Syntheses and self-assembly behaviors of the azobenzenyl modified beta-cyclodextrins isomers

A couple of analogues of azobenzenyl beta-cyclodextrins 1 and 2 with self-locked and self-unlocked conformations have been synthesized via the Huisgen cycloaddition from the same reactants, but in distinct reaction conditions (i.e., the hydrothermal synthesis and the "click" reaction, respectively), their conformations were sufficiently proved by X-ray crystal structural analysis, molecular modeling study, and 2D NMR spectroscopy, and their self-assembly behaviors in aqueous solution were also investigated by NMR spectroscopy. Interestingly, the self-locked conformer 1, which could be regarded as a new type of [1]rotaxane, self-assembled to a novel bimolecular capsule, where its azobenzene substituent was included in both its own cavity and the counterpart's cavity, in aqueous solution and in the solid state. In contrast, by adjusting the conformation of 1 to a self-unlocked one, the resulting conformer 2 was found to self-assemble to a linear supramolecule. These studies have shown the stronger impact of the reaction condition changing in cyclodextrin's modification products and will provide a new access to control the structure of supramolecular assemblies by tuning the conformation of building blocks.     

A microwave and quantum chemical study of the conformational properties and intramolecular hydrogen bonding of 1-fluorocyclopropanecarboxylic acid

The structural and conformational properties of 1-fluorocyclopropanecarboxylic acid have been explored by microwave spectroscopy and a series of ab initio (MP2/6-311++G(d,p) level), density functional theory (B3LYP/aug-cc-pVTZ level), and G3 quantum chemical calculations. Four "stable" conformers, denoted conformers I-IV, were found in the quantum chemical calculations, three of which (conformers I -III) were predicted to be low-energy forms. Conformer I was in all the quantum chemical calculations predicted to have the lowest energy, conformer III to have the second lowest energy, and conformer II to have the third lowest energy. Conformers II and III were calculated to have relatively large dipole moments, while conformer I was predicted to have a small dipole moment. The microwave spectrum was investigated in the 18-62 GHz spectral range. The microwave spectra of conformers II and III were assigned. Conformer I was not assigned presumably because its dipole moment is comparatively small. Conformer II is stabilized by an intramolecular hydrogen bond formed between the fluorine atom and the hydrogen atom of the carboxylic acid group. Conformer III has a synperiplanar orientation for the F-C-C=O and H-O-C=O chains of atoms. Its dipole moment is: mua = 3.4(10), mub = 10.1(13), and muc = 0.0 (assumed) and mu(tot) = 10.6(14) x 10(-30) C m [3.2(4) D]. Several vibrationally excited states of the lowest torsional mode of each of II and III were also assigned. The hydrogen-bonded conformer II was found to be 2.7(2) kJ/mol less stable than III by relative intensity measurements. Absolute intensity measurements were used to show that the unassigned conformer I is the most abundant form present at a concentration of roughly 65% at room temperature. Conformer I was estimated to be ca. 5.0 kJ/mol more stable than the hydrogen-bonded rotamer (conformer II) and ca. 2.3 kJ/mol more stable than conformer III. The best agreement with the theoretical calculations is found in the MP2 calculations, which predict conformer I to be 5.1 kJ/mol more stable than III and 1.7 kJ/mol more stable than II.     

IR-induced conformer interconversion processes of glycolaldehyde in low-temperature matrices,and ab initio calculations on the energetics and vibrational frequencies of the conformers

Both IR-induced and thermal conformer interconversion processes of glycolaldehyde (CHOCH₂OH) were studied in low-temperature Ar, Kr and Xe matrices. The observed photochemical reaction induced by broad-band IR irradiation is interpreted to proceed from the lowest-energy conformer Cc which prevails after deposition to conformer Tt. In Xe and Kr the photochemical steady state (ratio [Tt]/[Cc]) depends on the matrix temperature; two conformers, Tg and Tt, seem to be in thermal equilibrium, and at elevated temperatures species Tg is enriched, and then the reverse photoprocess Tg → Cc occurs more rapidly than the competing reverse process, Tt → Cc which prevails at 13 K. Because of the thermal equilibrium the routes of the forward and reverse photoprocesses are considered to be different. A thermal reverse process, Tt → Tg → Cc, is observed at temperatures above 30 K in Xe and Kr. The role of the torsional barrier heights in determining the rates of the photoprocesses is emphasized. To aid in the interpretation of the experimental results, ab initio calculations were carried out. Geometries and energies of all conformers of glycoaldehyde as well as the geometries of the most important saddle points were fully optimized at the HF/6-31G** level, and vibrational spectra were calculated on the HF/4-31G level; the latter conformed to the experimental conformer assignment.     

The selective dealkylations: the formylations of the three easily accessible calix[4]arene conformers immobilized by propyl and isopropyl groups

Formyl groups were introduced to the para positions of the three easily accessible calix[4]arene conformers immobilized by four propyl or isopropyl groups by Duff reaction. Propyl group led to exhaustively formylated products due to the weak steric hinderance effect. While as for the isopropoxy calix[4]arenes, with the increase of steric hinderance, 1,3-alternate conformer gave exhaustively formylated product with no alkyl group dealkylating; partial cone conformer gave the tetraformylated proximal A,B-diether in 1,3-alternate conformation; and cone conformer led to triformylated derivatives accompanied by the selective dealkylations of three or two diametrical alkyl groups. The results indicated that the structures of the products were greatly influenced by the steric hinderance effect of the starting compounds.     

Formation and conformational conversion of flattened partial cone oxygen bridged calix[2]arene[2]triazines

A stepwise fragment coupling reaction starting with substituted dichlorotriazine and resorcinol derivatives gave rise to thermodynamically favored 1,3-alternate tetraoxacalix[2]arene[2]triazines and kinetically controlled flattened partial cone tetraoxacalix[2]arene[2]triazines. The flattened partial cone conformer, which was stable due to the steric effect, converted into the 1,3-alternate conformer via ether bond cleavage upon treatment with an inorganic base.     

Anomalous conformational change in 1-butyl-3-methylimidazolium tetrafluoroborate-D2O mixtures

We have investigated the effect of deuterated water on the conformational equilibrium between the gauche and trans conformers of the [bmim] cation in mixtures of water and 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF(4)]), an ionic liquid, at room temperature. A comparison of the results obtained from solutions made with H(2)O and with D(2)O highlights an anomalous conformational change in the D(2)O solution showing an extended N-shaped behavior. The gauche conformer of the [bmim] cation in D(2)O increased up to x = ~50 (D(2)O mol %); however, it decreased up to higher water concentrations of x = ~85 before again increasing drastically toward x = ~100. We provide spectroscopic evidence that the anomalous conformational dynamics of the [bmim] cation in D(2)O is directly related to the H/D exchange reaction of the C-H group at position 2 of the imidazolium ring.     

A computational study of conformational interconversions in 1,4-dithiacyclohexane (1,4-dithiane)

Ab initio molecular orbital theory with the 6-31G(d), 6-31G(d,p), 6-31+G(d), 6-31+G(d,p), 6-31+G(2d,p), 6-311G(d), 6-311G(d,p), and 6-311+G(2d,p) basis sets and density functional theory (BLYP, B3LYP, B3P86, B3PW91) have been used to locate transition states involved in the conformational interconversions of 1,4-dithiacyclohexane (1,4-dithiane) and to calculate the geometry optimized structures, relative energies, enthalpies, entropies, and free energies of the chair and twist conformers. In the chair and 1,4-twist conformers the C-Hax and C-Heq bond lengths are equal at each carbon, which suggest an absence of stereoelectronic hyperconjugative interactions involving carbon-hydrogen bonds. The 1,4-boat transition state structure was 9.53 to 10.5 kcal/mol higher in energy than the chair conformer and 4.75 to 5.82 kcal/mol higher in energy than the 1,4-twist conformer. Intrinsic reaction coordinate (IRC) calculations showed that the 1,4-boat transition state structure was the energy maximum in the interconversion of the enantiomers of the 1,4-twist conformer. The energy difference between the chair conformer and the 1,4-twist conformer was 4.85 kcal/mol and the chair-1,4-twist free energy difference (deltaG degrees (c-t)) was 4.93 kcal/mol at 298.15 K. Intrinsic reaction coordinate (IRC) calculations connected the transition state between the chair conformer and the 1,4-twist conformer. This transition state is 11.7 kcal/mol higher in energy than the chair conformer. The effects of basis sets on the 1,4-dithiane calculations and the relative energies of saturated and unsaturated six-membered dithianes and dioxanes are also discussed.     

Stabilization and rovibronic spectra of the T-shaped and linear ground-state conformers of a weakly bound rare-gas-homonuclear dihalogen complex: He...Br2

Laser-induced fluorescence spectra of Br(2) entrained in a He supersonic expansion have been recorded in the Br(2) B-X, 8-0, 12-0, and 21-0 spectral regions at varying downstream distances, and thus different temperature regimes. Features associated with transitions of the T-shaped and linear He...Br(2)(X,nu(") = 0) complexes are identified. The changes in the relative intensities of the T-shaped and linear features with cooling in the expansion indicate that the linear conformer is energetically more stable than the T-shaped conformer. A He + Br(2)(X,nu(") = 0) ab initio potential-energy surface, computed at the coupled cluster level of theory with a large, flexible basis set, is used to calculate the binding energies of the two conformers, 15.8 and 16.5 cm(-1) for the T-shaped and linear complexes, respectively. This potential and an excited-state potential [M. P. de Lara-Castells, A. A. Buchachenko, G. Delgado-Barrio, and P. Villareal, J. Chem. Phys. 120, 2182 (2004)] are used to calculate the excitation spectra of He...(79)Br(2)(X,nu(") = 0) in the Br(2) B-X, 12-0 region. The calculated spectra are used to make spectral assignments and to determine the energies of the excited-state intermolecular vibrational levels accessed in the observed transitions. Temperature-dependent laser-induced fluorescence spectra and a simple thermodynamic model [D. S. Boucher, J. P. Darr, M. D. Bradke, R. A. Loomis, and A. B. McCoy, Phys. Chem. Chem. Phys. 6, 5275 (2004)] are used to estimate that the linear conformer is 0.4(2) cm(-1) more strongly bound than the T-shaped conformer. Two-laser action spectroscopy experiments reveal that the binding energy of the linear He...(79)Br(2)(X,nu(") = 0) conformer is 17.0(8) cm(-1), and that of the T-shaped He...(79)Br(2)(X,nu(") = 0) conformer is then 16.6(8) cm(-1), in good agreement with the calculated values.     

Conformations of cationized linear oligosaccharides revealed by FTMS combined with in‐ESI H/D exchange

Previously (Kostyukevich et al. Anal Chem 2014, 86, 2595), we have reported that oligosaccharides anions are produced in the electrospray in two different conformations, which differ by the rate of gas phase hydrogen/deuterium (H/D) exchange reaction. In the present paper, we apply the in‐electrospray ionization (ESI) source H/D exchange approach for the investigation of the oligosaccharides cations formed by attaching of metal ions (Na, K) to the molecule. It was observed that the formation of different conformers can be manipulated by varying the temperature of the desolvating capillary of the ESI interphase. Separation of the conformers was performed using gas phase H/D approach. Because the conformers have different rates of the H/D exchange reaction, the deuterium distribution spectrum becomes bimodal. It was found that the conformation corresponding to the slow H/D exchange rate dominates in the spectrum when the capillary temperature is low (~200 °C), and the conformation corresponding to the fast H/D exchange rate dominates at high (~400 °C) temperatures. In the intermediate temperature region, two conformers are present simultaneously. It was also observed that large oligosaccharide requires higher temperature for the formation of another conformer. It was found that the presence of the conformers considerably depends on the solvent used for ESI and the pH. We have compared these results with the previously performed in‐ESI source H/D exchange experiments with peptides and proteins. Copyright © 2015 John Wiley & Sons, Ltd.     

Detection of oligonucleotide gas-phase conformers: H/D exchange and ion mobility as complementary techniques

Gas-phase hydrogen/deuterium exchange of small oligonucleotides (dTG, dC(6) and C(6)) with CD(3)OD was performed in the second hexapole of a Fourier transform ion-cyclotron resonance (FTICR) mass spectrometer. Ion activation experiments were conducted by accelerating the ions at the entrance of the H/D exchange cell under conditions promoting exclusively collisional isomerization. These experiments allowed us to assess the presence of several conformers, and to probe the height of the isomerization barrier separating these conformers. Ion mobility experiments were also performed. Their results were consistent with the H/D exchange data. A model accounting for the competing isomerization and H/D exchange reactions is proposed. Comparing the ion acceleration experiments for H/D exchange and for ion mobility reveals that the most compact conformer displays the fastest H/D exchange. This observation shows that H/D exchange and ion mobility provide us with complementary information because hydrogen accessibility and macromolecule compactness are not univocally associated.     

Infrared and Raman spectra, conformational stability, ab initio calculations, and vibrational assignments for methylaminothiophosphoryl difluoride

Infrared spectra (4000–50 cm⁻¹) of the vapor, amorphous and crystalline solids and Raman spectra (3600–10 cm⁻¹) of the liquid with qualitative depolarization data as well as the amorphous and crystalline solids of methylaminothiophosphoryl difluoride, CH₃N(H)P(=S)F₂, and three deuterated species, CD₃N(H)P(=S)F₂, CH₃N(D)P(=S)F₂, and CD₃N(D)P(=S)F₂, have been recorded. The spectra indicate that in the vapor, liquid and amorphous solid a small amount of a second conformer is present, whereas only one conformer remains in the low temperature crystalline phase. The near-infrared spectra of the vapor confirms the existence of two conformers in the gas phase. Asymmetric top contour simulation of the vapor shows that the trans conformer is the predominant vapor phase conformer. From a temperature study of the Raman spectrum of the liquid the enthalpy difference between the trans and near-cis conformers was determined to be 368±15 cm⁻¹ (4.41±0.2 kJ/mol), with the trans conformer being thermodynamically preferred. Ab Initio calculations with structure optimization using the 6-31G(d) and 6-311+G(d,p) basis sets at the restricted Hartree–Fock (RHF) and/or with full electron correlation by the perturbation method to second order (MP2) support the occurrence of near-trans (5° from trans) and near-cis (20° from cis) conformers. From the RHF/6-31G(d) calculation the near-trans conformer is predicted to be the more stable form by 451 cm⁻¹ (5.35 kJ/mol) and from the MP2/6-311+G(d,p) calculation by 387 cm⁻¹ (4.63 kJ/mol). All of the normal modes of the near-trans rotamer have been assigned based on infrared band contours, depolarization values and group frequencies and the assignment is supported by the normal coordinate calculation utilizing harmonic force constants from the MP2/6-31G(d) ab initio calculations.     

The strength of parallel-displaced arene-arene interactions in chloroform

[reaction: see text] Triptycene-derived compounds have been prepared to serve as conformational equilibrium reporters for direct measurements of arene-arene interactions in the parallel-displaced orientation. A series of such compounds bearing arenes with different substituents were synthesized, and the ratios of the syn and anti conformers were determined by variable-temperature NMR spectroscopy. The syn conformer allows attached arenes to interact with each other while the anti conformer does not. The free energies derived from the syn/anti ratios in chloroform range from slightly positive (0.2 kcal/mol) to considerably negative (-0.98 kcal mol) values. The interactions between the arenes bearing electron-donating groups (EDG) are either negligible or slightly repulsive, while the interactions between arenes bearing electron-withdrawing groups (EWG) are attractive. Intermediate free energy values are obtained for those compounds bearing arenes with one EDG and one EWG.     

Conformational preferences for 1,2- and 1,4-difluorocyclohexane

The conformational preference for 1,2-difluorocyclohexane has been studied experimentally via NMR spectroscopy and computationally using CCSD/6-311+G(2df,p). The results confirm our previous conclusions that the diaxial conformer of trans-1,2-difluorocyclohexane has the lower energy in the gas phase, whereas the diequatorial conformer has the lower energy in solution. SCIPCM reaction field calculations reproduce the observed solvent effects. The 1,4-difluorocyclohexanes have also been reexamined computationally.     

Structural and NMR spectroscopic investigations of chair and twist conformers of the P2Se8(2-) anion

Four new salts of the P2Se8(2-) anion have been prepared, starting from easily available reagents using different reaction strategies including reaction of the elements, oxidation of P4Se3 with alkalimetal diselenides and elemental selenium, and the use of an ionic liquid as a reaction medium. Multinuclear NMR investigations show the presence of both chair-P2Se8(2-) and twist-P2Se8(2-) in solution, with twist-P2Se8(2-) being the predominant conformer. The interconversion between the two conformers is slow on the NMR time scale. Structural investigations of the new salts by single-crystal X-ray diffraction show that chair-P2Se8(2-) is the conformer mostly found in the solid state. A first structural characterization of twist-P2Se8(2-) is reported. The bonding situation in the P2Se8(2-) anion as well as the relative stability of the chair, twist, and boat conformers was elucidated by quantum chemical calculations.     

Synthesis and NMR characterization of the cis and trans isomers of [Pt(II)(N9-adeH)2(pz)2] and X-ray crystallography of the trans isomer

The reaction of tetrapyrazine Pt(II) with adenine under basic conditions yielded two products both disubstituted by adenine and bound in all cases to the N-9 nitrogen of adenine. Crystals amenable to X-crystallographic analysis were obtained for one product which was consequently identified as trans-[Pt(II)(N9-adeH)2(pz)2](NO3)(4).H2O. The other product, though, was identified as the cis isomer based on extensive and comparative NMR structural studies whereby the two compounds were examined as both neutral and tetraprotonated species in solution. The major product of the reaction was unexpectedly the cis isomer, thus obtained in contrast to the trans effect, and the reason for this result is speculated on. Computational calculations using DFT at the B3LYP/TZVP-MARI-J level of theory provided the head-to-tail conformer as the overwhelmingly more stable species over the head-to-head conformer for both compounds whilst the trans product was found to be more stable than the cis. Thus the reaction does not follow a thermodynamic course and rather is kinetically controlled in concert with the speculated mode of reaction.     

The relevant effect of an intramolecular hydrogen bond on the conformational equilibrium of cis-3-methoxycyclohexanol compared to trans-3-methoxycyclohexanol and cis-1,3-dimethoxycyclohexane

1H NMR data show that an increase in the concentration of cis-3-methoxycyclohexanol (cis-3-MCH) shifts the conformational equilibrium from the 1aa conformer, stabilized by an intramolecular hydrogen bond (IAHB), to the 1ee conformer [X(ee) = 44% (at 0.05 molL(-1)) to 59% (at 0.40 molL(-1)), in CCl4], which forms intermolecular hydrogen bonds (IEHB), as confirmed by IR data. The percentage of 1ee conformer increases with the solvent polarity, from 33% (DeltaG(ee-aa) = 1.72 kJmol(-1)) in cyclohexane (C6D12) to 97% (DeltaG(ee-aa) = -8.41 kJmol(-1)) in DMSO. For trans-3-methoxycyclohexanol (trans-3-MCH), 1ae and 1ea conformers are almost equally present in the studied solvents, 1ae increasing from 41%, in C6D12 (DeltaG(ae-ea) = 0.84 kJmol(-1)), to 49%, in DMSO (DeltaG(ae-ea) = 0.13 kJmol(-1)). A value of 18.4 kJmol(-1) for the strength of IAHB in cis-3-MCH was obtained, from the theoretical data, through the CBS-4M method.     

Thiocyclosporins: Preparation,Solution and Crystal Structure,and Immunosuppressive Activity

The reaction of cyclosporin A (CsA) with Lawesson's reagent under different conditions yields various thiocyclosporins, in which carbonyl O-atoms and/or the hydroxy O-atom of the MeBmt residue are replaced by an S-atom. The position of the S-atom is determined by NMR spectroscopy, and the conformations of the products are studied by NMR spectroscopy and X-ray crystallography. Some of the thiocyclosporins show interesting conformational properties. Whereas one conformation strongly dominates for CsA in CDCL₃, two conformers A and B, in a ratio 58:42 are found for [¹ψ², CS–NH]CsA. Extensive NMR studies including new 2D and 3D heteronuclear techniques and restrained MD calculations using ROE effects demonstrate that the major conformer A is identical to CsA, while the minor conformer B contains an additional cis peptide bond between the Sar³ and MeLeu⁴ residues. [⁴ψ⁵, CS? NH; ⁷ψ⁸, CS–NH]CsA exhibits a conformation very similar to crystalline CsA. However, the D-Ala⁸NH, MeLeu⁶Co γ-turn H-bond is not present in this dithio analogue. Also different is the MeBmt¹side-chain conformation, the dithio conformation showing a strong MeBmt¹OH, Sar³CO H-bond. Immunosuppressive activities of thiocyclosporins are measured in IL-2 and IL-8 reporter gene assays. Their activities are discussed in relation to their conformations.     

An intramolecular substitution of hydroperoxy-endoperoxide to a bis-endoperoxide

[reaction: see text] A new and stereospecific synthesis for bis-endoperoxide has been developed starting from tetrahydronaphthalene. Photooxygenation of tetrahydronaphthalene resulted in the formation of hydroperoxy-endoperoxide. The bromination reaction of hydroperoxy-endoperoxide gave bis-endoperoxide, whose exact configuration has been determined by X-ray analysis. The lowest-energy conformer of bis-endoperoxide is the boat-chair form.     

Role of electron-driven proton-transfer processes in the excited-state deactivation of the adenine-thymine base pair

Exploratory electronic structure calculations have been performed with the CC2 (simplified singles and doubles coupled-cluster) method for two conformers of the adenine (A)-thymine (T) base pair, with emphasis on excited-state proton-transfer reactions. The Watson-Crick conformer and the most stable (in the gas-phase) conformer of the A-T base pair have been considered. The equilibrium geometries of the ground state and of the lowest excited electronic states have been determined with the MP2 (second-order M?ller-Plesset) and CC2 methods, respectively. Vertical and adiabatic excitation energies, oscillator strengths, and dipole moments of the excited states are reported. Of particular relevance for the photochemistry of the A-T base pair are optically dark (1)pipi* states of charge-transfer character. Although rather high in energy at the ground-state equilibrium geometry, these states are substantially lowered in energy by the transfer of a proton, which thus neutralizes the charge separation. A remarkable difference of the energetics of the proton-transfer reaction is predicted for the two tautomers of A-T: in the Watson-Crick conformer, but not in the most stable conformer, a sequence of conical intersections connects the UV-absorbing (1)pipi* state in a barrierless manner with the electronic ground state. These conical intersections allow a very fast deactivation of the potentially reactive excited states in the Watson-Crick conformer. The results provide evidence that the specific hydrogen-bonding pattern of the Watson-Crick conformer endows this structure with a greatly enhanced photostability. This property of the Watson-Crick conformer of A-T may have been essential for the selection of this species as carrier of genetic information in early stages of the biological evolution.     

Conformational analysis. Part 40: a theoretical and NMR investigation of the conformations of cis‐ and trans‐cyclopentane‐1,3‐diol

The conformations of cis‐ ( 1 ) and trans‐cyclopentane‐1,3‐diol ( 2 ) have been studied by ab initio (Gaussian 98) and molecular mechanics (PCMODEL) calculations and by NMR spectroscopy. The calculations gave two low‐energy conformations for ( 1 ), 1A and 1B , both with axial hydroxyl groups. Two conformations with equatorial hydroxyl groups ( 1C and 1D ) were found but with much higher energy (ca 4.0 kcal mol^?1). Five low‐energy conformers were found for 2 . Four were envelope conformations and one a half‐chair. The complete analysis of the 400 MHz ¹H NMR spectra of 1 in a variety of solvents and 2 in chloroform was performed by extensive decoupling experiments, iterative computer analysis and spectral simulation. This gave all the H,H couplings in the molecule, including in 1 a long‐range ⁴J(H,H) coupling between H‐2cis and H‐4,5cis. The ³J(H,H) couplings were used to determine the conformer populations in these molecules. This was initially achieved using the Haasnoot, de Leeuw and Altona equation. to obtain the conformer couplings. It was found that this equation was not accurate for the C·CH₂·CH₂·C fragment in these molecules and the following equation was derived for this fragment from five‐ and six‐ membered cyclic compounds in fixed conformations: (1) The conformer populations were obtained by calculating the conformer couplings which were then compared with the observed couplings. Compound 1 in benzene solution is an approximately equal mixture of conformers 1A and 1B with small (<4%) amounts of 1C and 1D . In the polar solvents acetone and acetonitrile the populations of 1A and 1B are again equal, with 20% of 1C and <2% of 1D . In 2 the major conformers are 2B and 2D with small amounts of 2C , 2E and 2A . These novel findings are considered with previous data on cyclopentanol and cis‐ and trans‐cyclopentane‐1,2‐diol and it is shown that the axial hydroxyl substituent at the fold of the envelope appears to be a major factor in determining the conformational energies of these compounds. Copyright © 2003 John Wiley & Sons, Ltd.