A Computational Study of Chair–Twist Energy Differences and the Chair–Chair Conformational Interconversion in Tetrahydro-2H-thiopyran (Thiacyclohexane,Thiane)

Ab initio molecular orbital theory with the LANL2DZ, 3-21G, 6-31G(d), 6-31+G(d), 6-31+G(d,p), 6-311+G(d,p),6-31G(2d), 6-31G(3d), and 6-311G(d,p) basis sets and density functional theory (B3P86, B3LYP, B3PW91) have been used to calculate the structures, relative energies, enthalpies, entropies, and free energies of the chair, 1,4-twist, and 2,5-twist conformers of tetrahydro-2H-thiopyran (tetrahydrothiopyran, thiacyclohexane, thiane, pentamethylene sulfide). All levels of theory calculated similar energy values and the effect of basis sets on the calculated energies was small. The chair conformer of tetrahydro-2H-thiopyran was 5.27 kcal/mol more stable than the 1,4-twist conformer, which was slightly more stable (0.81 kcal/mol) than the 2,5-twist conformer. The chair–1,4-twist and chair–2,5-twist free energy differences ( G°_{c – t}) were 5.44 and 5.71 kcal/mol, respectively. Intrinsic reaction coordinate [IRC, minimum-energy path (MEP)] calculations connected the transition state between the chair and the 2,5-twist conformers. This transition state is 9.73 kcal/mol higher in energy than the chair conformer and the energy differences between the chair and the 1,4-boat and 2,5-boat transition states were 8.07 and 6.38 kcal/mol, respectively. Stereoelectronic hyperconjugative interactions were observed in the chair, 1,4-twist, and 2,5-twist conformers of tetrahydro-2H-thiopyran. The stereoelectronic hyperconjugative effects in the chair conformer of tetrahydro-2H-thiopyran have been compared to those in the respective chair conformers of tetrahydro-2H-pyran, tetrahydro-2H-selenane, and tetrahydro-2H-tellurane.     

Conformational analysis of the antimalarial agent quinine

Quinine, an active antimalarial compound, is one of the most abundant constituents extracted from the bark ofCinchona trees. The activity differences among structurally related molecules appear to depend on the absolute stereochemistry of some functional groups, a result that has stimulated a detailed conformational analysis of these molecules of biological interest. In the present study the potential energy surface (PES) for the antimalarial agent quinine (C₂₀H₂₄O₂N₂) has been comprehensively investigated using the molecular mechanics (MM) and quantum mechanical semiem-pirical AM1 and PM3 methods. Six distinct minimum-energy structures are located on the multidimensional PES and also characterized as true minima through harmonic frequency analysis. The relative stabilities and thermodynamic properties are reported. The coexistence of different conformers is discussed for the first time in the literature based on the calculated transition-state (TS) structures connecting the six minima located on the PES for the quinine molecule. The theoretical results reported in the present study are in agreement with the experimental proposal, based on NMR data, that there are two possible forms for the quinine molecule in solution.     

Synthetic and structural studies on macrocyclic amino cyclitols--conformational chameleons

Starting from quinic acid the synthesis of 1,4-butanediol-linked macrocyclic aminocyclitols 30, 32, 34, 36 and 38 is described. Assembly was achieved by olefin cross-metathesis of appropriate cyclohexyl allyl ethers followed by ring-closing metathesis of bis-O-allyl homodimers. In all five cases studied, the only products that were formed were those resulting from direct ring-closing metathesis; the formation of larger rings was not detected. These macrocycles exhibited diverse conformational behaviour which included formation of stable separable conformers 31a and 31b as well as conformationally dynamic macrocycles 35 in which a ring flip in one cyclohexane chair conformer induces a ring flip of the other cyclohexane ring through the linking chains of the macrocycles. The activation energy for the inversion of the chair conformation in this process was determined to be about 38 kJ mol(-1), which is about 7 kJ mol(-1) lower than the activation energy for the ring flip of the unsubstituted cyclohexane ring. In all cases, the conformational studies strongly suggest that intramolecular H-bonding between 1,3-diaxially oriented amido and alcohol or ether groups exerts a decisive contribution to the overall stabilisation of the preferred cyclohexane chair conformation.     

Can the conformational flexibility of cis-decalins be modulated through intramolecular O-H?O hydrogen bonding? Profiling the molecular and supramolecular attributes of designer cis-fused polycyclitols

In order to unravel the modalities of hydrogen bonding in conformationally flexible polycyclitols vis-à-vis their conformationally locked siblings, three diastereomeric perhydro-2,3,4a,6,7,8a-naphthalenehexols, all embodying a 4a,8a-dihydroxy-cis-decalin framework, have been synthesized via sequential stereo-controlled oxyfunctionalization of 1,4,5,8-tetrahydronaphthalene. Variable temperature NMR studies on the cis-fused polycyclitols thus obtained suggest that their inherent conformational flexibility in solution is restrained at ambient temperature owing either to the formation of a stable H-bonded molecular solvate or to the presence of strong intramolecular O-H?O H-bonding. Single crystal X-ray diffraction studies on the three hexols reveal an interesting commonality in their gross molecular packing and a ubiquitous presence of the R²₂(10) dimer motif—a supramolecular synthon rarely encountered in the crystal structures of conformationally locked and axially-rich hexols.     

Ab initio study of the conformational equilibrium of ethylene glycol

Summary The conformational equilibrium of ethylene glycol (CH₂OHCH₂OH) has been examined by performing geometry optimizations at the 6-31G*, MP2/6-31G* and 6-31G** levels. Final energies have been calculated at the MP3 level with the optimized geometries. The two most stable conformers are atGg andgGg but it is verified that the inclusion of electronic correlations reduces their energy difference of 0.6 kcal/mol at the HF level to less than 0.2 kcal/mol. The possible coexistence of the two most stable conformers is in agreement with some previous studies of Frei et al. For thetXg conformer a detailed analysis of the intramolecular potential as a function of rotation around the C-C bond is also reported.     

Charge-Transfer Salts of Ferrocene Derivatives with Bis(maleonitriledithiolato)metallate(III) Complexes ([M(mnt)2]−, M=Ni,Pt): A Ground-State High-Spin [(Ni(mnt)2)2]2− Dimer

New hexamethylated ferrocene derivatives containing thioether moieties (1,1′-bis[(tert-butyl)thio]-2,2′,3,3′,4,4′-hexamethylferrocene ( 3a , b )) or fused S-heteropolycyclic substituents (rac-1-[(1,3-benzodithiol- 2-yliden)methyl]-2,2′,3,3′,4,4′-hexamethylferrocene ( 5 ) and rac-1-[1,2-bis(1,3-benzodithiol-2-yliden)ethyl]-2,2′,3,3′,4,4′-hexamethylferrocene ( 14 )), as well as a series of ferrocene-substituted vinylogous tetrathiafulvalenes (1,1′-bis[1,2-bis(1,3-benzodithiol-2-yliden)ethyl]ferrocene ( 6a ), 1,1′-bis[1-(1,3-benzodithiol-2-yliden)-2-(5,6-dihydro-1,3-dithiolo[4,5-b] [1,4]dithiin-2-yliden)ethyl]ferrocene ( 6b ), [1,2-bis(1,3-benzodithiol-2-yliden)ethyl]ferrocene ( 21a ), [1-(1,3-benzodithiol-2-yliden)-2-(5,6-dihydro-1,3-dithiolo[4,5-b] [1,4]dithiin-2-yliden)ethyl]ferrocene ( 21b ), [1,2-bis(5,6-dihydro-1,3-dithiolo[4,5-b] [1,4]dithiin-2-yliden)ethyl]ferrocene ( 21c ), [1-(5,6-dihydro-1,3-dithiolo[4,5-b] [1,4]dithiin-2-yliden)-2-(1,3-benzodithiol-2-yliden)ethyl]ferrocene ( 21d )) were prepared and fully characterized. Their redox properties show that some of them are easily oxidized and undergo transformation to paramagnetic salts containing bis(maleonitriledithiolato)-metallate(III) anions [M(mnt)₂]⁻ (M=Ni, Pt; bis[2,3-dimercapto-κS)but-2-enedinitrilato(2⁻)]nickelate (1⁻) or -platinate (1⁻). The derivatives [ 3a ] [Ni(mnt)₂] ( 26 ), [ 3a ] [Pt(mnt)₂] ( 27 ), [Fe{(η⁵-C₅Me₄S)₂S}] [Ni(Mnt)₂] ( 28 ), [Fe{(η⁵-C₅Me₄S)₂S}] [Pt(mnt)₂] ( 29 ), [ 5 ] [Ni(mnt)₂]⋅ClCH₂CH₂Cl ( 30 ), [ 6a ] [Ni(mnt)₂] ( 31 ), [ 6a ] [Ni(mnt)₂]⋅ClCH₂CH₂Cl ( 31a ), [ 6a ] [Pt(mnt)₂] [ 32 ), and [ 6b ] [Ni(mnt)₂] ( 33 ) were prepared and fully characterized, including by SQUID (superconducting quantum interference device) susceptibility measurements. X-Ray crystal-structural studies of the neutral ferrocene derivatives 6a , b , 21c , d , and 1,1′-bis[1-(1,3-benzodithiol-2-yliden)-2-oxoethyl]ferrocene ( 23 ), as well as of the charge-transfer salts 26 – 28 , 30 , and 31a , are reported. The salts 28 and 30 display both a D⁺A⁻A⁻D⁺ structural motif, however, with a different relative arrangement of the [{Ni(mnt)₂}₂]²⁻ dimers, thus giving rise to different but strong antiferromagnetic couplings. Salt 26 exhibits isolated ferromagnetically coupled [{Ni(mnt)₂}₂]²⁻ dimers. Salt 27 displays a D⁺A⁻D⁺A⁻ structural motif in all three space dimensions, and a week ferromagnetic ordering at low temperature. Salt 31a , on the contrary, shows segregated stacks of cations and anions. The cations are connected with each other in two dimensions, and the anions are separated by a 1,2-dichloroethane molecule.     

Conformers and intramolecular hydrogen bonding of the oxalic acid monomer and its anions

Density functional theory, B3LYP/6‐31G** and B3LYP/6‐311+G(2d,p), and ab initio MP2/6‐31G** calculations have been carried out to investigate the conformers, transition states, and energy barriers of the conformational processes of oxalic acid and its anions. QCISD/6‐31G** geometrical optimization is also performed in the stable forms. Its calculated energy differences between the two most stable conformers are very near to the related observed value at 7.0 kJ/mol. It is found that the structures and relative energies of oxalic acid conformers predicted by these methods show similar results, and that the conformer L1 (C_2h) with the double‐interfunctional‐groups hydrogen bonds is the most stable conformer. The magnitude of hydrogen bond energies depends on the energy differences of various optimized structures. The hydrogen bond energies will be about 32 kJ/mol for interfunctional groups, 17 kJ/mol for weak interfunctional groups, 24 kJ/mol for intra‐COOH in (COOH)₂, and 60 kJ/mol for interfunctional groups in (COOH)COO⁻¹ ion if calculated using the B3LYP/6‐311+G(2d,p) method. © 2000 John Wiley & Sons, Inc. Int J Quant Chem 76: 541–551, 2000     

Structure of the 2-isopropylaminoethanol isolated molecule: Conformational analysis and intramolecular interactions

In this paper, a systematic exploration of all the possible conformers of 2-isopropylaminoethanol (2-IPAE) was carried out using the Density Functional Theory (B3LYP) and the 6-311++G(d,p) basis set. At this level, 66 unique conformers within a Gibbs energy range of ca. 31 kJ mol⁻¹ were found in the potential energy surface and their geometrical and thermodynamic properties were determined and discussed. A significant molecular strain was evidenced by the dihedrals and distances between non-bonded hydrogen atoms. According to the geometrical parameters, a O–H···N hydrogen bond was found to be present in the three most stable conformers, representing 68% of the conformational composition at 298.15 K. The energetic and geometrical data derived from the DFT calculations were further complemented by a NBO analysis of the most stable conformers.     

A Direct Assembly Approach to the Synthesis of N,N′-Bridged Calix[4]pyrroles: The Synthesis of a 1,5-Diazacyclononatriene Locked in a Saddle Conformation

Ring closure of 1,2-bis(1-pyrrolylmethyl)benzene in the acid-catalysed condensation with acetone yields the 1,5-diazacyclononatriene [ O -C₆H₄(CH₂NC₄H₃-2)₂C(CH₃)₂] as the sole identifiable product. The twisted or saddle conformation of the 1,5-diazacyclononatriene, which was confirmed by X-ray crystal structure determination, is conformationally rigid in solution. The conformation of the 1,5-diazacyclononatriene prevents the formation of the target N,N′-bridged calix[4]pyrrole by further acid-catalysed condensation with acetone, the reaction affording unidentified oligomers/polymers instead. The acid-catalysed condensation of 1,3- and 1,4-bis(1-pyrrolylmethyl)benzene with acetone also yields unidentified oligomers/polymers.     

Synthetic and NMR Studies on Calix[n]Arene (n = 4,6,8) Triflates,Mesylates, and Tosylates

Abstract

The synthesis and full characterization of eight new calix[n]arene sulfonate esters including their conformational analysis were carried out. While p-tBucalix[6]arene and p-tBu-calix[8]arene esters are conformationally labile in the temperature interval of 25–100°C, p-tBu-calix[4]arene mono-and diesters were isolated as stable conformers at ambient temperature. Two 1,3-functionalised compounds of these derivatives, p-tert-butylcalix[4]arene ditriflate (5) and dimesylate (6) were shown unexpectedly high conformational stability up to 100°C by dynamic NMR measurements. The NMR measurements confirm the pinched-cone conformation for both derivatives. For the dealkylated calix[4]arene derivatives the partial cone conformer of the triesters have been obtained as major products in all cases.     

First‐principles conformational analysis of the C36H36 spheriphane,a prototype hydrocarbon host cage

Comprehensive B3LYP/6‐311G** electronic structure calculations establish that, unlike closely related species such as cyclophanes, the C₃₆H₃₆ spheriphane (heptacyclo[13.13.2^1,15.2^8,22.1^3,27.1^6,10.1^13,17.1^20,24] hexatriaconta‐1,3(33),6,8,10(34),13,15,17(35),20,22,24(36),27‐dodecaene) possesses only seven energetically distinct conformers, out of which five exist in enantiomeric pairs and two are achiral. These local energy minima are interrelated through an intricate net of 20 reaction paths involving single inversions at the ? CH₂? CH₂? bridges. In particular, the T and C₃ conformers, which are predicted to coexist in comparable concentrations at ambient temperatures, are linked through three consecutive single‐bridge inversions that proceed through the overall barrier of only 5.3 (kcal/mol). This barrier is compatible with coalescence temperatures well below those employed in the recently measured ¹H and ¹³C NMR spectra, explaining the observed lack of line splittings. Both the T→C₃ pathway and the racemizations of the low‐energy conformers involve C₁ and C₂ intermediates that are expected to be present in detectable amounts. © 2001 John Wiley & Sons, Inc. J Comput Chem 22: 1279–1286, 2001     

Synthesis of [m.n]Cyclophanes: Regiochemistry Transfer from Vinyl Halides to Cyclophanes via Fischer Carbene Complexes

The double benzannulation of bis‐carbene complexes of chromium with α,ω‐diynes generates [m.n]cyclophanes in which all three rings are generated in a single reaction. This triple annulation process is very flexible allowing for the construction of symmetrical [n.n]cyclophanes and unsymmetrical [m.n]cyclophanes as well as isomers in which the two benzene rings are both meta bridged or both para bridged, and isomers that contain both meta and para bridges. The connectivity patterns of the bridges in the cyclophanes can be controlled by regioselectivity transfer from the bis‐vinyl carbene complexes in which the substitution pattern of the vinyl groups in the carbene complexes dictate the connectivity pattern in the [m.n]cyclophanes. This synthesis of [n.n]cyclophanes is quite flexible with regard to ring size and can be used with tether lengths ranging from n=2 to n=16 and thus to ring sizes with up to 40 member rings. The only limitation to regioselectivity transfer from the carbene complexes to the [m.n]cyclophanes was found in the synthesis of para,para‐cyclophanes with four carbon tethers for which the loss of fidelity occurred with the unexpected formation of meta,para‐cyclophanes.     

NMR studies of conformations and dynamic processes—III : Cyclophanes with unsaturated bridges

Three cyclophanes, each displaying a different type of dynamic process, have been studied by NMR methods. The barriers to these processes are attributed mainly to the decrease in π-electron overlap between the benzene rings and adjacent double bonds which occurs in the transition state for each process. In [5₂] paracyclophanetetraene, two successive flippings of the benzene rings interconvert the two hydrogens in the methylene groups (Scheme 1). In tetramethyl [2₄] paracyclophanetetraene, the passage of one methyl group through the central cavity of the molecule interconverts two conformations of similar, but not equal, free energy (Scheme 2). In [2₆] orthoparacyclophanehexaene, the orthosubstituted rings change sides by passing through the centre of the cyclophane (Scheme 3).     

Computational study of conformations and of sulfinyl oxygen-induced pentacoordination at silicon in 4-chloro-4-silathiacyclohexane 1-oxide and 4,4-dichloro-4-silathiacyclohexane 1-oxide

Second-order Møller-Plesset theory (MP2) and density functional theory (B3LYP) with the 6-311G(d,p) and 6-311+G(d,p) basis sets have been used to calculate the equilibrium geometries and relative energies of the chair, twist, and boat conformations of 4-chloro-4-silathiacyclohexane 1-oxide and 4,4-dichloro-4-silathiacyclohexane 1-oxide. The chair conformers of the axial sulfoxides are lower in energy than the chair conformers of the corresponding equatorial sulfoxides. MP2/6-311+G(d,p) predicted the chair conformer of axial trans-4-chloro-4-silathiacyclohexane 1-oxide (4a) to be 6.12, 0.44, and 0.45 kcal/mol, respectively, more stable than the corresponding 1,4-twist (4b), 2,5-twist (4c) and 1,4-boat (4d) conformers and 6.93 kcal/mol more stable than the 2,5-boat transition state ([4e]^‡). Structures 4c and 4d are stabilized by intramolecular coordination of the sulfinyl oxygen with silicon that results in trigonal bipyramidal geometry at silicon. The 1,4-boat conformer (7d) of axial 4,4-dichloro-4-silathiacyclohexane 1-oxide is also stabilized by transannular coordination of the sulfinyl oxygen with silicon. The energy difference (E_rel = 4.23 kcal/mol) between the chair conformer (7a) and 7d is larger than that between 4a and 4d. The relatively lower stability of the 1,4-boat conformer (7d) of axial 4,4-dichloro-4-silathiacyclohexane 1-oxide (7a) may be due to repulsive interactions of the axial halogen and sulfinyl oxygen atoms. The relative energies and structures of the conformers and transition states of cis- and trans-4-chloro-4-silathiacyclohexane 1-oxide and 4,4-dichloro-4-silathiacyclohexane 1-oxide are discussed in terms of hyperconjugative interactions, orbital interactions, nonbonded interactions, and intramolecular sulfinyl oxygen-silicon coordination.     

Dipyridyl/pyridinium thieno[2,3-b]thiophenes as new atropisomeric systems. Synthesis, conformational analysis and energy minimization

Synthesis of a new class of cofacially oriented dipyridyl(pyridinium)lthieno[2,3-b]thiophenes with or without -CO₂Et and -COMe substituents at C2, and C5 positions of thieno[2,3-b]thiophene ring was readily accomplished using a double Dieckman cyclization protocol as the key step. While C2/C5 substituted dipyridylthieno[2,3-b]thiophenes exhibited syn/anti atropisomerism at least up to 70 °C with Arrhenius energy of activation (ΔG^≠) in the range of 17-18 kcal/mol, on the other hand unsubstituted dipyridylthieno[2,3-b]thiophene and its bis-N-quaternized salt were found to show free conformational rotation with an estimated ΔG^≠ of lower than 10 kcal/mol. Conformational energy minimization using AM1 protocol revealed a slight preference for the anti over syn isomers. Compared to the unsubstituted dipyridylthieno[2,3-b]thiophenes, higher energy barriers to rotation (3.7-5.1 kcal/mol) in substituted dipyridylthieno[2,3-b]thiophenes can be attributed to steric encumbrance resulting from -CO₂Et and -COMe substituents located on the non-rotating thienothiophene platform.     

Persistance of the Cyclopnane Radical Anions and its Relation to Structure

Reactions of [2_N]cyclophanes (N = 2, ?6) with solvated electrons in 1,2-di-methoxyethane at 193 K have been studied by ESR. and ENDOR. spectroscopy. All but the two most highly bridged cyclophanes (N = 5 and 6) are reduced to paramagnetic species under these conditions. Whereas the radical anions of [2.2]-paracyclophane and [2₃](1,2,4)- and [2₄](l,2,4,5)cyclophanes are sufficiently persistent to be characterized by their hyperfine data, those of the remaining five cyclophanes undergo a rapid cyclization to the radical anions of 4,5,9,10-tetrahydropyrenes. These have been identified as the unsubstituted tetrahydropyrene (from [2.2]-metacyclophane and [2₃](l,2,3)cyclophane), the 2,7-dimethyl-derivative (from [2₃](1,3,5)- and [2₄](l,2,3,5)cyclophanes) and the 1,8-dimethyl-derivative (from (2₄l,2,3,4)cyclophane). The persistence of the cyclophane radical anions seems to depend on the numbers, n_meta and n_para, of the meta-and para-positions of the bridging ethano groups in the two benzene rings. The prerequisite for the radical anion to be persistent is n_meta?n_para.     

Cyclobishelicenes: Shape-Persistent Figure-Eight Aromatic Molecules with Promising Chiroptical Properties

Cyclobis[n]helicenes (n=3 or 5) are chiral D₂-symmetric π-conjugated macrocycles with stable lemniscular, or figure-eight, shapes. The conformational analysis of five different cyclobis[n]helicenes revealed that these molecules can only exist as their lemniscular conformers with high barriers to enantiomerization (>200 kJ mol⁻¹). The enantiomers of a cyclobis[5]helicene were resolved by HPLC and their unusual chiroptical properties were attributed to the inherent chirality of their macrocyclic figure-eight.     

Ab initio conformational analysis of 1,3-propanedithiol

By carrying out Hartree-Fock full, symmetry unconstrained geometry optimizations on the 25 symmetrically unique staggered conformers, using the 4-31+G^* basis set it was found that, on the Hartree-Fock level, gTTg and gTTg′ are the lowest energy rotamers in 1,3-propanedithiol. We also found a number of clear conformational trends. Intramolecular hydrogen bonding was found to be of minor importance. The introduction of electron correlation yields a stabilization of the rotamers with one or two gauche SCCC arrangements relative to those with less gauche SCCC arrangements. Consistent with this, we find that on the MP2 level the most stable conformers are gGGg′ and gGGg.     

Phosphorinane and Enol Rings in One Molecule. Evidence for Reciprocal Stabilization of Half-Chair Conformations

Abstract.

The X-ray crystal structure of 2-(2′,4′-dioxo-3′-pentyl)-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane (2) reveals significant half-chair distortion of the axially oriented cisenol ring. The molecule also undergoes in-plane deformations. R(O...O) = 2.410 Å in the enol moiety indicates a very strong hydrogen bonding. The enol content, δ_OH and thermodynamic parameters for the axial-equatorial conformational and keto-enol equilibriums were obtained from ¹H, ³¹P NMR and IR measurements in comparison with the planar 4,6-dimethyl isomer (1) containing equatorially oriented enol ring. The X-ray single crystal structure of 5,5-dimethyl-2-(methoxycarbonyl-3′-oxo-2′-butyl)-2-oxo-1,3,2-dioxaphosphorinane (3) reveals the unusual half-chair conformation of the dioxaphosphorinane cycle disposed a trans-enol ring substituent. ¹H, ³¹P NMR and IR solution data support the same structure displays a strong conformational preference while the minor forms are chair conformers with an axial or equatorial cis-enol ring.