Conformer Pairs Research Articles

Effects of multiple conformers per compound upon 3-D similarity search and bioassay data analysis

BackgroundTo improve the utility of PubChem, a public repository containing biological activities of small molecules, the PubChem3D project adds computationally-derived three-dimensional (3-D) descriptions to the small-molecule records contained in the PubChem Compound database and provides various search and analysis tools that exploit 3-D molecular similarity. Therefore, the efficient use of PubChem3D resources requires an understanding of the statistical and biological meaning of computed 3-D molecular similarity scores between molecules.ResultsThe present study investigated effects of employing multiple conformers per compound upon the 3-D similarity scores between ten thousand randomly selected biologically-tested compounds (10-K set) and between non-inactive compounds in a given biological assay (156-K set). When the “best-conformer-pair” approach, in which a 3-D similarity score between two compounds is represented by the greatest similarity score among all possible conformer pairs arising from a compound pair, was employed with ten diverse conformers per compound, the average 3-D similarity scores for the 10-K set increased by 0.11, 0.09, 0.15, 0.16, 0.07, and 0.18 for STST-opt, CTST-opt, ComboTST-opt, STCT-opt, CTCT-opt, and ComboTCT-opt, respectively, relative to the corresponding averages computed using a single conformer per compound. Interestingly, the best-conformer-pair approach also increased the average 3-D similarity scores for the non-inactive–non-inactive (NN) pairs for a given assay, by comparable amounts to those for the random compound pairs, although some assays showed a pronounced increase in the per-assay NN-pair 3-D similarity scores, compared to the average increase for the random compound pairs.ConclusionThese results suggest that the use of ten diverse conformers per compound in PubChem bioassay data analysis using 3-D molecular similarity is not expected to increase the separation of non-inactive from random and inactive spaces “on average”, although some assays show a noticeable separation between the non-inactive and random spaces when multiple conformers are used for each compound. The present study is a critical next step to understand effects of conformational diversity of the molecules upon the 3-D molecular similarity and its application to biological activity data analysis in PubChem. The results of this study may be helpful to build search and analysis tools that exploit 3-D molecular similarity between compounds archived in PubChem and other molecular libraries in a more efficient way.

Photoinduced Dynamics of Formic Acid Monomers and Dimers: The Role of the Double Hydrogen Bond

Nonadiabatic dynamics in the framework of time-dependent density functional theory was used to simulate gas-phase relaxation dynamics of pairs of conformations of formic acid monomers (cis and trans FAM) and dimers (acyclic aFAD and cyclic cFAD). In the early phase of the excited state dynamics, elongation of the C═O bond and pyramidalization of the carbon atom is observed in both FAM and FAD. Subsequently, the photodynamics of FAM is shown to be dominated by fragmentation processes occurring mostly in the excited state and resulting in HCO and OH radicals. In only a few cases does the dissociation take place from the vibrationally excited ground electronic state, whereby CO and H(2)O are the major reaction products. In the dimers, single proton transfer triggers ultrafast relaxation to the ground electronic state. In the single hydrogen bonded dimer about half of the trajectories dissociate into electronically excited monomers, whereas this potentially destructive dissociation is effectively suppressed in the double hydrogen bonded dimer. Upon relaxation to the ground electronic state, separation of FAD into monomers takes place, but without their further fragmentation on the time scale of the simulation. We conclude that the crucial difference between the FAM and FAD photodynamics is that the latter is dominated by nondestructive radiationless deactivation pathways during which a key protective role is assumed by the single (aFAD) or double (cFAD) intermonomer hydrogen bonds.

Microwave, Raman and infrared spectra, r0 structural parameters, conformational stability, and ab initio calculations of cyclobutylisocyanate

The microwave spectrum of cyclobutylisocyanate, c-C4H7NCO, has been investigated from 21,000 to 11,000 MHz and 11 transitions for the more stable equatorial-trans conformer were assigned. The rotational constants of the ground vibrational state have been determined and the molecule has been shown to be a near symmetric prolate rotor (К = −0.99). The B and C rotational constants have been confidently determined to be B = 1508.68(3) and C = 1476.55(2) MHz, respectively, whereas the value for the A rotational constant of 6,891(302) MHz had a large uncertainty. Variable temperature (−100 to −55 °C) studies of the infrared spectra (3,500–400 cm−1) of cyclobutylisocyanate dissolved in liquid xenon as well as the infrared spectra of the gas and solid have been recorded. In addition, the Raman spectra (3,600–100 cm−1) of the liquid have been investigated. These spectral data indicated the present of three conformers in the fluid states which are the equatorial-trans, equatorial-gauche, and axial-trans forms. The second part of the conformational name refers to the relative position of the NCO moiety relative to the alpha hydrogen. By utilizing four conformer pairs, an enthalpy difference of 131 ± 13 cm−1 (1.57 ± 0.16 kJ/mol) was obtained with the equatorial-trans conformer the more stable form, which is in good agreement with the ab initio predicted value of 137 ± 36 cm−1 (1.64 ± 0.43 kJ/mol). To aid in the vibrational assignment, ab initio and DFT calculations have been carried out by using a variety of basis sets up to 6-311G(3df,3pd).

PubChem3D: Biologically relevant 3-D similarity

BackgroundThe use of 3-D similarity techniques in the analysis of biological data and virtual screening is pervasive, but what is a biologically meaningful 3-D similarity value? Can one find statistically significant separation between "active/active" and "active/inactive" spaces? These questions are explored using 734,486 biologically tested chemical structures, 1,389 biological assay data sets, and six different 3-D similarity types utilized by PubChem analysis tools.ResultsThe similarity value distributions of 269.7 billion unique conformer pairs from 734,486 biologically tested compounds (all-against-all) from PubChem were utilized to help work towards an answer to the question: what is a biologically meaningful 3-D similarity score? The average and standard deviation for the six similarity measures STST-opt, CTST-opt, ComboTST-opt, STCT-opt, CTCT-opt, and ComboTCT-opt were 0.54 ± 0.10, 0.07 ± 0.05, 0.62 ± 0.13, 0.41 ± 0.11, 0.18 ± 0.06, and 0.59 ± 0.14, respectively. Considering that this random distribution of biologically tested compounds was constructed using a single theoretical conformer per compound (the "default" conformer provided by PubChem), further study may be necessary using multiple diverse conformers per compound; however, given the breadth of the compound set, the single conformer per compound results may still apply to the case of multi-conformer per compound 3-D similarity value distributions. As such, this work is a critical step, covering a very wide corpus of chemical structures and biological assays, creating a statistical framework to build upon.The second part of this study explored the question of whether it was possible to realize a statistically meaningful 3-D similarity value separation between reputed biological assay "inactives" and "actives". Using the terminology of noninactive-noninactive (NN) pairs and the noninactive-inactive (NI) pairs to represent comparison of the "active/active" and "active/inactive" spaces, respectively, each of the 1,389 biological assays was examined by their 3-D similarity score differences between the NN and NI pairs and analyzed across all assays and by assay category types. While a consistent trend of separation was observed, this result was not statistically unambiguous after considering the respective standard deviations. While not all "actives" in a biological assay are amenable to this type of analysis, e.g., due to different mechanisms of action or binding configurations, the ambiguous separation may also be due to employing a single conformer per compound in this study. With that said, there were a subset of biological assays where a clear separation between the NN and NI pairs found. In addition, use of combo Tanimoto (ComboT) alone, independent of superposition optimization type, appears to be the most efficient 3-D score type in identifying these cases.ConclusionThis study provides a statistical guideline for analyzing biological assay data in terms of 3-D similarity and PubChem structure-activity analysis tools. When using a single conformer per compound, a relatively small number of assays appear to be able to separate "active/active" space from "active/inactive" space.

PubChem3D: Shape compatibility filtering using molecular shape quadrupoles

BackgroundPubChem provides a 3-D neighboring relationship, which involves finding the maximal shape overlap between two static compound 3-D conformations, a computationally intensive step. It is highly desirable to avoid this overlap computation, especially if it can be determined with certainty that a conformer pair cannot meet the criteria to be a 3-D neighbor. As such, PubChem employs a series of pre-filters, based on the concept of volume, to remove approximately 65% of all conformer neighbor pairs prior to shape overlap optimization. Given that molecular volume, a somewhat vague concept, is rather effective, it leads one to wonder: can the existing PubChem 3-D neighboring relationship, which consists of billions of shape similar conformer pairs from tens of millions of unique small molecules, be used to identify additional shape descriptor relationships? Or, put more specifically, can one place an upper bound on shape similarity using other "fuzzy" shape-like concepts like length, width, and height?ResultsUsing a basis set of 4.18 billion 3-D neighbor pairs identified from single conformer per compound neighboring of 17.1 million molecules, shape descriptors were computed for all conformers. These steric shape descriptors included several forms of molecular volume and shape quadrupoles, which essentially embody the length, width, and height of a conformer. For a given 3-D neighbor conformer pair, the volume and each quadrupole component (Qx, Qy, and Qz) were binned and their frequency of occurrence was examined. Per molecular volume type, this effectively produced three different maps, one per quadrupole component (Qx, Qy, and Qz), of allowed values for the similarity metric, shape Tanimoto (ST) ≥ 0.8.The efficiency of these relationships (in terms of true positive, true negative, false positive and false negative) as a function of ST threshold was determined in a test run of 13.2 billion conformer pairs not previously considered by the 3-D neighbor set. At an ST ≥ 0.8, a filtering efficiency of 40.4% of true negatives was achieved with only 32 false negatives out of 24 million true positives, when applying the separate Qx, Qy, and Qz maps in a series (Qxyz). This efficiency increased linearly as a function of ST threshold in the range 0.8-0.99. The Qx filter was consistently the most efficient followed by Qy and then by Qz. Use of a monopole volume showed the best overall performance, followed by the self-overlap volume and then by the analytic volume.Application of the monopole-based Qxyz filter in a "real world" test of 3-D neighboring of 4,218 chemicals of biomedical interest against 26.1 million molecules in PubChem reduced the total CPU cost of neighboring by between 24-38% and, if used as the initial filter, removed from consideration 48.3% of all conformer pairs at almost negligible computational overhead.ConclusionBasic shape descriptors, such as those embodied by size, length, width, and height, can be highly effective in identifying shape incompatible compound conformer pairs. When performing a 3-D search using a shape similarity cut-off, computation can be avoided by identifying conformer pairs that cannot meet the result criteria. Applying this methodology as a filter for PubChem 3-D neighboring computation, an improvement of 31% was realized, increasing the average conformer pair throughput from 154,000 to 202,000 per second per CPU core.

Spectroscopic and theoretical studies of some N, N-diethyl-2-[(4′-substituted)phenylsulfonyl]acetamides

The analysis of the IR carbonyl band of the N, N-diethyl-2-[(4′-substituted)phenylsulfonyl]acetamides Et 2NC(O)CH 2S(O) 2 C 6H 4 Y (Y = OMe 1, Me 2, H 3, Cl 4, Br 5, NO 2 6) supported by B3LYP/6-31G(d,p) calculations for 3, indicated the existence of three pairs ( anti and syn) of cis ( c) and gauche ( g 1 and g 2) conformers in the gas phase, being the gauche conformers significantly more stable than the cis ones. The anti geometry is more stable than the syn one, for each pair of cis and gauche conformers. The summing up of the orbital (NBO analysis) and electrostatic interactions justifies quite well the populations and the ν CO frequencies of the anti and syn pairs of c, g 1 and g 2 conformers. The IR higher carbonyl frequency component whose population is ca. 10%, in CCl 4, may be ascribed to the least stable and most polar cis conformer pair (in the gas phase) and the lower frequency component whose population is ca. 90%, to the summing up of the populations of the two most stable and least polar gauche conformer pairs ( g 1 and g 2) (in the gas phase). The reversal of the cis( c)/ gauche ( g 1 + g 2) population ratio observed in chloroform ca. 60% ( cis)/40% ( gauche) and the occurrence of the most polar cis( c) conformer only, in acetonitrile, strongly suggests the coalescence of the two gauche components in a unique carbonyl band in solution. A further support to this rationalization is given by the single point PCM solvation model performed by HF/6-31G(d,p) method, which showed a progressive increase of the c/( g 1 + g 2) ratio going from gas to CCl 4, to CHCl 3 and to CH 3CN. X-ray single crystal analysis of 4 indicates that this compound assumes, in the solid state, the syn-clinal ( gauche) conformation with respect to the [O C CH 2 S] moiety, and the most stable anti geometry relative to the [C(O)N(CH 2CH 3) 2] fragment. In order to obtain larger energy gain from the crystal packing the molecules of 4 are linked in centrosymmetric dimers through two C H⋯O interactions (C H [O–Ph]⋯O [SO2]) forming a step ladder.

PubChem3D: Similar conformers

BackgroundPubChem is a free and open public resource for the biological activities of small molecules. With many tens of millions of both chemical structures and biological test results, PubChem is a sizeable system with an uneven degree of available information. Some chemical structures in PubChem include a great deal of biological annotation, while others have little to none. To help users, PubChem pre-computes "neighboring" relationships to relate similar chemical structures, which may have similar biological function. In this work, we introduce a "Similar Conformers" neighboring relationship to identify compounds with similar 3-D shape and similar 3-D orientation of functional groups typically used to define pharmacophore features.ResultsThe first two diverse 3-D conformers of 26.1 million PubChem Compound records were compared to each other, using a shape Tanimoto (ST) of 0.8 or greater and a color Tanimoto (CT) of 0.5 or greater, yielding 8.16 billion conformer neighbor pairs and 6.62 billion compound neighbor pairs, with an average of 253 "Similar Conformers" compound neighbors per compound. Comparing the 3-D neighboring relationship to the corresponding 2-D neighboring relationship ("Similar Compounds") for molecules such as caffeine, aspirin, and morphine, one finds unique sets of related chemical structures, providing additional significant biological annotation. The PubChem 3-D neighboring relationship is also shown to be able to group a set of non-steroidal anti-inflammatory drugs (NSAIDs), despite limited PubChem 2-D similarity.In a study of 4,218 chemical structures of biomedical interest, consisting of many known drugs, using more diverse conformers per compound results in more 3-D compound neighbors per compound; however, the overlap of the compound neighbor lists per conformer also increasingly resemble each other, being 38% identical at three conformers and 68% at ten conformers. Perhaps surprising is that the average count of conformer neighbors per conformer increases rather slowly as a function of diverse conformers considered, with only a 70% increase for a ten times growth in conformers per compound (a 68-fold increase in the conformer pairs considered).Neighboring 3-D conformers on the scale performed, if implemented naively, is an intractable problem using a modest sized compute cluster. Methodology developed in this work relies on a series of filters to prevent performing 3-D superposition optimization, when it can be determined that two conformers cannot possibly be a neighbor. Most filters are based on Tanimoto equation volume constraints, avoiding incompatible conformers; however, others consider preliminary superposition between conformers using reference shapes.ConclusionThe "Similar Conformers" 3-D neighboring relationship locates similar small molecules of biological interest that may go unnoticed when using traditional 2-D chemical structure graph-based methods, making it complementary to such methodologies. The computational cost of 3-D similarity methodology on a wide scale, such as PubChem contents, is a considerable issue to overcome. Using a series of efficient filters, an effective throughput rate of more than 150,000 conformers per second per processor core was achieved, more than two orders of magnitude faster than without filtering.

Sensory Rhodopsin-I as a Bidirectional Switch: Opposite Conformational Changes from the Same Photoisomerization

The phototaxis receptor sensory rhodopsin I (SRI) exists in two protein conformations, each of which is converted to the other by light absorption by the protein's retinylidene chromophore. One conformer inhibits a histidine-kinase attached to its bound transducer HtrI and its formation induces attractant motility responses, whereas the other conformer activates the kinase and its formation induces repellent responses. We performed Fourier transform infrared spectroscopy with temperature, pH, and mutation-induced shifts in the conformer equilibrium, and found that both conformers when present in the unphotolyzed dark state contain an all- trans retinal configuration that is photoisomerized to 13- cis, i.e., the same photoisomerization causes the opposite conformational change in the photointerconvertible pair of conformers depending on which conformer is present in the dark. Therefore, switching between the protein global conformations that define the two conformers is independent of the direction of isomerization. Insights into this phenomenon are gained from analysis of the evolution of the receptor from light-driven proton pumps, which use similar conformers for transport. The versatility of the conformational changes of microbial rhodopsins, including conformer interexchangeability in the photocycle as shown here, is likely a significant factor in the evolution of the diverse functionality of this protein family.

Conformational and thermodynamic analysis of the COXIB scaffold using quantum chemical calculations

AbstractSelective cyclo‐oxygenase‐2 inhibitors (COXIBs) are prominent members of the nonsteroidal anti‐inflammatory drugs. The neutral and protonated COXIB scaffold has been subjected to molecular computations in the gas phase and implicit solvent to measure the relative changes in the thermodynamic functions, enthalpy (Hrel), potential energy (Urel), Gibbs free energy (Grel) and entropy (Srel) induced by selected substituents. Conformational analysis of the COXIB scaffold indentified four pairs of atropisomeric conformers (from I, I′ to IV, IV′) associated with a molecular structure containing a double rotor system. All conformers had similar stability. Para‐substitution with substituents that cover a wide range of Hammett sigma values did not alter the geometries of the neutral COXIB conformers; however, the protonated COXIB scaffold was showed an increase in structural and thermodynamic perturbations due to inductive effects. Flexibility and structural resilience of the COXIB scaffold under the conditions studied herein could be an important feature of the COXIBs, especially considering the previously proposed flexibility of the cyclo‐oxygenase binding site. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2011

Origin of anomeric effect: A density functional steric analysis

The anomeric effect (the tendency of heteroatomic substituents adjacent to a heteroatom within the cyclohexane ring to prefer the axial orientation instead of the sterically less hindered equatorial position) is traditionally explained through either the dipole moment repulsion or the hyperconjugation effect. In this work, by employing our recent work in density functional steric analysis, we provide a novel two-component explanation, which is consistent with the common belief in chemistry that the effect has a stereoelectronic origin. With α-D-glucopyranose as the prototype, we systematically explore its conformational space and generate 32 isomers, leading to a total of 80 axial-equatorial conformation pairs. The energy difference analysis of these pairs shows that while statistically speaking the tendency is valid, the anomeric effect is not always true and can be violated. Three energy components, exchange-correlation, classical electrostatic, and density functional steric, are found to be directly proportional to the total energy difference between axial and equatorial isomers. We also found that the total dipole moment change, not the hyperconjugation effect, is a reasonable indicator of the total energy difference. However, all these correlations alone are not strong enough to provide a compellingly convincing explanation for the general validity of the effect. With the help of strong correlations between energy components, an explanation with two energy components, steric and electrostatic, was proposed in this work. We show that the axial-equatorial energy difference in general, with the anomeric effect as a special case, is dictated by two factors of the stereoelectronic origin, steric hindrance and classical electrostatic interactions, synchronously working together. Another explanation in terms of exchange-correlation and electrostatic interactions has also been obtained in this work.

Rigorous Calculation of Free Energy Difference Between Open and Closed States of Adenylate Kinase from Explicit Solvent Molecular Dynamics

Biological functions of proteins are closely connected to their dynamics in the native state. These dynamics are governed by the protein's native energy landscape. Therefore, constructing detailed maps of these landscapes is essential for studying protein function and dynamics, especially, in more interesting cases of allosteric proteins, molecular motors or enzymatic catalysis. One fundamental approach to creating energy landscape maps is to start from measuring free energy differences between a pair of protein conformations, for instance, two allosteric states. Doing it in a computer simulation with explicit solvent is a challenging problem, but recently we have developed a general method for this purpose. Given two conformations of a polymer chain, our procedure can calculate the free energy difference in a computationally efficient way. The essence of the method is in a proper “reaction coordinate” that drives the system from one conformation to the other one, and in a special confinement potential which limits the phase space needed to be explored without affecting the free energy difference. We have used the method on a small protein Trp-cage as a proof of concept. Also we have calculated free energy difference between the open and closed states of adenylate kinase with no ligand. Although, this is a thoroughly studied enzyme both experimentally and in silico, the efforts to calculate free energy difference between the two allosteric states have not yet achieved a final result.

The r0 structural parameters, conformational stability, barriers to internal rotation, and vibrational assignments for trans and gauche ethanol

The infrared spectrum (4000–400 cm −1) of the gas and variable temperature (−55 to −100 °C) spectra of xenon solutions of ethanol (ethyl alcohol), CH 3CH 2OH, have been recorded. From these data complete vibrational assignments have been made for both the trans (anti) and gauche conformers. By utilizing the conformer pair of the CH 3 rock fundamental modes in the xenon solution the enthalpy difference has been determined to be 62 ± 12 cm −1 (0.75 ± 0.14 kJ mol −1) with the trans form the more stable conformer from variable temperature spectra of xenon solutions. It is estimated that there is approximately 40 ± 1% of the trans form present at ambient temperature. By using the previously reported fifteen rational constants of the five heavy atom isotopomers for the trans conformer and the three rotational constants for the gauche form combined with the structural parameters predicted from the MP2(full)/6-311+G(d,p) calculations, the adjusted- r 0 parameters have been obtained. The heavy atom structural parameters for the trans [ gauche] are: the distance (Å), C–O = 1.433(3) [1.430(3)], C–C = 1.518(3) [1.523(3)]; and angle (°), CCO = 107.6(5) [112.5(5)], HOCC = 180.0 [56.9(5)]. The Δ J, Δ JK, Δ K, δ J, δ K centrifugal distortion constants have been predicted from ab initio and density functional theory calculations which are compared to the corresponding experimentally determined values. The harmonic force field, infrared intensities, band contours, and vibrational frequencies have been obtained for both conformers from ab initio MP2 (full)/6-31G(d) calculations and the results are compared to the experimental values when appropriate. The results are discussed and compared to the corresponding quantities of some similar molecules.

Conformational stability, r0 structural parameters, and vibrational assignments of mono-substituted cyclobutanes: Fluorocyclobutane

Variable temperature (−55 to −100 °C) studies of the infrared spectra (3500–400 cm −1) of fluorocyclobutane, c-C 4H 7F, dissolved in liquid xenon have been carried out as well as the infrared spectra of the gas. By utilizing eight pairs of conformers at 10 different temperatures, the enthalpy difference between the more stable equatorial conformer and the axial form has been determined to be 496 ± 40 cm −1 (5.93 ± 0.48 kJ/mol). The percentage of the axial conformer present at ambient temperature is estimated to be 8 ± 1%. The ab initio MP2(full) average predicted energy difference from a variety of basis sets is 732 ± 47 cm −1 (9.04 ± 0.44 kJ/mol) and the average value of 602 ± 20 cm −1 from density functional theory predictions by the B3LYP method are significantly larger than the experimentally determined enthalpy value. By utilizing previously reported microwave rotational constants for the equatorial and axial conformers combined with ab initio MP2(full)/6-311+G(d,p) predicted structural values, adjusted r 0 parameters have been obtained. The determined heavy atom structural parameters for the equatorial [axial] conformer are: distances (Å) C–F = 1.383(3) [1.407(3)], C α–C β = 1.543(3) [1.546(3)], C β–C γ = 1.554(3) [1.554(3)] and angles (°) ∠C αC βC γ = 85.0(5) [89.2(5)], ∠C βC αC β = 89.3(5) [89.2(5)], ∠F–(C βC αC β) = 117.4(5) [109.2(5)] and a puckering angle of 37.4(5) [20.7(5)]. The conformational stabilities, harmonic force fields, infrared intensities, Raman activities, depolarization ratios and vibrational frequencies have been obtained for both conformers from MP2(full)/6-31G(d) ab initio calculations and compared to experimental values where available. The results are discussed and compared to the corresponding properties of some other monosubstituted cyclobutanes with halogen and pseudo-halogen substituents.

Microwave, Raman, and Infrared Spectra; Adjusted r0 Structural Parameters; Conformational Stability; and Vibrational Assignment of Germylcyclohexane

The FT-microwave spectrum of germylcyclohexane, c-C(6)H(11)GeH(3), has been recorded, and more than 40 transitions for the (70)Ge, (72)Ge, and (74)Ge isotopomers (isotopologues) have been assigned for the chair-equatorial conformer. The heavy atom adjusted r(0) structural parameters have been determined [distances, C(gamma)-C(delta) = 1.533(3) A, C(gamma)-C(beta) = 1.532(3) A, C(alpha)-C(beta) = 1.540(3) A, C(alpha)-Ge = 1.957(3) A; angles, angleC(gamma)C(delta)C(beta) = 111.2(5) degrees , angleGeC(alpha)C(beta) = 111.1(5) degrees , with the dihedral angle angleC(gamma)C(delta)C(beta)C(alpha) = 55.6(10) degrees ]. Raman and/or infrared spectra of gas, liquid, and solid germylcyclohexane have been recorded. The temperature dependency of the Raman spectrum of the conformer pair 712 (equatorial)/683 (axial) cm(-1) gives an enthalpy difference of 453 +/- 38 cm(-1) (1.30 +/- 0.11 kcal/mol) with the chair-equatorial conformer the more stable form. At ambient temperature, the abundance of the axial conformer is 11 +/- 1%. Substituent effects on the enthalpy difference and structure of monosubstituted cyclohexanes are discussed for a number of molecules.

ChemInform Abstract: Transoid, Ortho, and Gauche Conformers of n-Si4Cl10: Raman and Mid-IR Matrix-Isolation Spectra.

Calculations at the HF/6-31G*, MP2(FC)/6-31G*, and B3LYP/6-31G* levels of theory predict the existence of three pairs of enantiomeric conformers on the potential energy surface of n-Si4Cl10: trans...

Microwave, infrared, and Raman spectra, r0 structural parameters, conformational stability, and vibrational assignment of ethynylcyclohexane

The FT-microwave spectrum of ethynylcyclohexane, c-C 6H 11CCH has been investigated from 11,000 to 21,000 MHz and 32 transitions for the chair-equatorial conformer and 22 transitions for the chair-axial form have been observed and assigned from which the rotational constants and five centrifugal distortion constants have been obtained. By utilizing the six microwave rotational constants along with ab initio MP2(full)/6-311 + G(d,p) predicted structural values, adjusted r 0 parameters have been obtained for the two conformers. The determined heavy atom structural parameters for the equatorial[axial] conformer are: the distances (Å) C 1 C 9,10 = 1.532(3)[1.537(3)], C 9,10 C 15,16 = 1.544(3)[1.534(3)], C 4 C 15,16 = 1.541(3)[1.545(3)], C 6 C 7 = 1.210(3)[1.212(3)] and angles in degrees: ∠C 1C 9,10C 15,16 = 111.0(5)[111.2(5)], ∠C 6C 4C 15,16 = 110.7(5)[110.3(5)] and τC 1C 9,10C 15,16C 4 = 56.4(10)[55.3(10)]. Variable temperature (−60 to −100 °C) studies of a xenon solution were carried out and by using 10 conformer pairs an enthalpy difference of 124 ± 13 cm −1 (1.48 ± 0.16 kJ/mol) was obtained with the more stable form the chair-equatorial conformer. At ambient temperature, the abundance of the chair-equatorial conformer is 55 ± 3%. By measuring the temperature dependency of the Raman spectrum of the liquid of the conformer pair at 822 (axial)/842 (equatorial) cm −1, a standard enthalpy difference of 172 ± 32 cm −1 (2.06 ± 0.38 kJ/mol) was obtained again with the chair-equatorial conformer the more stable form. From MP2(full)/6-311 + G(d,p) ab initio calculations the chair-axial conformer is predicted to be more stable by 135 cm −1 (1.62 kJ/mol) whereas in contrast the density functional theory calculations by the B3LYP method with the same basis set gives the chair-equatorial conformer more stable by 289 cm −1 (3.46 kJ/mol). A complete vibrational assignment is given for the chair-equatorial conformer and most of the fundamentals for the chair-axial form have been assigned. To support the vibrational assignments, normal coordinate calculations with two scaling factors for the force constants from MP2(full)/6-31G(d) calculations were carried out to predict the fundamental vibrational frequencies, infrared intensities, Raman activities, depolarization values and infrared band contours. The results of these spectroscopic and theoretical studies are discussed and compared to the corresponding results for some similar molecules.

Conformational stability, structural parameters and vibrational assignment from variable temperature infrared spectra of xenon and krypton solutions and ab initio calculations of ethylisocyanate

Variable temperature (−55 to −155 °C) studies of the infrared spectra (400–3500 cm −1) of ethylisocyanate, CH 3CH 2NCO, dissolved in liquid xenon and krypton have been recorded. Additionally the infrared spectra of the gas and solid have been re-investigated. These spectroscopic data indicate two conformers in the fluid states which are the cis and trans forms with a large proportion of molecules in the gas phase at ambient temperature in the excited states of the NCO torsional mode which has a very low barrier to conformational interchange. Variable temperature (−110 to −155 °C) studies of krypton solutions were carried out and by using two conformer pairs, an enthalpy difference of 100 ± 4 cm −1 (1.20 ± 0.05 kJ/mol) was obtained with the cis conformer the more stable form. To aid in the analyses of the vibrational and rotational spectra, ab initio calculations have been carried out by the perturbation method to the second order (MP2) with full electron correlation using a variety of basis sets up to 6-311+G(2df,2pd) and cc-PVQZ. With the basis sets 6-311+G(2d,2p) and larger, the barrier at the cis position ranged from a low value of 11 cm −1 to a high value of 31 cm −1 with a value of 19 cm −1 from the largest basis set of cc-PVQZ. Thus, the gauche well is probably so shallow that it does not contain a bound vibrational state. This results in the cis conformer as the most stable form which is consistent with the experimental rotational and vibrational data. The predicted energy difference from these calculations between the cis conformer and the transitional-state skew form is ∼100 cm −1 which is consistent with the assigned microwave lines for four excited states of the NCO torsion. Density functional theory calculation by the B3LYP method with many of the same basis sets provided little information. By utilizing the previously reported microwave rotational constants with the structural parameters predicted by the ab initio MP2(full)/6-311+G(d,p) calculations, adjusted r 0 structural parameters have been obtained for the cis form. The determined heavy atom parameters are: r(C N) = 1.211(5), r(C O) = 1.167(5), r(C N) = 1.448(5), r(C C) = 1.516(5) Å for the distances and angles of ∠CCN = 112.6(5), ∠CNC = 137.5(5), ∠NCO = 172.9(5)°. The centrifugal distortion constants, dipole moments, conformational stability, vibrational frequencies, infrared intensities and Raman activities have been predicted from ab initio calculations and compared to experimental quantities when available. These results are compared to the corresponding quantities of some similar molecules.

Conformational stability from variable temperature infrared spectra of xenon solution, r0 structural parameters, and vibrational assignment of fluorocyclohexane

The infrared spectra (3500–300 cm −1) of the gas and xenon solutions of fluorocyclohexane have been recorded. By the utilization of nine different temperatures of nine conformer pairs the enthalpy difference between the more stable chair-equatorial conformer and the chair-axial form was determined to be 48 ± 5 cm −1 (137 ± 14 cal/mol). The ab initio predicted values ranged from 121 cm −1 with the chair-axial conformer more stable from the MP2(full)/6-311G(d,p) calculations to 24 cm −1 with the chair-equatorial form more stable with diffuse functions. The r 0 structural parameters have been obtained from predicted parameters from ab initio MP2(full)/6-311+G(d,p) calculations adjusted to fit the previously reported microwave determined rotational constants. The determined heavy atom structural parameters for the equatorial[axial] conformer are: the distances (Å) C 1–C 7,8 = 1.533(3)[1.531(3)], C 7,8–C 13,14 = 1.543(3)[1.538(3)], C 4–C 13,14 = 1.518(3)[1.520(3)], C 4–F 6 = 1.404(3)[1.410(3)] and angles in degrees ∠C 1C 7,8C 13,14 = 111.0(5)[111.2(5)], ∠F 6C 4C 13,14 = 108.7(5)[107.9(5)] and τC 8C 1C 7C 13 = 55.9(10)[55.9(10)]. The harmonic force fields, infrared intensities, Raman activities, depolarization ratios, and vibrational frequencies have been obtained for both conformers from MP2(full)/6-31G(d) ab initio calculations. With two scaling factors of 0.88 for the C–H stretches and 0.9 for the remaining ones, the fundamental wavenumbers have been predicted and along with the depolarization values and infrared band contours (B-type for A″ modes) a complete vibrational assignment has been made for both conformers. The results are discussed and compared to the corresponding properties of some similar molecules.

Conformational stability, r0 structural parameters, barriers to internal rotation, vibrational assignments and ab initio calculations of c-C 3H 5GeH 2CH 3

The infrared spectra (3100–40 cm −1) of gaseous and amorphous solid and Raman spectra (3200–20 cm −1) of the liquid at various temperatures for methylgermylcyclopropane, c-C 3H 5GeH 2CH 3, have been obtained. Additionally, variable temperature (−55 to −100 °C) studies of the infrared spectra of the sample dissolved in xenon have been recorded. From these spectral data, two conformers have been identified with one the cis (syn) form where the methyl group is over the three-membered ring and the other the gauche form. By utilizing six conformer pairs of the vibrational bands the enthalpy difference of the sample dissolved in xenon has been determined to be 43 ± 11 cm −1 (0.51 ± 0.13 kJ mol −1) with the gauche form the more stable conformer. It is estimated that there is approximately 30 ± 3% of the cis form present at ambient temperature. It was not possible to achieve crystallization of the compound by annealing it, and both conformers were present at all temperatures. The Ge–H distances of 1.531 and 1.533 Å for the gauche conformer have been determined from their stretching frequencies. By utilizing the microwave rotational constants of the gauche conformer for five isotopomers ( 70Ge, 72Ge, 73Ge, 74Ge, 76Ge) combined with the structural parameters predicted from the MP2(full)/6-311+G(d,p) calculations, the adjusted r 0 structural parameters have been obtained. The heavy atom distances (Å) are: (GeC 2) = 1.925(5); (C 2C 4) = 1.517(3); (C 2C 5) = 1.519(3); (C 4C 5) = 1.502(3); (GeC 6) = 1.947(5) and the angles (°) are: ∠ CGeC = 110.6(5); ∠ GeC 2C 4 = 120.1(5); ∠ GeC 2C 5 = 119.2(5). For the cis form very small differences of 0.003 and 0.001 Å from those of the gauche form are predicted for the GeC bonds whereas the other distances are predicted to be the same or differ at the most by 0.002 Å. A complete vibrational assignment is given for both the conformers. To support the vibrational assignments, normal coordinate calculations with scaled force constants from MP2(full)/6-31G(d) calculations were carried out to predict the fundamental vibrational frequencies, infrared intensities, Raman activities, depolarization values and infrared band contours. Barriers to internal rotation have been predicted. The results are discussed and compared to the corresponding properties of some similar molecules.

Microwave, Raman, and infrared spectra, r0 structural parameters, conformational stability, and vibrational assignment of cyanocyclohexane

The FT-microwave spectrum of cyanocyclohexane, c-C 6H 11CN has been investigated from 11,000 to 21,000 MHz and 99 transitions for the chair-equatorial conformer and 76 transitions for the chair-axial form have been observed and assigned from which the rotational constants and five centrifugal distortion constants have been obtained. By utilizing the six microwave rotational constants along with ab initio MP2(full)/6-311 + G(d,p) predicted structural values, adjusted r 0 parameters have been obtained for the two conformers. The determined heavy atom structural parameters for the axial[equatorial] conformer are: the distances (Å) C 1–C 8,9 = 1.536(3)[1.536(3)], C 8,9–C 14,15 = 1.532(3)[1.532(3)], C 4–C 14,15 = 1.544(3)[1.544(3)], C 6 N 7 = 1.162(3)[1.161(3)] and angles in degrees: ∠C 1C 8,9C 14,15 = 111.6(5)[110.8(5)], ∠C 6C 4C 14,15 = 110.0(5)[110.8(5)] and τC 1C 8,9C 14,15C 4 = 55.6(10)[56.9(10)]. Variable temperature (−55 to −100 °C) studies of a xenon solution were carried out and by using two conformer pairs from which an enthalpy difference of 63 ± 9 cm −1 (0.75 ± 0.11 kJ/mol) was obtained with the more stable form the chair-axial conformer. At ambient temperature, the abundance of the chair-axial conformer is 58 ± 8%. By measuring the temperature dependency of the Raman spectrum of the liquid of the conformer pair at 819 (axial)/842 (equatorial) cm −1, a standard enthalpy difference of 46 ± 16 cm −1 (0.54 ± 0.19 kJ/mol) was obtained again with the chair-axial conformer the more stable form. From MP2(full)/6-311 + G(d,p) ab initio calculations the chair-axial conformer is predicted to be more stable by 120 cm −1 (1.44 kJ/mol) whereas in contrast the density functional theory calculations by the B3LYP method with the same basis sets gives the chair-equatorial conformer more stable by 180 cm −1 (2.16 kJ/mol). A complete vibrational assignment is given for the chair-axial conformer and most of the fundamentals for the chair-equatorial form have been assigned. To support the vibrational assignments, normal coordinate calculations with two scaling factors for the force constants from MP2(full)/6-31G(d) calculations were carried out to predict the fundamental vibrational frequencies, infrared intensities, Raman activities, depolarization values and infrared band contours. The results of these spectroscopic and theoretical studies are discussed and compared to the corresponding results for some similar molecules.