PMC:4264129 / 189434-198393 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/4264129","sourcedb":"PMC","sourceid":"4264129","source_url":"http://www.ncbi.nlm.nih.gov/pmc/4264129","text":"4. Concluding Remarks\nThe focus of this review has been to compare gas-phase experimental structures where intramolecular hydrogen bonds (H-bonds) have been established, to in-solution theoretical calculations where experimental data are rarely available. The concept of the chemical bond has been the subject of a continuous research since the publication of the seminal paper of Lewis [242], and even recently a new chemical bond paradigm in terms of chemical action functional was published by Putz [243]. Intramolecular hydrogen bonds were assigned to structures on the basis of the 2011 IUPAC definition. A H-bond was defined as an attractive interaction in the form of (X)H…Y, where X is an atom more electronegative than H and Y has and electron pair which can favorably interact with the generally polar H. In addition to common heteroatoms, Y includes aromatic systems, whose electron clouds can interact with a polar hydrogen in the form of an H…Y π interaction. The source of the H-bond stabilization is mainly electrostatic and has remarkable contributions from a charge transfer from the acceptor to the donor. As a result, the H-bond has a partial covalent bond character between H and Y. The X–H…Y bond angle tends to be linear. It is important that no upper limit for the H…Y distance has been defined\nThe geometric parameters change only moderately for most systems upon dissolution if the conformation remains basically unaltered. The key parameters for intramolecular H-bonds are the (H)XCCY torsional angles (Y = O, N, halogen in five-member rings or C in COOH and N in NO2 for six-member rings). This torsion angle can change remarkably upon dissolution in a solvent, leading to the separation of more than 300 pm for the X and Y atoms. In such cases, the intramolecular H-bond was considered in this review to have disrupted in solution. For intermolecular H-bonds, the XH and Y groups belong to two different molecules. An intermolecular H-bond was considered to be stable when the H…Y separation is 150–250 pm and there is a slightly bent X–H…Y moiety.\nIntramolecular H-bonds were accepted for systems where the covalent structure allows for the formation of a five-, six- and seven-member ring including the polar hydrogen. This view was taken even if no (3, −1) BCP was found for the conformer in AIM analysis. Alternatively, structures with three- and four-member intramolecular rings were not considered as hydrogen-bonded species. The carboxylic group should be especially mentioned, where the larger stability of the syn O=C–O–H conformation in unsubstituted acids was not attributed to the existence of an intramolecular O–H…O= bond, but due to the electrostatic destabilization of the anti-conformation with facing electron pairs of the two oxygens.\nResults of gas-phase experimental studies provide evidence for the existence of conformations favorable for an intramolecular H-bond with five- and six-member rings. Regarding seven-member rings, experiments indicate that the most stable conformations lack an intramolecular H-bond. Dissolution in slightly polar, non-protic organic solvents has little impact upon the gas-phase H-bond pattern. Indeed, these solvents are not competitors for forming a solute-solvent intermolecular H-bond vs. the intramolecular mode even when the solvent includes H-bond acceptor atoms such as in chlorinated methanes. Conformational equilibria of the enolic malondialdehyde could be affected, however, by a small amount of methanol in chloroform solution, where the methanol oxygen is a competitor for disrupting an intramolecular hydrogen bond. Non-protic solvents may also support the dimerization of solutes having two polar sites.\nThe theoretical challenge is the prediction of the H-bond pattern, intramolecular vs. intermolecular in aqueous (or some protic organic) solution. The survey generally shows that the structure found in the gas phase remains at least partially maintained in aqueous solution. Calculations mostly predict a shift in the conformer populations to allow for a larger population of the species with disrupted intramolecular H-bond. Appearance of the XCCY trans conformation is a clear indication for this shift. Unfortunately, in-solution experiments do not provide quantitative information regarding the composition of the total gauche fraction or details for ortho phenols with rigid XCCY skeletons where the polar hydrogen is not necessarily in an intramolecular bonding position. A remarkable exception is the group of aliphatic amino acids where studies have included the amino substituent in α, β, or γ position to the carboxylic group. All form zwitterions for which the intramolecular H-bond must then differ from its gas-phase counterpart. In contrast, the ortho-amino benzoic acid does not form a zwitterion in aqueous solution and maintains its gas-phase bonding pattern.\nThe calculated shift in the conformer population is a subtle problem. Examples show that the continuum dielectric solvent model may or may not lead to predictions in accord with the sparsely available experimental data. The basic conceptual problem is that this method, in its originally introduced version, does not account for the probably important solute-solvent intermolecular H-bond(s). Today, the supermolecule approach is widely used. It considers a small number of explicit solvent molecules surrounding the solute in a cavity carved in the dielectric solvent. Problems related to its application were discussed in detail. The main issue is that when a satisfactorily large number of solvent molecules are considered during the geometry optimization, the calculation is not practical. The convergence slows down enormously when a high-level theoretical method and a large basis set are applied. In the case of a DFT method, application of at least the aug-cc-pvtz basis set is needed for reliable estimation of relative internal free energies. The related frequency calculations then cause time-demanding calculations. An alternative for the calculation of the relative solvation free energy is the FEP method, which is also widely used with MC and MD simulations.\nPolar structures like carboxylic acids or acid-base systems may form dimeric pairs/complexes in the gas phase. Another goal in this review to survey theoretical calculations that were performed to explore whether these structures are maintained in solution and if so, what protonation state will be stable in such complexes. Comparison of four theoretical and two experimental studies that followed the acetic acid dimerization, the obtained results are diverse. Molecular dynamics calculations, even performed by using the self-consistent charge ab initio method, predict no dimerization of this acid in aqueous solution. MD, however, provides changes in energies, not in free energies upon structural changes in the solution. In contrast, when integration of the pmf from MC and MD studies is undertaken so as to account for free energy changes, the predicted dimer fraction is 37%–45%. Calculated from the experimental dimerization constant, acetic acid could be dimerized by up to 14%.\nThe general solution for all of the computational problems mentioned above probably lies in using ab initio molecular dynamics modeling. This should allow for the application of a high-level method (e.g., CCSD(T)), large basis set (aug-cc-pvtz) and flexible molecular geometry for all participants of the system. Simulations having a few hundred solvent molecules, which is necessary for a reasonable modeling of the solution, and a production phase of tens of ns are not affordable today. However, the rapidly increasing capacity of computers and ongoing production of more efficient programs will likely allow performing such calculations in the not too far future. Despite attractive features of the Car-Parrinello method [107], the required computer time is still too large for routine use of the method for in-solution calculations. Nonetheless, QM/MM [106] and self-consistent charge density-functional based tight-binding [131] methods applying at least medium-size basis set can be used even today for solving the problem addressed in the title of this review.\nIf none of these suggestions is practical for following a specific structural problem, MD is recommended for solution structure simulations provided care is taken to establish a proper parameterization of the force field. The latter is not trivial, however, for molecules with possible intramolecular vs. intermolecular H-bonds. For calculating conformer/tautomer equilibria, this author recommends the supermolecule approach in a continuum solvent for geometry optimization and relative internal free energy calculation at high theoretical level while including a satisfactorily large number of solvent molecules. Finally, in the case of a protic solvent, MC/FEP and MD/FEP methods are recommended for relative solvation free energy 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