The order of reactivity of the C,-H, bond of the SB dianion, pH 12.0, predicted by calculation based on stereoe- lectronic effects, though not quantitatively parallel to the ob- served rate constants, is qualitatively in agreement with the experimental results.

Etude de la reaction d'alkylimines du phenyl-2 propanal avec des organometalliques allyliques