On the destabilization (strain) energy of biphenylene

Biphenylene is subject to a variety of destabilizing effects (antiaromaticity, ring strain) and resonance stabilization. Careful construction of a group equivalent reaction that isolates the destabilization energy from other chemical effects, notably resonance energy, leads to a revised estimate of the destabilization energy of biphenylene as 57 kcal mol(-1). Extension of these ideas to higher homologoues of biphenylene, including starphenylene, point out pitfalls of any approach toward uniquely defining reactions that measure chemical effects.     

Structures of N,N-dialkoxyamides: pyramidal anomeric amides with low amidicity

The first X-ray structures of two anomeric N,N-dialkoxyamides (2 and 3) have been obtained, which confirm that they are highly pyramidalized at nitrogen and have long N-CO bonds, a characteristic of other anomeric amides and a consequence of drastically reduced amidicity. The crystals also demonstrate chirality at the amide nitrogen in the solid state. The structures are well-predicted by density functional calculations using N,N-dimethoxyacetamide as a model. The amidicity of N,N-dimethoxyacetamide has been estimated by two independent methods, COSNAR and a new transamidation method, which give almost identical resonance stabilization energies of -8.6 kcal mol(-1) and only 47% that of N,N-dimethylacetamide computed at the same level. The total destabilization is composed of a resonance and an inductive contribution, which we have evaluated separately. The electronegative oxygens at nitrogen are responsible for localization of the nitrogen lone pair on the amide nitrogen, a factor that contributes to a loss of resonance over and above the impact of pyramidalization at nitrogen, as well as the fact that N,N-dimethoxyacetamide is predicted to protonate on the carbonyl oxygen in preference to nitrogen.     

Development of a new family of conformationally restricted peptides as potent nucleators of beta-turns. Design, synthesis, structure, and biological evaluation of a beta-lactam peptide analogue of melanostatin

Novel enantiopure (i)-(beta-lactam)-(Gly)-(i+3) peptide models, defined by the presence of a central alpha-alkyl-alpha-amino-beta-lactam ring placed as the (i+1) residue, have been synthesized in a totally stereocontrolled way by alpha-alkylation of suitable N-[bis(trimethylsilyl)methyl]-beta-lactams. The structural properties of these beta-lactam pseudopeptides have been studied by X-ray crystallography, Molecular Dynamics simulation, and NOESY-restrained NMR simulated annealing techniques, showing a strong tendency to form stable type II or type II' beta-turns either in the solid state or in highly coordinating DMSO solutions. Tetrapeptide models containing syn- or anti-alpha,beta-dialkyl-alpha-amino-beta-lactam rings have also been synthesized and their conformations analyzed, revealing that alpha-alkyl substitution is essential for beta-turn stabilization. A beta-lactam analogue of melanostatin (PLG amide) has also been prepared, characterized as a type-II beta-turn in DMSO-d6 solution, and tested by competitive binding assay as a dopaminergic D2 modulator in rat neuron cultured cells, displaying moderate agonist activity in the micromolar concentration range. On the basis of these results, a novel peptidomimetic design concept, based on the separation of constraint and recognition elements, is proposed.     

Ring strain energies: substituted rings, norbornanes, norbornenes and norbornadienes

Ring strain energies (RSEs) are predicted using homodesmotic reactions at the B3LYP/6-31G^* level of theory. Substituents are conserved in the acyclic reference and any difference in energy between the ring and the acyclic reference corresponds exclusively to RSE. Small rings are stabilized by alkyl substituents and this stabilization decreases as the size of the ring increases. There is a destabilization of medium sized rings. Greater stabilization is found upon alkyl substitution at a double bond in an unsaturated ring and this stabilization decreases as ring size increases. The effects of cis-1,2-disubstitution on RSEs have been evaluated and indicate stabilization for both small and medium sized rings. RSEs of saturated and unsaturated polycyclic systems agree well with the RSEs derived from experimental thermochemical data. RSEs are reported for substituted norbornanes, norbornenes, and norbornadienes to complement experimental studies.     

General Olefin Synthesis by the Palladium‐Catalyzed Heck Reaction of Amides: Sterically Controlled Chemoselective N?C Activation

Metal‐catalyzed reactions of amides proceeding via metal insertion into the N CO bond are severely underdeveloped due to resonance stabilization of the amide bond. Herein we report the first Heck reaction of amides proceeding via highly chemoselective N CO cleavage catalyzed by Pd⁰ utilizing amide bond ground‐state destabilization. Conceptually, this transformation provides access to a myriad of metal‐catalyzed transformations of amides via metal insertion/decarbonylation.     

General Olefin Synthesis by the Palladium‐Catalyzed Heck Reaction of Amides: Sterically Controlled Chemoselective NC Activation

Metal‐catalyzed reactions of amides proceeding via metal insertion into the N? CO bond are severely underdeveloped due to resonance stabilization of the amide bond. Herein we report the first Heck reaction of amides proceeding via highly chemoselective N? CO cleavage catalyzed by Pd⁰ utilizing amide bond ground‐state destabilization. Conceptually, this transformation provides access to a myriad of metal‐catalyzed transformations of amides via metal insertion/decarbonylation.     

Thermodynamic analysis of strain in heteroatom derivatives of indene

Thermochemical properties of indene, 2,3-benzofuran, indole, and N-methylindole have been studied to obtain a better quantitative understanding of the energetics associated with these compounds containing five-membered ring units. We used combustion calorimetry, transpiration, and high-level first-principles calculations to derive gaseous enthalpies of formation of the five-membered heterocyclic compounds. Our new values together with selected values for the parent heterocyclic compounds, available from the literature were used for calculation of the strain enthalpies H(S) of five-membered C, N, and O-containing cycles. The quantitative analysis of the resulting stabilization or destabilization of a molecule due to interaction of the benzene ring with the heteroatom has been performed.     

Computational study of pharmacophores: beta-sultams

The strain and resonance energies in beta-sultam derivatives have been calculated by using a high-level ab initio method (G3/B3LYP) in order to resolve the question of the principal driving force affecting solvolysis of these new antibiotics. We found that only the combined effect of stabilizing (via amide or sulfonamide resonance interactions) and destabilizing (ring strain) influences can account for the observed rates of solvolysis in beta-lactams and beta-sultams.     

Thermodynamic analysis of strain in the five-membered oxygen and nitrogen heterocyclic compounds

Cyclopentane is conventionally strained. Replacement of a carbon atom by a heteroatom obviously impacts angular strain in the five-membered ring compounds. Changes of strains in the five-membered cycles are also caused by a double bond or atttached benzene rings. We studied the thermochemical properties of Indane, 2,3-dihydrobenzofuran, indoline, N-methyl-indoline, carbazole, and N-ethyl-carbazole to obtain a better quantitative understanding of the energetics associated with these compounds containing five-membered ring units. We used combustion calorimetry, transpiration method, and high-level first-principles calculations to derive gaseous enthalpies of formation of the five-membered heterocyclic compounds. Our new values together with the selected values for parent heterocyclic compounds, available from the literature, were used for calculation of the strain energies H(S) of five-membered C-, N-, and O-containing cycles. Quantitative analysis of the resulting stabilization or destabilization of a molecule due to interaction of benzene rings with the heteroatom has been performed.     

How strained is the “flat” benzene ring in superphane ?

The strain energy in the bowl-shaped benzene ring incorporated in superphane has been estimated by the MO theoretical calculations at 20.6 kcal/mole (the 4–31 G calculations). The π-orbitals on the ring are not parallel to each other, but loss in the π-resonance energy does not appear to be serious. The strain in the σ-framework is considered to be responsible for most of the destabilization.     

The Driving Force for the Acylation of β-Lactam Antibiotics by L,D-Transpeptidase 2: Quantum Mechanics/Molecular Mechanics (QM/MM) Study

β-lactam antibiotics, which are used to treat infectious diseases, are currently the most widely used class of antibiotics. This study focused on the chemical reactivity of five- and six-membered ring systems attached to the β-lactam ring. The ring strain energy (RSE), force constant (FC) of amide (C−N), acylation transition states and second-order perturbation stabilization energies of 13 basic structural units of β-lactam derivatives were computed using the M06-2X and G3/B3LYP multistep method. In the ring strain calculations, an isodesmic reaction scheme was used to obtain the total energies. RSE is relatively greater in the five-(1a–2c) compared to the six-membered ring systems except for 4b, which gives a RSE that is comparable to five-membered ring lactams. These variations were also observed in the calculated inter-atomic amide bond distances (C−N), which is why the six-membered ring lactams C−N bond are more rigid than those with five-membered ring lactams. The calculated ΔG^# values from the acylation reaction of the lactams (involving the S−H group of the cysteine active residue from L,D transpeptidase 2) revealed a faster rate of C−N cleavage in the five-membered ring lactams especially in the 1–2 derivatives (17.58 kcal mol⁻¹). This observation is also reflected in the calculated amide bond force constant (1.26 mDyn/A) indicating a weaker bond strength, suggesting that electronic factors (electron delocalization) play more of a role on reactivity of the β-lactam ring, than ring strain.     

Cationic polymerization of cyclic olefins

The polymerization and the polymerizabilities of indene, benzofuran, and 1,2-dihydronaphthalene are discussed from the point of view of ring strain, ring stabilization, and steric hindrance in the transition state. Monomer reactivities of these olefins were estimated from copolymerization with styrene and from the rate of addition of iodine bromide in acetic acid. Rates and degrees of polymerization are compared with monomer reactivities and resonance energies of indene, 1,2-dihydronaphthalene, and benzofuran as a measure of ring strain and stabilization. It is found that indence is 1.5–2.0 times more reactive than styrene. This high reactivity of indene is attributed to the ring strain in the monomer state and to the low amount of steric hindrance in the transition state of the coplanar five-membered cyclic olefin. 1,2-Dihydronaphthalene is strained and therefore reactive, but propagation to higher molecular weight products is impeded due to the steric hindrance. The reactivity of benzofuran is decreased by conjugative stabilization of C?C double bonds at the reaction site.     

Factors governing intrinsic chemical reactivity differences between clavulanic and penicillanic acids

To help elucidate why penicillin-G is inactivated by certain bacterial beta-lactamase enzymes, whereas clavulanic acid (Clav, which is similar to penicillin-G except at positions 1, 2, and 6) inhibits beta-lactamase, the intrinsic chemical reactivities of these two antibiotics were assessed in this work. Ab initio and continuum dielectric methods were used to map out the gas-phase and solution-phase free-energy profiles for the alkaline hydrolyses of Clav and penicillanic acid (Peni, which is similar to penicillin-G except at position 6) as well as of a fictitious hybrid compound, Peni-db, which is similar to Clav and Peni except at positions 1 and 2, respectively. Furthermore, the ring strain energies of various lactam rings and the five-membered rings of Peni and Clav as well as their respective rate-limiting transition states were computed to assess the contribution of four- and five-membered ring strains to the antibiotic's activity. The predicted product distribution, rate-limiting step, and relative reaction rates for the alkaline hydrolysis of Peni and Clav are in accord with the experimental findings. The rate-limiting step in the alkaline hydrolysis of Peni, Clav, or Peni-db is the approach of the negatively charged hydroxide ion toward the anionic reactant to form a tetrahedral intermediate. The alkaline hydrolysis of Clav generates more stable products than that of Peni mainly because the O1 atom and the hydroxyethylidene group in Clav facilitate the opening of the five-membered ring; furthermore, the O1 atom can abstract a proton easier than the less polar S1 in Peni. Clav undergoes basic hydrolysis faster than Peni mainly because its hydroxyethylidene group leads to an increase in the positive charge on the carbonyl C7 atom, therefore enhancing favorable electrostatic interactions with the incoming hydroxide anion. To a lesser extent, the oxygen at position 1 in Clav also contributes to the rate acceleration because of the greater solvent stabilization of the oxygen-containing transition state as compared to the respective ground state. The inherent strain of the four-membered beta-lactam ring or five-membered ring does not enhance the alkaline hydrolyses of beta-lactam molecules such as Peni or Clav, consistent with the observation that the rate-limiting step does not involve a breakdown of the four-membered beta-lactam ring or five-membered thiazolidine/oxazolidine rings.     

Can Substituted Cyclopentadiene Become Aromatic or Antiaromatic?

Cyclopentadiene derivatives with electronegative (F, Cl) or electropositive (H(3)Si, Me(3)Si) bis-5,5-substituents were studied at the B3LYP/6-311G* level of theory. It was found that there is no special stabilization or destabilization for any of the derivatives; the energetic effects that were previously attributed to aromatic stabilization or antiaromatic destabilization are the result of interactions in the reference systems. A nucleus-independent chemical shift (NICS) scan study at the HF-GIAO/6-311+G* theoretical level of these and similar derivatives suggest that they all show different magnitudes of diamagnetic ring current. None of the derivatives shows a paramagnetic ring current. Thus, cyclopentadienes are neither aromatic nor antiaromatic. It is also concluded that a diamagnetic ring current is perhaps necessary but certainly not a sufficient condition for aromaticity. The NICS scan procedure describes the type of ring current in the system, whereas a single isotropic NICS value (i.e., NICS(1)) may wrongly assign the type of ring current. It is shown that neither NICS(1) nor the NICS scan procedure can be used as a single aromaticity criterion.     

Conformation analyses, dynamic behavior, and amide bond distortions of medium-sized heterocycles. 2. Partially and fully reduced 1-benzazocines, benzazonines, and benzazecines

Partially and fully reduced forms of benzo-fused eight- to ten-membered nitrogen heterocycles (1-benzazecines, 1-benzazonines and 1-benzazecines) have been prepared. Conformational features, transannular distances and dynamic behavior were studied using X-ray crystallography and VT NMR spectroscopy. The amide moiety in the nine-membered benzazonine ring 5b favors N-pyramidization, whereas the ten-membered benzazecine 5c adopts an amide twist. Molecular mechanics calculations reveals a correlation between the amide twist (tau) and ring stability. The dynamic behavior of the heterocycles in solution were also found to be dependent on the extent and nature of the amide distortion. We thus conclude that ring strain of these medium-sized heterocyclic rings is relieved through amide distortion, which leads to a more stable structure.     

Intramolecular hydrogen bonding in imidazole-4(5)-alkoxycarbonyl-5(4)-carboxamide derivatives

The ir spectrum of imidazole derivatives, which have an alkoxycarbonyl group and a carboxamide group at the 4- and 5-positions of the imidazole ring respectively, exhibits the shift of the ester carbonyl band to a lower wave number. This phenomenon was investigated by spectroscopic measurements of a group of relevant compounds. The results indicate that the shift is caused by the intramolecular hydrogen bonds between the hydrogen atom of the amide and the carbonyl oxygen of the ester which is enhanced by the resonance stabilization of the imidazole ring.     

Benzene triradicals: stabilization or destabilization?

A new group additivity scheme has been developed to evaluate the stabilization/destabilization effects of benzene triradicals. It is shown that benzene triradicals manifest a significant destabilization effect and not stabilization effect as previously thought.     

Substituent effects on the stability of extended benzylic carbocations: a computational study of conjugation

A set of design rules for the prediction of relative stabilities of methoxy substituted naphthyl methyl carbocations are presented based on a series of DFT calculations. The peri-effect, over-crowding, substitutions on the ring carrying the CH(2)(+) group and substitution on the opposite ring are the principal factors that influence the stability of the carbocations. All of these factors have to be taken simultaneously into account. The most pronounced destabilization occurs when the methyl part of the methoxy substituent lies out of the plane of the aromatic core because this causes the resonance stabilization of the carbocation to become hindered. The performance of the DFT-calculations was assessed on the results of a G3(MP2)//B3LYP calculation-a method that is known to predict energies to within chemical accuracy. These values were found to compare well with those obtained at the B3LYP/6-31G(d) level. Thus, a computationally inexpensive method such as the B3LYP/6-31G(d) might prove to be a powerful tool in the design of future complex extended aromatic systems.     

Reliable determination of amidicity in acyclic amides and lactams

Two independent computational methods have been used for determination of amide resonance stabilization and amidicities relative to N,N-dimethylacetamide for a wide range of acyclic and cyclic amides. The first method utilizes carbonyl substitution nitrogen atom replacement (COSNAR). The second, new approach involves determination of the difference in amide resonance between N,N-dimethylacetamide and the target amide using an isodesmic trans-amidation process and is calibrated relative to 1-aza-2-adamantanone with zero amidicity and N,N-dimethylacetamide with 100% amidicity. Results indicate excellent coherence between the methods, which must be regarded as more reliable than a recently reported approach to amidicities based upon enthalpies of hydrogenation. Data for acyclic planar and twisted amides are predictable on the basis of the degrees of pyramidalization at nitrogen and twisting about the C-N bonds. Monocyclic lactams are predicted to have amidicities at least as high as N,N-dimethylacetamide, and the β-lactam system is planar with greater amide resonance than that of N,N-dimethylacetamide. Bicyclic penam/em and cepham/em scaffolds lose some amidicity in line with the degree of strain-induced pyramidalization at the bridgehead nitrogen and twist about the amide bond, but the most puckered penem system still retains substantial amidicity equivalent to 73% that of N,N-dimethylacetamide.