Study of geometrical parameters in N-H...N type of hydrogen bonds

Geometrical parameters associated with N-H ... N types of hydrogen bonds have been analysed using crystal structure data on nucleic acids, amino acids and related compounds. Histograms depicting the frequency distribution of N-H ... N length (l) and H-N ... N angle (θ) have been drawn and conclusions on the favoured geometry of such bonds have been arrived at. The distribution ofl shows a pronounced maximum in the range between 2.9? and 3.0? with an overall average of 2.98 ?. The θ distribution shows a pronounced maximum for the hydrogen bond angle in the range 0°-10°, with a rapid fall-off in frequency for nonlinear hydrogen bonds. The frequency shows a cos⁶θ dependence as compared to cos²θ dependence term used earlier to predict the angular dependence of hydrogen bond potential energy in proteins and polypeptides.     

Synthesis ofcloso-3,3-(η3,η2-tricyclo[5.2.1.02,6]deca-4, 8-diene-3-yl)-1-(hydroxymethyl)-3,2,1-dicarbollylrhodium and the crystal structure of its dinier with the O-H...Rh bond

Protonation of the [closo-3,3-(⁴-C₁₀H₁₂)-1-(CH₂OH)-3,1,2-RhC₂B₉H₁₀]^– PPN⁺ (C₁₀H₁₂ — dicyclopentadiene, PPN⁺ — bis(triphenylphosphine)iminium cation) at the ethylene bond of the norbornene moiety yields the neutralcloso-3,3,3-(-C₁₀H₁₃)-1-(CH₂OH)-3,1,2-RhC₂B₉H₁₀ with an agostic C-H...Rh bond. On prolonged storage in EtOH, the latter complex is converted intocloso-3,3-(^3,2-C₁₀H₁₁)-1-(CH₂OH)-3,1,2-RhC₂B₉H₁₀ with -allylolefinic type coordination. Its crystal structure as dimeric aggregates with O-H...O and O-H...Rh bonds was determined by X-ray diffraction.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 776–778, April, 1995.     

Comparative estimation of the energies of intramolecular C-H…O,N-H…O,and O-H…O hydrogen bonds according to the QTAIM analysis and NMR spectroscopy data

The energies of intramolecular C-H…O, N-H…O, and O-H…O hydrogen bonds in model compounds are empirically estimated based on the values of the hydrogen bond induced weak-field shift of the bridging hydrogen atom signal in the ¹H NMR spectrum. It is supported by a theoretical estimation of these energies based on the electron density value at the hydrogen bond critical point calculated within the QTAIM method. Good agreement between the empirical and theoretical estimates is found, which gives evidence of their reliability. It is shown that from the standpoint of their strength the intramolecular N-H…O and O-H…O hydrogen bonds can be classified as moderate whereas the intramolecular C-H…O hydrogen bonds must be classified as very weak interactions similar in their energy significance to van der Waals interactions.     

Theoretical study of hydrogen bonding interaction in nitroxyl (HNO) dimer: interrelationship of the two N-H...O blue-shifting hydrogen bonds

The hydrogen bonding interactions of the HNO dimer have been investigated using ab initio molecular orbital and density functional theory (DFT) with the 6-311++G(2d,2p) basis set. The natural bond orbital (NBO) analysis and atom in molecules (AIM) theory were applied to understand the nature of the interactions. The interrelationship between one N-H...O hydrogen bond and the other N-H...O hydrogen bond has been established by performing partial optimizations. The dimer is stabilized by the N-H...O hydrogen bonding interactions, which lead to the contractions of N-H bonds as well as the characteristic blue-shifts of the stretching vibrational frequencies nu(N-H). The NBO analysis shows that both rehybridization and electron density redistribution contribute to the large blue-shifts of the N-H stretching frequencies. A quantitative correlations of the intermolecular distance H...O (r(H...O)) with the parameters: rho at bond critical points (BCPs), s-characters of N atoms in N-H bonds, electron densities in the sigma*(N-H), the blue-shift degrees of nu(N-H) are presented. The relationship between the difference of rho (|Deltarho|) for the one hydrogen bond compared with the other one and the difference of interaction energy (DeltaE) are also illustrated. It indicates that for r(H...O) ranging from 2.05 to 2.3528 A, with increasing r(H...O), there is the descending tendency for one rho(H...O) and the ascending tendency for the other rho(H...O). r(H...O) ranging from 2.3528 to 2.85 A, there are descending tendencies for the two rho(H...O) with increasing r(H...O). On the potential energy surface of the dimer, the smaller the difference between one rho(H...O) and the other rho(H...O) is, the more stable the structure is. As r(H...O) increases, the blue-shift degrees of nu(N-H) decrease. The cooperative descending tendencies in s-characters of two N atoms with increasing r(H...O) contribute to the decreases in blue-shift degrees of nu(N-H). Ranging from 2.05 to 2.55 A, the increase of the electron density in one sigma*(N-H) with elongating r(H...O) weakens the blue-shift degrees of nu(N-H), simultaneously, the decrease of the electron density in the other sigma*(N-H) with elongating r(H...O) strengthens the blue-shift degrees of nu(N-H). Ranging from 2.55 to 2.85 A, the cooperative ascending tendencies of the electron densities in two sigma*(N-H) with increasing r(H...O) contribute to the decreases in blue-shift degrees of nu(N-H).     

Very strong C-H...O, N-H...O, and O-H...O hydrogen bonds involving a cyclic phosphate.

Very short C-H...O, N-H...O, and O-H...O hydrogen bonds have been generated utilizing the cyclic phosphate [CH2(6-t-Bu-4-Me-C6H2O)2]P(O)OH (1). X-ray structures of (i) 1 (unsolvated, two polymorphs), 1...EtOH, and 1...MeOH, (ii) [imidazolium](+)[CH2(6-t-Bu-4-Me-C6H2O)2PO2](-)...MeOH [2], (iii) [HNC5H4-N=N-C5H4NH](2+)[(CH2(6-t-Bu-4-Me-C6H2O)2PO2)2](2-)...4CH3CN...H2O [3], (v) [K, 18-crown-6](+)[(CH2(6-t-Bu-4-Me-C6H2O)2P(O)OH)(CH2(6-t-Bu-4-Me-C6H2O)2PO2)](-)...2THF [4], (vi) 1...cytosine...MeOH [5], (vii) 1...adenine...1/2MeOH [6], and (viii) 1...S-(-)-proline [7] have been determined. The phosphate 1 in both its forms is a hydrogen-bonded dimer with a short O-H...O distance of 2.481(2) [triclinic form] or 2.507(3) A [monoclinic form]. Compound 2 has a helical structure with a very short C-H...O hydrogen bond involving an imidazolyl C-H and methanol in addition to N-H...O hydrogen bonds. A helical motif is also seen in 5. In 3, an extremely short N-H...O hydrogen bond [N...O 2.558(4) A] is observed. Compounds 6 and 7 also exhibit short N-H...O hydrogen bonds. In 1...EtOH, a 12-membered hydrogen-bonded ring motif, with one of the shortest known O-H...O hydrogen bonds [O...O 2.368(4) A], is present. 1...MeOH is a similar dimer with a very short O(-H)...O bond [2.429(3) A]. In 4, the deprotonated phosphate (anion) and the parent acid are held together by a hydrogen bond on one side and a coordinate/covalent bond to potassium on the other; the O-H...O bond is symmetrical and very strong [O...O 2.397(3) A].     

Nature of weak inter- and intramolecular interactions in crystals 3. Intermolecular P=O...C=O contact in crystals of phenyl methylisopropoxyphosphorylformate

Phenyl methylisopropoxyphosphorylformate was studied by high resolution X-ray diffraction. The chemical bonding in the vicinity of the phosphoryl group was studied by analyzing the deformation electron density, the Laplacian of the electron density, and the electron localization function. A P=O...C=O intermolecular contact was revealed and its nature was analyzed.__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 553–558, March, 2005.     

Water clusters in supramolecular inclusion hydrates. Crystal structure of decaazatricyclo[28.2.2.213.16]tetratriacontane nanohydrate

Inclusion compounds of solvate water molecules in a crystal matrix are investigated by X-ray diffraction analysis of a macrocyclic polyamine decaazatricyclo[28.2.2.2^13.16]tetratriacontane nanohydrate (I). When included in a crystal, water molecules are bonded by water-water (O-H...O) and water—macrocycle (0-H...N and N-H...O) hydrogen bonds, forming a linear cluster. Translated fromZhurnal Strukturnoi Khimii, Vol. 40, No. 5, pp. 993–1001, September–October, 1999.     

A theoretical study of keto-enol isomerism and internal rotation in the H<Subscript>2</Subscript>Salen molecule,N,N′-ethylene-bis(salicylidenimine) — schiff base

Geometric parameters, vibrational spectra, and the energies of isomerization of seven keto-enol isomeric forms of the H₂Salen molecule (N,N′-ethylene-bis(salicylidenimine)) are calculated using electron density functional theory (DFT/B3LYP) and correlation consistent valence triple-zeta Gaussian basis sets (cc-pvtz). The isomer with two enol groups (EE₁) and C ₂ symmetry configuration is most energetically favorable. Calculations of the keto-enol equilibrium show that at T ≥ 250 K the H₂Salen gas phase is a mixture of four conformers (rotamers of the main isomer EE₁). The contribution of other isomers does not exceed a few percent. The NBO analysis reveals that the system of π-conjugated bonds involves not only the atoms of the benzene moiety, but also the O, C, and N atoms nearest to the benzene ring. The energy stabilization of the isomer EE₁ is shown to be due to the presence of two strong intramolecular N...H hydrogen bonds. Intramolecular N...H and O...H hydrogen bonds are observed in all other isomers. The bathochromic shift of O-H and N-H vibrational frequencies, caused by the effect of hydrogen bonds, is 520–790 cm⁻¹.     

O-H ... O(S) hydrogen bonds in 2-hydroxy(thio)benzamides. Survey of spectroscopic and structural data

Summary From a survey of spectroscopic and structural data of six corresponding 2-hydroxybenzamides and 2-hydroxythiobenzamides (amide, N-methylamide, N,N-dimethylamide, piperidide, morpholide, 2,6-dimethylpiperidide) remarkable similarities between O(N)-H ... O and O(N)-H ... S hydrogen-bonds are obtained, concerning both, hydrogen-bond patterns and hydrogen-bond strengths. In dilute solution the OH groups of all compounds are intramolecularly associated to the (thio)carbonyl O (S) atoms with distinctly larger hydrogen-bond strengths for primary and secondary amides [ (O-H)=2950–3020 cm^–1, (OH)=12.16–11.99 ppm] and thioamides [ (O-H)=2960–3000 cm^–1, (OH)=11.65–11.13 ppm], than for tertiary amides [ (O-H)=3200–3250 cm^–1, (OH)=9.95–8.95 ppm] and thioamides [ (O-H)=3245–3330 cm^–1, (OH)=8.09–7.06 ppm]. In the solid state, the OH groups of the primary and secondary (thio)amides are also engaged in rather strong intramolecular O-H ... O=C [O ... O=2.51 Å, (O-H)=2700–2750 cm^–1] and O-H ... S=C [O ... S=2.90–2.94 Å, (O-H)=2700–2840 cm^–1] hydrogen-bonds; thetrans-NH groups of the primary (thio)amides and the NH groups of the secondary (thio)amides connect the molecules to N-H ... O-H [N ... O=2.93–3.10 Å, (N-H)=3319–3407 cm^–1] hydrogen-bonded chains; the remainingcis-NH groups of the primary (thio)amides give rise to eight-membered cyclic dimers via N-H ... O=C [N ... O=2.93 Å, (N-H)=3226 cm^–1] and N-H ... S=C [N ... S=3.46–3.47 Å, (N-H)=3233–3277 cm^–1] hydrogen-bonds. Contrary, the OH groups of the tertiary (thio)amides are intermolecular associated in the solid state and link the molecules to O-H ... O=C [O ... O=2.63–2.75 Å, (O-H)=3075–3135 cm^–1] and O-H ... S=C [O ... S=3.18–3.26 Å, (O-H)=3130–3190 cm^–1] hydrogen-bonded chains.

---

O-H ... O(S)-Wasserstoffbrückenbindungen in 2-Hydroxy(thio)benzamiden. Ein Überblick über spektroskopische und strukturelle Daten

Zusammenfassung Aus einer Zusammenstellung von spektroskopischen und strukturellen Daten von sechs entsprechenden 2-Hydroxybenzamiden und 2-Hydroxythiobenzamiden (Amid, N-Methylamid, N,N-Dimethylamid, Piperidid, Morpholid, 2,6-Dimethylpiperidid) ergeben sich bemerkenswerte Analogien zwischen O(N)-H ... O und O(N)-H ... S H-Brücken, die sowohl die H-Brücken-Muster als auch die H-Brücken-Stärken betreffen. In verdünnter Lösung sind die OH-Gruppen aller Verbindungen intramolekular mit den O(S)-Atomen der (Thio)Carbonylgruppen assoziiert, wobei die H-Brücken bei den primären und sekundären Amiden [ (O-H)=2950–3020 cm^–1, (OH)=12.16–11.99 ppm] und Thioamiden [ (O-H)=2960–3060 cm^–1, (OH)=11.65–11.13 ppm] deutlich stärker sind, als bei den tertiären Amiden [ (O-H)=3200–3250 cm^–1, (OH)=9.95–8.95 ppm] und Thioamiden [ (O-H)=3245–3330 cm^–1, (OH)=8.09–7.06 ppm]. Im Festkörper weisen die primären und sekundären (Thio)Amide ebenfalls sehr starke intramolekulare O-H ... O=C [O ... O=2.51 Å, (O-H)=2700–2750 cm^–1] und O-H ... S=C [O ... S=2.90–2.94 Å, (O-H)=2700–2840 cm^–1] H-Brücken auf; dietrans-NH-Gruppen der primären (Thio)Amide und die NH-Gruppen der sekundären (Thio)Amide verknüpfen die Moleküle über N-H ... O-H H-Brücken [N ... O=2.93–3.10 Å, (N-H)=3318–3407 cm^–1] zu Ketten; die verbleibendencis-NH-Gruppen der primären (Thio)Amide bilden zyklische, über N-H ... O=C [N ... O=2.93 Å, (N-H)=3226 cm^–1] und N-H ... S=C [N ... S=3.46–3.47 Å, (N-H)=3233–3277 cm^–1] H-Brücken gebundene, 8-Ring-Dimere. Im Gegensatz dazu sind die OH-Gruppen der tertiären (Thio)Amide im Festkörper intermolekular assoziiert und verknüpfen die Moleküle über O-H ... O=C [O ... O=2.63–2.75 Å, (O-H)=3075–3135 cm^–1] und O-H ... S=C [O ... S=3.18–3.26 Å, (O-H)=3130–3190 cm^–1] H-Brücken zu Ketten.

     

Crystal and molecular structure of 1,1-quasigermatranediol-1,1-dihydroxy-2,8-dioxa-5-azagermocane

By X-ray diffraction the crystal and molecular structure of quasigermatranediol (HO)₂Ge(OCH₂CH₂)₂NH at 155 K is determined. By quantum chemical method using second-order Møller-Plesset perturbation theory (MP2) and a split-valence 6-311++G(d,p) basis set with polarization and diffuse functions for all types of atoms, the structural parameters of this molecule are calculated. In the crystal, the quasigermatranediol molecules are arranged in columns due to O-H...O and N-H...O hydrogen bonds of medium strength. The columns are linked together via weak O-H...O and N-H...O hydrogen bonds. By calorimetry, the phase transition in a crystal of quasigermatranediol at 150–145 K is revealed.     

Kristallstruktur von N,N,N′,N′-Tetraisopropyl-p-phenylen-diammonium-dichlorid und-bis(tetrachloroaluminat)

Summary Protonation of the sterically overcrowded N,N,N,N-tetraisopropyl-p-phenylenediamine leads to a significant shortening of the C-N bond lengths of 7 pm as well as to a widening of the phenyl ipso-angle to 122°. All structural changes can be attributed to the twisted diisopropylammonium substituents and their electron acceptor properties.

     

Intramolecular H-bonds: DFT and QTAIM studies on 3-(aminomethylene)pyran-2,4-dione and its derivatives

Intramolecular N-H...O hydrogen bonds in 3-(aminomethylene)pyran-2,4-dione and its simple derivatives (F, Li, and BeH substituents) were analyzed theoretically. The systems were optimized at the B3LYP/6-311++G(d,p) level of approximation. For some fluorine derivatives the corresponding tautomers with O-H...N intramolecular H-bonds were investigated, and for such pairs of tautomers, the calculations on transition states of the N-H...O <--> N...H-O proton-transfer reaction were carried out. The geometrical and energetic parameters for these species were characterized. The topological parameters derived from Bader theory were also analyzed; these are characteristics of H-bond critical points and also of ring critical points. Besides N-H...O and O-H...N intramolecular hydrogen bonds, there are the other intramolecular interactions, mostly ionic such as Be(+delta)...(-delta)O, Li(+delta)...(-delta)O, and Li(+delta)...(-delta)F. The F...O interactions also exist for some of species investigated. They may be classified as energetically stabilizing ones since the corresponding bond paths and critical points exist. The numerous correlations and dependencies between geometrical, topological, and energetic parameters were detected and described.     

Nature of weak inter- and intramolecular interactions in crystals. 1. The F...O and F...H contacts in the crystal of 2-trifluoroacetyl-5-trifluoromethylpyrrole

The topological analysis of the electron density distribution in the crystal of 2-trifluoroacetyl-5-trifluoromethylpyrrole revealed that the F...H and F...O intermolecular contacts correspond to attractive interactions. The energies of these interactions were estimated from the experimental data and it was shown that these contacts are similar to the C—H...O contacts. Analysis of the deformation electron density revealed that the F...O contacts correspond to transfer of the lone electron pair of a fluorine atom to the antibonding -orbital of the C=O bond.     

4-hydroxy-2H-1,2-benzothiazine-3-carbohydrazide 1,1-dioxide-oxalohydrazide (1:1): X-ray structure and DFT calculations

The title compound, 4-hydroxy-2H-1,2-benzothiazine-3-carbohydrazide 1,1-dioxide-oxalohydrazide (1:1), is determined using X-ray diffraction techniques and the molecular structure is also optimized at the B3LYP/6-31G(d,p) level using density functional theory (DFT). The asymmetric unit consists of four independent molecules. The oxalohydrazide molecules have the centre of symmetry at the mid-point of the central C-C bond. Each thiazine ring adopts a half-chair conformation. Intermolecular C-H...O, N-H...O and N-H...N hydrogen bonds produce R ₂ ² (10), R ₂ ² (13), R ₃ ³ (12) and R ₃ ³ (15) rings, which lead to one-dimensional polymeric chains. An extensive three-dimensional supramolecular network of N-H...N, N-H...O, C-H...O and O-H...O hydrogen bonds is responsible for crystal structure stabilization.     

Structures and rearrangement reactions of 4-aminophenol(H2O)1+ and 3-aminophenol(H2O)1+ clusters

In this paper the structures of 4-aminophenol(H2O)1+ and 3-aminophenol(H2O)1+ clusters are investigated in molecular beam experiments by different IR/UV-double resonance techniques as well as the mass analyzed threshold ionization spectroscopy yielding both inter- and intramolecular vibrations of the ionic and neutral species. Possible structures are extensively calculated at the level of density functional theory (DFT) or at the ab initio level of theory. From the experimental and theoretical investigations it can be concluded that in the case of 4-aminophenol(H2O)1 one O-H...O hydrogen-bonded structure exists in the neutral cluster but two structures containing either an O-H...O or a N-H...O hydrogen-bonded arrangement are observed in the spectra of the ionic species. This observation is a result of an intramolecular rearrangement reaction within the ion which can only take place if high excess energies are used. A reaction path via the CH bonds is calculated and explains the experimental observations. In the case of 3-aminophenol(H2O)1+ only one O-H...O bound structure is observed both in the neutral and ionic species. Ab initio and DFT calculations show that due to geometrical and energetical reasons a rearrangement cannot be observed in the 3-aminophenol(H2O)1+ cluster ion.     

Structural features and N-H…O and O-H…O hydrogen-bonded supramolecular frameworks in 2-methylanilinium hydrogen DL-malate hydrate, 4-methoxyanilinium and 4-methylanilinium hydrogen DL-malate salts

In the crystal structure of 2-methylanilinium hydrogen DL-malate hydrate (I), an additional water molecule is present in asymmetric unit. In the crystal structures of 4-methoxyanilinium hydrogen DL-malate (II) and 4-methylanilinium hydrogen DL-malate (III), the hydrogen malate anions exhibit configurational disorder with major component occupy S-configuration and minor component occupy R-configuration provided both (II) and (III) are prepared from a racemic mixture of DL-malic acid. In crystal structures of compounds (I)–(III), the hydrogen malate anions and anilinium cations from O-H…O and N-H…O hydrogen bonds which exhibit interesting supramolecular frameworks. In compound (I), the N-H…O and O-H…O hydrogen-bonded anionic-cationic framework form two-dimensional hydrophilic and hydrophobic layers in which the lattice water molecules are embedded in hydrophilic layers. However, in crystal structures of (II) and (III), the hydrogen DL-malate anions form two-dimensional anionic substructure through O-H…O hydrogen bond, in which the anilinium cations are anchored through N-H…O hydrogen bonds.

     

Facile chemoselective rhodium carbenoid N-H insertion reactions: synthesis of 3-arylamino- or 3-heteroarylpiperidin-2-ones

Rhodium(II) acetate catalyzed reactions of various substituted 3-diazopiperidin-2-ones with a range of aromatic amines, indoles, and benzotriazole yield exclusively the corresponding N-H insertion products despite competing C-H or O-H insertions. This strategy provides an example of a facile chemoselective N-H insertion reaction delivering a library of 3-arylamino and 3-heteroarylpiperidin-2-one derivatives in high yields.     

Crystal structure of bromoalkyl derivatives of 6-methyl-uracil and isocyanuric acid

Single crystal XRD is used to study the crystal structure of 1-(4-bromobutyl)-3,6-dimethyluracil and 1,3-dimethyl-5-(5-bromopentyl)-isocyanurate in comparison with structurally similar compounds studied previously. It is shown that unlike macrocyclic compound, for which the crystal structure is determined by the presence of the stacking effect, in the crystals of their artificial precursors stacking interactions are not observed. For 1-(4-bromobutyl)-3,6-dimethyluracil, C-H...O interactions and C=O...Br interactions for 1,3-dimethyl-5-(5-bromopentyl)-isocyanurate are found. Original Russian Text Copyright ? 2009 by Yu. K. Voronina, L. F. Saifina, E. S. Romanova, O. A. Lodochnikova, and I. A. Litvinov __________ Translated from Zhurnal Strukturnoi Khimii, Vol. 50, No. 3, pp. 608–611, May–June, 2009.     

Modeling competitive interactions in proteins: vibrational spectroscopy of M+(n-methylacetamide)1(H2O)n=0-3, M=Na and K, in the 3 microm region

To properly understand the preferred structures and biological properties of proteins, it is important to understand how they are influenced by their immediate environment. Competitive intrapeptide, peptide...water, ion...water, and ion...peptide interactions, such as hydrogen bonding, play a key role in determining the structures, properties, and functionality of proteins. The primary types of hydrogen bonding involving proteins are intramolecular amide...amide (N-H...O=C) and intermolecular amide...water (O-H...O=C and H-O...H-N). n-Methylacetamide (NMA) is a convenient model for investigating these competitive interactions. An analysis of the IR photodissociation (IRPD) spectra of M+(n-methylacetamide)1(H2O)n=0-3 (M=Na and K) in the O-H and N-H spectral regions is presented. Ab initio calculations (MP2/cc-pVDZ) are used as a guide in identifying both the type and location of hydrogen bonds present. In larger clusters, where several structural isomers may be present in the molecular beam, ab initio calculations are also used to suggest assignments for the observed spectral features. The results presented offer insight to the nature of ion...NMA interactions in an aqueous environment and reveal how different ion...ligand pairwise interactions direct the extent of water...water and water...NMA hydrogen bonding observed.     

Liquid chromatographic studies on the aqueous solution conformation of substituted benzamide drug models

The aqueous solution conformation of a series of model benzamides related to the orthopramide dopamine receptor antagonists is evaluated by reversed-phase liquid chromatography (LC). The structure-retention relationship studies demonstrate the existence of an intramolecular hydrogen bond formed in aqueous solution for these compounds. The six-membered pseudoring formed by the association of the amide N-H and the oxygen of the 2-methoxy group (N-H...O) produces enhanced reversed-phase retention (increased capacity factors, k') relative to the 3- and 4-isomers. Deletion of either the acceptor oxygen or the donor N-H results in decreased C18 retention of the 2-isomer relative to the 3- and 4-isomers. These structure-retention relationship studies reveal the value of reversed-phase LC methods for evaluation of the aqueous solution conformation of the orthopramide-type compounds. Further studies show that N-substituted 2-hydroxybenzamides are intramolecularly associated in aqueous solution through either N-H...O or O-H...O six-membered rings. The 6-methoxysalicylamides are believed to be stabilized through O-H to carbonyl oxygen bonding in addition to the N-H...O pseudoring. For the 2,6-dimethoxybenzamides, steric factors prevent methoxy-amide coplanarity, thus no intramolecular hydrogen bond is formed. The result is a dramatic decrease in retention for the 2,6-isomer relative to the other positional isomers. These studies suggest that remoxipride and related 2,6-dimethoxybenzamides cannot form the six-membered pseudoring believed to be topographically equivalent to the aromatic ring in dopamine.