Puckering Amplitude Research Articles

Theoretical study on the deoxyribose radicals formed by hydrogen abstraction

The structures of C[sub 1], C[sub 2], C[sub 3], and C[sub 4] centered deoxyribose radicals are optimized at the UHF/6-31G level. For each radical two puckered conformations are observed, which are significantly different from those of deoxyribose. In C[sub 1] and C[sub 2] radicals the pseudorotation angle, P, is shifted toward higher values compared to that of deoxyribose. In C[sub 3] and C[sub 4] radicals the shift of P is in the opposite direction. In addition, the puckering amplitude [tau][sub m] is significantly decreased in the radicals, indicating a flattening of the five-membered ring. The C[sub 2] centered radical has the sp[sup 2]-type electronic structure, while C[sub 1], C[sub 3], and C[sub 4] centered radicals are pyramidal. The enthalpies for H-atom abstraction from deoxyribose are calculated at the MP2/6-31G[sup *] level including ZPE and a scaling of correlation energy. The abstractions from C[sub 1], C[sub 3], and C[sub 4] positions require similar energies, whereas the abstraction from the C[sub 2] carbon of deoxyribose is less favorable by 3-4 kcal/mol. The susceptibility of different deoxyribose hydrogens for abstraction is estimated on the basis of their bond strength and their accessibility in nucleotides and in DNA. 33 refs., 3 figs., 7 tabs.

Structure determinations of (dl)-trans-3-hydroxy-5-iodomethyl-2,2-diphenyltetrahydrofuran and (dl)-trans-N,N,N-trimethyl-(3-hydroxy-2,2-diphenyltetrahydro-5-furyl)methylammonium iodide

The conformation of the five-membered ring in muscarine-related compounds was studied. The conformations observed in the two title compounds, (1) 5-iodomethyl2,2-diphenyltetrahydrofuran-3-ol and (2) trimethyl[(3-hydroxy-2,2-diphenyltetrahydro-5-furyl)methyl]ammonium iodide, are slightly different. In the iodomethyl compound the ring adopts an E 3 envelope conformation in which the C atom connected to the hydroxy group is out of the best plane through the remaining ring atoms. The ring adopts a 4 T 3 twist conformation in the iodide salt with the C atom connected to the hydroxy group and the methylene C atom out of the plane of the ring. In both cases, the hydroxy group is in an axial orientation. The puckering amplitudes are of the same magnitude (40.8 and 41.5 o , respectively)

Structure of (–)-muscarone iodide

The crystal structure of (-)-cis-trimethyl{[(2S,5S)-2-methyl-3-oxotetrahydro-5-furyl]methyl}ammonium iodide (muscarone iodide) is comparable to the structure obtained for the racemic mixture [Frydenvang & Jensen (1992). Acta Cryst. C48, 469-474]. The space group is different as no mirror planes can exist for the pure enantiomer. The conformation of the muscarone ion is a distorted twist, 1 T 5 - 1 E [phase=80.2 (2) o ], with the puckering amplitude θ m =35.8 (1) o . The quaternary ammonium group adopts an anti orientation [O-C-C-N 161.0 (1) o ]. The crystal packing is nearly identical to that of the racemic mixture

The structure and ring puckering vibrations of thietane from its dipolar couplings

The r α structure of thietane has been obtained from its previously measured dipolar couplings. The molecular geometry can be described by a model of hindered pseudorotation characterized by a double minimum potential function. The optimized values for the geometric parameters are: r CH = 1·077 Å, HCαH = 109·7°, HCβH = 108·8° and -6·8° for the bending coordinate. The puckering amplitude q corresponding to the potential minimum is 0·24Å, but the height of the inversion barrier (δV) cannot be determined because the surface σ(q, δV) for the root mean square (RMS) deviations between observed and calculated dipolar couplings shows a valley of minimum deviation instead of local minima.

Synthesis of 2′,3′- cis-fused pyrrolidino-β-D-nucleosides and their conformational analysis by 500 MHz 1H-NMR

The unique “off-template” stereoselectivity in the intramolecular free radical cyclization of 3-aza-5-hexenyl endocyclic radical has been demonstrated for the first time through the synthesis of 2′,3′- cis-fused pyrrolidino-β-D-nucleosides, 19a, 20a, 21a, 22a, 23a, 35a, 36a, 37a and 38a, which are not hithertofore available by any known procedures. The 2′-linked chiral carbon (C c) in 19a, 20a, 21a and 22a has shown 25:1 to 10:1 stereoselectivity depending upon the bulk of its substituent. The 3′-linked chiral carbon (C c) in 35a, 36a and 37a, on the other hand, has shown only 4:1 to 2:1 stereoselectivity. Finally, a full conformational analysis of 2′,3′-cis-fused pyrrolidino-β-D-nucleosides 19a, 20a, 21a, 22a, 23a, 35a, 36a, 37a and 38a is reported using 1H-NMR at 500 MHz. The solution geometry of the furanose and the pyrrolidine rings were studied on the basis of vicinal proton-proton coupling constants using the concept of pseudorotation. The furanose rings in 19a – 23a have a geometry biased toward a South-type conformation [70 – 81 % S, 126° < P S < 131° (C1′-exo-C2′-endo), 28° < Ψ m < 32°, rms error ±0.05]. In compounds 35a – 38a, the riboses have a conformation biased toward the North-type [∼90 % N, 20° < P N < 38° (C3′-endo) and 27°< Ψ m < 30°, rms error ±0.05]. In compounds 19a – 22a, the pyrrolidine geometry is biased toward the North-type conformation (C2′-exo), with a phase angle of pseudorotation Q N ≈ −28° and a puckering amplitude Ψ * m ≈ 40° (rms error ±0.5). In compounds 35a – 37a, the pyrrolidine has a geometry biased toward a South-type conformation (C2′-endo), with Q S ≈ 175° and Ψ * m ≈ 39° (rms error ±0.8). The furanose and the pyrrolidine rings share the C2′C3′ bond and have correlated conformations. The pyrrolidine adopts a North-type conformation in 19a – 22a when the ribose is in a South-type conformation. In contrast, the pyrrolidine ring adopts a South-type conformation when the ribose is in a North-type conformation (in 35a – 37a). Compounds 19a – 23a and 35a – 38a show a preference for the γ + conformation (∼70%). The glycosyl conformation for all pyrrolidine-fused systems was found to be anti.

Therαstructure of oxetane as studied by NMR spectroscopy in a nematic medium

The proton and carbon-13 NMR spectra of oxetane partially orientated in a nematic solvent was analysed, and the dipolar coupling constants Dij thus determined were used to obtain information about the r α structure of the molecule. It is concluded that the oxetane molecule oscillates between two equivalent bent conformers characterized by a puckering amplitude of 0.128(5) Å. The optimized values for the remaining geometric parameters are: r CHα = 1·094(1) Å, r CHβ = 1·082(1) Å, HCαH = 109·9(1)°, HCβH = 110·2(1)°, and -4·8(5)° for the bending coordinate. The puckering potential function for oxetane cannot be determined because the surface σ(V 2, V 2) for the RMS deviations between observed and calculated Dij values shows a valley of minimum deviation instead of local minima.

Methylene group deformational coordinates in four-membered rings

The dependence of methylene group deformational coordinates upon the puckering amplitude q has been analyzed for a set of ab initio geometries of the four-membered ring (CH 2) 3X. For small values of the puckering amplitude, the rocking and twisting deformational coordinates are proportional to q, whereas for q > 0.3 Å, the inclusion of a cubic term in q is necessary in order to describe the dependence of those deformational coordinates with the puckering amplitude. The wagging deformational coordinate shows a linear correlation with the square of q, although the effect is so weak that, for small variations in q, the wagging coordinate can be considered constant.

Structural analysis of 2′,3′-dideoxyinosine, 2′,3′-dideoxyadenosine, 2′,3′-dideoxyguanosine and 2′,3′-dideoxycytidine by 500-MHz 1H-NMR spectroscopy and ab-initio molecul orbital calculations

Solution structure of anti-AIDS drug, 2′,3′-dideoxyinosine (ddI) has been assessed by NMR spectroscopy and pseudorotational analysis in conjunction with its analogues: 2′,3′-dideoxyadenosine (ddA), 2′,3′-dideoxyguanosine (ddG) and 2′,3′-dideoxycytidine (ddC). The absence of 3′-hydroxyl groups in these compounds has prompted us to establish the relationship between proton-proton and corresponding endocyclic torsion angels in the 2′,3′-dideoxyribofuranos moiety on the basis of five available crystal structures of 2′,3′-dideoxynucleosides. A subsequent pseudorotational analysis on ddI (1), ddA (2),ddG (3) and ddC (4) shows that the twist C 2′- exo-C 3′- endo forms of sugar are overwhelmingly preferred (75–80%) over the C 2′- endo envelope forms. The phase angles ( P) for North and South conformers with the corresponding puckering amplitude ( Ψ m) for ddI (1), ddA (2) and ddG (3) are as follows: P N = 0.1°, P S = 161° and Ψ m = 34.1° for ddI (1); P N = 1.4°, P S = 160° and Ψ m = 34.2° for ddA (2) and P N = 2.4°, P S = 163° and Ψ m = 33.6° for ddG (3). The predominant North conformer of ddC (4) is intermediate between twist C 2′- exo-C 3′- endo envelope ( P = 10.9°) with a Ψ m of 34.7°. Note that these preponderant North-sugar structures (approx. 75–80%) found in the solution studies of ddI (1), ddA (2), dg (3) and ddC (4) are not reflected in the X-ray crystal structures of 2′,3′-dideoxyadenosine and 2′,3′-dideoxycytidine. The constituent sugar residues in both of these crystal structures are found to be in the South-type geometry (ddA crystalizes in C 3′- exo envelope form, while ddC adopts the form intermediate between the C 3′- exo envelope and C 3′- endo-C 4′- exo twist form). This means that X-ray structures of ddA (2) and ddC (4) only represent the minor conformer of the overall pseudorotamer population in solution. An assumption that the structure of the pentofuranose sugar (i.e. P and Ψ m) participating in conformational equilibrium described by he two-state model remains unchanged at different temperatures has been experimentally validated by assessing five unknown pseudorotational parameters with eight unique observables ( 3J 1′2′, 3J 1′2″, 3J 2′3′, 3J 2′3″, 3J 2″3′, 3J 2″3″, 3J 3′4′ and 3J 3″4′ ) for 2′,3′-dideoxynucleosides. A van 't Hoff plot of (ln (% S/% N)) as a function of reciprocal temperature shows a clear straight line through all seven observed data points for each of 2′,3′-dideoynucleosides (1–4). Note that this van 't Hoff plot gave the thermodynamics of the North and South conformational states of the pentofuranose moiety. The slope of the curve gave the values for enthalpies ( ΔH) for ddI (1), ddA (2), ddG (3) and ddC (4) which are 5.5, 4.1, 4.2 and 6.9 kJ/mol, respectively; corresponding values for entropies ( ΔS) derived from the point of interception on the ordinate are 8.2, 5.2, 5.2 and 12.7 J/mol K, respectively. Finally, independent ab-initio MO studies (GAUSSIAN 92) on the conformation of ddI (1) have been performed using HF/2–21G level of theory. Results of these MO calculations have been compared with the experimental NMR data which show excellent agreement.

Therαstructure of cyclobutane from its dipolar couplings

The molecular structure of cyclobutane has been analysed from its previously measured dipolar couplings. Assuming that the cyclobutane molecule oscillates between two equivalent bent conformers, the C-H bond length decreases from an anomalous value of 1·144 A to 1·097 A when harmonic vibration corrections are applied to observed dipolar couplings. The optimized values for the remaining geometric parameters are: 0·26 A for the puckering amplitude, 109.8° for the HCH bond angle and 3.5° for the methylene rocking coordinate. The inversion barrier (ΔV) value cannot be determined because the RMS deviation between observed and calculated direct couplings remains practically unaltered for ΔV values greater than 4 kJ mol-1.

Relationships between torsional angles and ring-puckering coordinates Part IV.Application to four-membered rings

The dependence of the intracyclic torsion angles, φ j and bond angles θ j upon the puckering amplitudes Φ and q has been analyzed for a set of ab initio geometries of four-membered rings (CH 2) 3X as well as for a set of X-ray structures of derivatives. The coefficients in the corresponding expressions have been estimated both theoretically, from the bond angles and bond lengths of planar reference conformations, and by parameterization. The coefficients in equations φ j (Φ), φ j(q), and Φ(q) calculated for the ab initio structures from the planar ring geometries are in good agreement with those obtained by parameterization. Likewise, the results from the analysis of X-ray structures are in reasonable agreement with the ab initio ones. The torsion angles φ j are described more accurately by using the Φ amplitudes than the q ones. However, the bond angles θ j are described with similar accuracy using Φ or q. For the X-ray structures the description of the θ j angles is not very good, the r.m.s. deviations σ being greater than 1° due mainly to substituent and/or packing effects. However, for the sum of the bond angles in each ring the deviation σ is smaller than 0.1 °. A planar ring geometry has been estimated for each X-ray structure from the θ j angles which has been used to calculate the coefficients in the corresponding equation φ j (Φ). The deviation σ for φ j decreases to 0.03° when using these individual equations against the value of 0.2° obtained when, for parameterizing φ j (Φ), the same planar ring is used for all derivatives of each parent compound.

A two-dimensional ring puckering potential energy surface for ethylene carbonate from ab initio and flexible model computations

A two-dimensional ring puckering potential energy surface has been derived for ethylene carbonate using ab initio and flexible model computations. The surface is expressed as a mixed Taylor—Fourier series expansion of the generalized ring puckering coordinates ( q, φ). The ab initio molecular energies have been used to determine the degree of truncation of the series which gives an accurate representation of the surface in the region of q, φ space spanned by data from microwave spectroscopy. The ab initio geometries have been used for the kinetic energy part of the flexible model computations. By scaling the coefficients of the ab initio potential it is possible to obtain reasonably good agreement with the observed inversion splitting, fundamental puckering vibrational frequencies and most of the variation in the rotational constants with excitation of the ring puckering vibrations. This potential function has a twisted C 2 symmetry equilibrium conformation with a puckering amplitude of 27 pm. The lowest energy path to ring inversion passes through the planar ring conformation where there is a barrier of 2.7 kJ mol − (229 cm −1).

Dependence of the dipolar couplings of tetrahydrofuran on the pseudorotation parameters

The dipolar couplings Dij previously measured for tetrahydrofuran (THF) in nematic Phase IV have been analysed in order to obtain information about the puckering amplitude and pseudorotation potential of this molecule. The effective ordering matrix (EOM) method and the ELS theoretical model have been applied by using a hindered pseudorotation potential of type V 2 cos 2φ + V 4 cos 4φ. The optimized value for the equilibrium puckering amplitude of 0·39 A is close to the value of 0·38 A determined by electron diffraction. The actual pseudorotation potential for THF cannot be determined because the surfaces σ(V 2, V 4) for the rms deviations between observed and calculated Dij values show flat valleys instead of local minima. Notwithstanding, the results obtained by means of the ELS model, which allows for the dependence of orientational ordering on molecular shape, are more consistent with the spectroscopic result of almost free pseudorotation for the THF than those provided by the EOM method.

Conformational analysis of brominated pA2'-5'A2'-5'A analogs. An NMR and model-building study.

NMR and model-building studies were carried out on pA2'-5'A2'-5'A and analogs in which one or more of the A residues were replaced by 8-bromoadenosine. Chemical shifts, coupling constants and NOE data were used to obtain structural information. The N/S equilibrium constant of the ribose rings as well as the phase angles and puckering amplitudes were determined from the experimental coupling constants with the aid of an improved version of the PSEUROT program. Chemical shifts in combination with NOE data were used to monitor base-base interactions and the orientation of the bases (syn or anti). The combined data suggest that different types of stacking interactions are present in the various compounds. Bromination of the first or second residue in the trimers results in a preference for N-type sugar and syn orientation of the base in these residues. When A(3) is brominated, an S-type sugar conformation together with a syn orientation of the base is favoured at the 2' terminus. Energy-minimized models of the different stacking interactions are presented which fit the present collection of data. The possible correlation between biological activity of these compounds and their conformation is briefly discussed.

Gas-phase structures of perfluorotetrahydrothiophene, c-C 4F 8S, tetrahydrothiophene-1-oxide, c-C 4F 8SO, and tetrahydrothiophene-1,1-dioxide, c-C 4F 8SO 2

The geometric structures of the three title compounds have been determined by gas-phase electron diffraction. In all cases the five-membered rings are strongly puckered and possess half chair conformations with the following geometric parameters ( r a values with 3σ error limits). c-C 4F 8S: (CC) mean=1.548(4), SC=1.822(4) Å, CSC=94.5(3)°, SCC=107.4(3)°, CCC=106.4(4)° and puckering amplitude q=0.411(8) Å. c-C 4F 8SO: (CC) mean=1.553(5), SC=1.903(4) Å, CSC=89.4(4)°, SCC=110.2(4)°, CCC=106.5(6)°, q=0.403(8) Å. c-C 4F 8SO 2: (CC) mean=1.556(6), SC=1.882(7) Å, CSC=93.2(10)°, SCC=107.7(10)°, CCC=107.9(12)°, q=0.382(10) Å. Comparison with the analogous protonated rings reveals that upon fluorination the degree of puckering decreases slightly in c-C 4F 8S and c-C 4F 8SO, whereas it increases strongly in c-C 4F 8SO 2.

Simulation of the interconversion path between stable conformations of the furanose ring: methyl β-D-2-deoxyribofuranoside and simpler ribose and deoxyribose analogues

The results of simulation of the pseudorotation path in methyl β-D-2-deoxyribofuranoside, cyclopentane, tetrahydrofuran, 3-hydroxytetrahydrofuran, and 2,3-dihydroxytetrahydrofuran by using a geometrical ring-puckering model and an empirical all-atom force-field method are presented. For all these molecules energetic and geometric profiles of the N–S interconversion pathway are presented for various exocyclic group orientations. The difference in the simulated conformational behaviour of certain model compounds in the vapour state and in polar-solution conditions is discussed. The influence of the orientation and presence of exocyclic groups and the role of C- and O-ring structure on the conformational behaviour of the compounds examined is investigated. Conformational analysis of the furanose ring in several model compounds of increasing structure complexity reveals great diversity in their conformational behaviour in both geometric and energetic respects. The only features of conformational behaviour attributed to ring structure are: (a) the existence of energy minima in wide N and S regions of pseudorotation wheel; (b) the existence of N–S interconversion path via puckered-ring conformations. The puckering amplitude q varies considerably during N–S interconversion path and is no longer a quantitative feature of furanosering structure.

Structural and biochemical properties of bidentate tetraaquarhodium(III) complexes of inorganic pyrophosphate and adenosine 5'-diphosphate.

The structural and biochemical properties of the alpha,beta-bidentate tetraaquarhodium(III) complexes of inorganic pyrophosphate [Rh(H2O)4PP] and adenosine diphosphate [Rh(H2O)4ADP] are examined. These Rh(III) complexes are exchange-inert analogues of the corresponding physiologically important MgIIPP and MgIIADP complexes. The crystal structure of [Rh(H2O)4H2P2O7]+Cl- shows that the six-membered chelate ring adopts a twist-boat conformation with an unusually high puckering amplitude of 0.756 (3) A. The Rh coordination distances average 2.02 (1) A, while the bridge P-O bonds are virtually equal in length. All 10 protons of the complex participate in hydrogen bonding. There are two intramolecular hydrogen bonds between the phosphate oxygen atoms and the axially coordinated water molecules. The Rh(H2O)4PP complex was found to be a substrate for yeast inorganic pyrophosphatase, with Ki = 0.063 (7) mM and Vm = 500 (100) min-1. The two screw sense isomers of Rh(H2O)4ADP were prepared from (Rp)-[alpha-16O,18O]ADP and assigned configuration on the basis of the magnitude of their 31P NMR isotopic chemical shifts. The Rh(H2O)4ADP complex binds a number of kinases as tightly as MgADP. Arginine kinase and creatine kinase were shown to bind the delta Rh(H2O)4ADP isomer 7 and 45 times tighter, respectively, than the lambda isomer. The reactivity of Rh(H2O)4PP with pyrophosphatase is comparable to that of Cr(H2O)4PP, and the binding affinities of the Rh(H2O)4ADP screw sense isomers for kinases are also comparable to those observed for the corresponding Cr(H2O)4ADP screw sense isomers.

The X-ray crystal structure of dl-(1,3,5/2,4)-1,2,3,4-tetraacetoxy-5-(acetoxymethyl)cyclohexane

The crystal and molecular structure of thepseudo-sugar dl-(1,3,5/2,4)-1.2.3.4-tetraacetoxy-5-(acetoxymethyl)cyclohexane (“pseudo-β- dl-glucopyranose pentaacetate”) has been determined by X-ray diffraction and statistical-phasing procedures. The data were refined to R = 0.049 and R w = 0.054 over 1543 reflections with I greater than 3σ(I). The racemic crystals are monoclinic, space group P2 1/ c, a = 11.580(2), b = 8.276(1), c = 22.031(2) Å, β = 104.33(1)°, D c = 1.26g/cm 3, with four molecules in the unit cell. The ring has a 4 C 1( d), 1 C f( l) conformation, with puckering amplitude of 0.582(4) Å, a pseudorotation angle of −168.35°, and a gg orientation about the C-5C-6 bond.

The gas-phase structure of dodecafluorooctahydrothiophene, c-C 4F 8SF 4

The geometric structure of c-C 4F 8SF 4 has been determined by gas-phase electron diffraction. The five-membered ring has the twist form ( C 2 symmetry) with a puckering amplitude q = 0.42 (2) Å. The following principle geometric parameters ( r a values) with estimated uncertainties have been derived: (CC) av = 1.541(10), SC = 1.896(7), SF e = 1.558(6), SF a = 1.594(6) Å, CSC = 90.0(9)°, SCC = 109.1(8)°, CCC = 106.5(12)°, F aSF e = 90.5(15)° and F eSF e = 87.7(29)°. Vibrational amplitudes for long non-bonded C⋯F and F⋯F distances indicate a high barrier to pseudorotation of the ring.

Relationships between torsion angles and ring-puckering coordinates: Part III. Application to heterocyclic puckered five-membered rings

The conformational analysis of five-membered rings is greatly facilitated by the concept of pseudorotation. The well-known pseudorotation equation for torsion angles (C. Altona and M. Sundaralingam J. Am. Chem. Soc., 94 (1972) 8205) yields a good correspondence between calculated and observed torsion angles for equilateral or nearly equilateral rings. In this communication the pseudorotation equation is extended by additional terms in order to yield an improved correspondence between calculated and observed torsion angles, especially for heterocyclic puckered rings (e.g. tetrahydrothiophene, 1,2-oxathiolane). The additional parameters, valid for a given class of five-membered rings, can be obtained either from a dataset of X-ray structures or from model structures optimized by ab initio or (semi)empirical calculations. Endocyclic bond angles in five-membered rings are correlated with the phase angle of pseudorotation P and with the puckering amplitude φ m. Coefficients for bond angle regressions with pseudorotation parameters are given for furanose and proline rings and for ring D in steroids. The geometry of a five-membered ring can be calculated with the computer program PSEU for any desired value of P and φ m. The nine independent coordinates are calculated from five torsion angles (obtained from a given P and φ m by means of the extended pseudorotation equation) and five bond distances by means of a least-squares procedure. Coefficients for functions relating the pseudorotation parameters to exocyclic bond angles and exocyclic torsion angles in furanose fragments are also established. Cartesian coordinates for model β- D-ribo- and β- D-deoxyribo furanoside fragments encompassing the full pseudorotation pathway are presented as supplementary material.

The structure and pseudorotation of cyanocyclopentane as determined by gas phase electron diffraction

The structure of cyanocyclopentane has been determined by gas phase electron diffraction. The molecule was found to have a low barrier to pseudorotation with two minima corresponding to C S envelope conformations with the CN in the quatorial and axial positions. The best least squares value obtained for the barrier to pseudorotation was 240(330) cal mol −1, and the energy difference between the equatorial and axial conformers was found to be 180(330) cal mol −1 with the equatorial form being preferred. The puckering amplitude for the five-membered ring was found to be 0.42(28) Å, and an average CC(ring) distance of 1.544(1) Å was obtained. Other parameters obtained from least squares analysis of the experimental data include: r g(CCN) = 1.477(7) Å, r g(CN) = 1.160(2) Å, r g(CH) = 1.102(6) Å, <CCCN = 112.1(1.3)°, and <HCH avg = 107.2(3.2)°. The results obtained are in excellent agreement with related cyclopentyl compounds, and with the microwave spectroscopic results obtained for cyanocyclopentane.