Amide Dimers Research Articles

N-(2-Aminophenyl)maleamic acid

The title compound [also called (Z)-3-(2-amino­phenyl­carbamo­yl)propenoic acid], C10H10N2O3, is a non-planar amidated maleic acid derivative, with the mean planes through the 2-amino­phenyl and maleamic acid groups inclined at an angle of 43.08 (10)°. Symmetry-related mol­ecules are linked by inter­molecular N—H⋯N hydrogen bonds, forming centrosymmetric amine–amide dimers. The dimers are linked by N—H⋯O and C—H⋯O hydrogen bonds and weak N—H⋯π and π–π inter­actions [C-to-centroid distance 3.510 (3) Å] into a three-dimensional network.

Amide−N-Oxide Heterosynthon and Amide Dimer Homosynthon in Cocrystals of Carboxamide Drugs and Pyridine N-Oxides

The carboxamide-pyridine N-oxide heterosynthon is sustained by syn(amide)N-H...O-(oxide) hydrogen bond and auxiliary (N-oxide)C-H...O(amide) interaction (Reddy, L. S.; Babu, N. J.; Nangia, A. Chem. Commun. 2006, 1369). We evaluate the scope and utility of this heterosynthon in amide-containing molecules and drugs (active pharmaceutical ingredients, APIs) with pyridine N-oxide cocrystal former molecules (CCFs). Out of 10 cocrystals in this study and 7 complexes from previous work, amide-N-oxide heterosynthon is present in 12 structures and amide dimer homosynthon occurs in 5 structures. The amide dimer is favored over amide-N-oxide synthon in cocrystals when there is competition from another H-bonding functional group, e.g., 4-hydroxybenzamide, or because of steric factors, as in carbamazepine API. The molecular organization in carbamazepine.quinoxaline N,N'-dioxide 1:1 cocrystal structure is directed by amide homodimer and anti(amide)N-H...O-(oxide) hydrogen bond. Its X-ray crystal structure matches with the third lowest energy frame calculated in Polymorph Predictor (Cerius(2), COMPASS force field). Apart from generating new and diverse supramolecular structures, hydration is controlled in one substance. 4-Picoline N-oxide deliquesces within a day, but its cocrystal with barbital does not absorb moisture at 50% RH and 30 degrees C up to four weeks. Amide-N-oxide heterosynthon has potential utility in both amide and N-oxide type drug molecules with complementary CCFs. Its occurrence probability in the Cambridge Structural Database is 87% among 27 structures without competing acceptors and 78% in 41 structures containing OH, NH, H(2)O functional groups.

How robust is the hydrogen-bonded amide ‘ladder’ motif?

The well-known hydrogen-bonded ladder displayed by amides in the solid state, is readily disrupted and reduced to an R22(8) motif if a competitive hydrogen-bond acceptor is incorporated in the molecular structure of the amide. When a weaker hydrogen-bond acceptor (i.e. –NO2, –CN, –Cl, –Br) is present, the ladder persists in about every other case, whereas if a stronger hydrogen-bond acceptor is introduced (such as a N-heterocycle), the ladder is very unlikely to appear. If a strong hydrogen-bond acceptor is present, the amide⋯amide dimer ‘survives’ a little over 50% of the time. This conclusion is based upon the synthesis and structural characterization of six pyrazole-decorated benzamides in addition to an examination of relevant data from the CSD. The anti hydrogen atom of the amide moiety is much more likely to engage in an N–H⋯N(heterocycle) hydrogen bond instead of an N–H⋯OC (amide) interaction.

Computational investigations of the influence of polymorphism on the lattice dynamics of molecular organic crystals

The teraHertz range (60 GHz 4 THz = 2-130 cm) is a relatively unexplored, but information-rich part of the vibrational spectrum of molecular crystals. The motions in this frequency range are at lower energies than most of the internal vibrations ofmolecules (e.g., bond stretching and angle bending), but correspond instead to translations and librations of molecules. Thus, spectroscopic and computational investigations of this frequency range are a source of information on the intermolecular interactions in molecular crystals. Lattice dynamics calculations are being developed within the crystal structure modelling program DMAREL[1-2], for the use of elaborate model intermolecular potentials. Such calculations have been performed to characterise the measured teraHertz spectra of several molecular organic crystals, correlating regions of the spectra to distortions of certain intermolecular interactions. One of the systems studied is the polymorphic pharmaceuticalmolecule carbamazepine, whose basic hydrogen bonding amide dimers remains unchanged between polymorphs (Figure).

Correlation between the 6Li,15N Coupling Constant and the Coordination Number at Lithium

The 6Li,15N coupling constants of lithium amide dimers and their mixed complexes with n-butyllithium, formed from five different chiral amines derived from (S)-[15N]phenylalanine, were determined in diethyl ether (Et2O), tetrahydrofuran (THF) and toluene. Results of NMR spectroscopy studies of these complexes show a clear difference in 6Li,15N coupling constants between di-, tri- and tetracoordinated lithium atoms. The lithium amide dimers with a chelating ether group exhibit 6Li,15N coupling constants of approximately 3.8 and approximately 5.5 Hz for the tetracoordinated and tricoordinated lithium atoms, respectively. The lithium amide dimers with a chelating thioether group show distinctly larger 6Li,15N coupling constants of approximately 4.4 Hz for the tetracoordinated lithium atoms, and the tricoordinated lithium atoms have smaller 6Li,15N coupling constants, approximately 4.9 Hz, than their ether analogues. In diethyl ether and tetrahydrofuran, mixed dimeric complexes between the lithium amides and n-butyllithium are formed. The tetracoordinated lithium atoms of these complexes have 6Li,15N coupling constants of approximately 4.0 Hz, and the 6Li,15N coupling constants of the tricoordinated lithium atoms differ somewhat, depending on whether the chelating group is an ether or a thioether; approximately 5.1 and approximately 4.6 Hz, respectively. In toluene, mixed trimeric complexes are formed from two lithium amide moieties and one n-butyllithium. In these trimers, two lithium atoms are tricoordinated with 6Li,15N coupling constants of approximately 4.6 Hz and one lithium is dicoordinated with 6Li,15N coupling constants of approximately 6.5 Hz.

Engineering the weak N–H⋯π hydrogen bond in 4-tritylbenzamide host and controlling the interaction through guest selection

The title amide host 1 crystallizes in the wheel-and-axle framework via amide N–H⋯O dimer and includes several aromatic and aliphatic guest molecules in cavities of 40 Å2 size between supramolecular axles. Bulky triphenylmethyl groups make it impossible for the second NH donor to engage in strong hydrogen bonding and this promotes a weak intermolecular N–H⋯π interaction in inclusion adducts of aromatic and hydrophobic guests (structure type 1, guest = xylenes, chloro/bromo-toluene). On the other hand, the N–H⋯π interaction is absent for guests with CO groups because of stronger N–H⋯Oguest hydrogen bonding (type 2, guest = EtOAc, MeNO2). Crystal structures of both types are virtually identical except for the rotation of CONH2 group that transforms the N–H⋯π interaction to the N–H⋯O hydrogen bond. In addition to controlling the occurrence of the weak N–H⋯π hydrogen bond through host⋯guest recognition, a third structure type with N–H⋯Ohost and N–H⋯π hydrogen bonds is present in the anisole adduct. Amide group conformations, strong and weak hydrogen bonds, and close packing of aromatic residues determine the three structure types of composition 1·(guest)0.5 in space group P. The CH2Cl2 solvate, 1·(CH2Cl2)1.5, has a different crystal packing in space group C2/c with guest molecules included in channels between amide dimers and also between Ph3C groups. The design and control of the weak N–H⋯π hydrogen bond are shown for the first time in a family of isomorphous crystal structures. Infrared spectroscopy and variable temperature X-ray diffraction are consistent with the hydrogen bond nature of the N–H⋯π interaction. Differential scanning calorimetry and thermal gravimetric analysis confirm the functional behavior of inclusion host 1 and show differences in the release of CH2Cl2 molecules from the two types of channels. Crystal latttice energies follow the order structure type 3 < type 2 < type 1 in the range of −90 to −76 kcal mol−1 per host molecule.

Crystal engineering with hydrogen bonds and halogen bonds

Molecular tapes mediated via strong O–H⋯N hydrogen bonds and weak C–I⋯O interactions are present in complexes of 4-nitrobenzoic acid·4-iodopyridine and 3,5-dinitrobenzoic acid·4-iodopyridine. Crystal structure of 4-nitrobenzamide·4-iodobenzamide has amide dimer tape and iodo⋯nitro interaction in orthogonal directions. There is good structural insulation in the hydrogen bonding and halogen bonding domains in these crystal structures. However, the less polarizable bromine and chlorine atoms show cross-pairing interactions that are less predictable. These preliminary results show that both carboxylic acid⋯pyridine and iodo⋯nitro heterosynthons may be simultaneously exploited for crystal design.

Vibrational Frequencies of Amides and Amide Dimers: The Assessment of PW91XC Functional

PW91XC functional has recently been assessed for the interaction energies of selected dimers in which the nonbonded interactions play a critical role. In this study, we assess the PW91XC functional with the 6-31+G* basis set for the vibrational spectra of amide and amide dimers. The set of molecules chosen consists of (a) the monomeric amides: formamide, acetamide, cis-NMF, trans-NMF, N,N-DMF, cis-NMA, trans-NMA, (b) the covalent dipeptides N-acetyl−glycine-N‘-methylamide in C7eq and C5 conformations and the C7ax, C7eq, C5ext, β2, αp conformers of N-acetyl-l-alanine-N‘-methylamide, (c) the dimers cis-NMA cyclic dimer, two conformations of trans-NMA dimer and four conformations of formamide dimer. This set has been also used for the assessment of the EDF1 functional for the prediction of vibrational spectra. Comparison of PW91XC/6-31+G* results with EDF1, B3LYP, and MP2 values with the same basis set accentuate PW91XC as the best performing functional for amide I and II modes while for amide III mode EDF1 performs better. Overall, PW91XC has the better performance with EDF1 following close. We propose that PW91 may be used for the study of proteins and polypeptidic chains.

Study on the stevioside analogues of steviolbioside, steviol, and isosteviol 19-alkyl amide dimers: synthesis and cytotoxic and antibacterial activity.

A new group of steviolbioside amide dimers 2a-g, derivatives 2h-i and their related steviol and isosteviol amide dimers 3a and 4a were prepared by reacting aliphatic alkylamine and alkyldiamines with PyBOP and DIEA. The synthesized compounds had cytotoxic effects on cancer and human embryonic lung cells. Compounds 3a, 4a, 2b and 2h were cytotoxic to cancer cells and to a lesser extent to human embryo lung cells. Compounds 2f, 2g and 4 of this series had favorable antibacterial effects, and were superior to penicillin G at inhibiting growth of Bacillus subtilis (BCRC 10029). The cytotoxicity and antibacterial effects may depend on the dimerization and derivative moieties in relation to the respective aglycons.

Heteromeric intermolecular interactions as synthetic tools for the formation of binary co-crystals

The crystal structure of 4-nitrobenzamide pyrazinecarboxamide (1 ∶ 1) contains two homomeric amide⋯amide dimers, which is in sharp contrast with the structural motifs displayed by the vast majority of binary co-crystals (illustrated here with five new examples), where the driving force for the supramolecular assembly is one or more strong heteromeric intermolecular interactions.

Molecular Complexes of Homologous Alkanedicarboxylic Acids with Isonicotinamide: X-ray Crystal Structures, Hydrogen Bond Synthons, and Melting Point Alternation

Crystallization of α,ω-alkanedicarboxylic acids (HOOC−(CH2)n-2−COOH, n = 2−6) with isonicotinamide (IN) is carried out in 1:2 and 1:1 stoichiometry. Five cocrystals of (diacid)·(IN)2 composition (diacid = oxalic acid, malonic acid, succinic acid, glutaric acid, and adipic acid) are characterized by X-ray diffraction at 153(2) K. Tapes of acid−pyridine O−H···N and amide−amide N−H···O hydrogen bond synthons stabilize these five crystal structures as predicted by the hierarchic model: the best donor (COOH) and best acceptor group (pyridine N) hydrogen bond as acid−pyridine and the second best donor−acceptor group (CONH2) aggregates as an amide dimer. Glutaric acid and adipic acid cocrystallize in 1:1 stoichiometry also, (diacid)·(IN), with acid−pyridine and acid−amide hydrogen bonds. Synthon energy calculations (ΔEsynthon, RHF/6-31G**) explain the observed hydrogen bond preferences in 1:2 (five examples) and 1:1 (two examples) cocrystals. The acid−pyridine hydrogen bond is favored over the acid−amide dimer ...

Supramolecular synthons in phenol–isonicotinamide adducts

Molecular complexes of four phenols (hydroquinone, resorcinol, phloroglucinol and 4-hydroxybenzoic acid) with isonicotinamide are characterized by X-ray diffraction. (Hydroquinone)0.5·(isonicotinamide) 1 and (resorcinol)·(isonicotinamide)22 have tapes of O–H⋯N and amide N–H⋯O dimer synthons. In (phloroglucinol)·(isonicotinamide)2·(H2O)23, six component self-assembly results in stacked dimers with four O–H⋯N and four amide N–H⋯O hydrogen bonds and the third phenol OH aggregates with two water molecules in a supramolecular chair cyclohexane array. Phenol⋯pyridine and amide N–H⋯O dimers are robust synthons in 1–3 for the self-assembly of 0D discrete aggregates and infinite 1D chains. Hydrogen bonding of amide dimers via N–H⋯Ophenol/water is ascribed to cooperative effects. The crystal structure of (4-hydroxybenzoic acid)·(isonicotinamide) 4 establishes the robustness of phenol⋯pyridine hydrogen bonding in the presence of carboxylic acid groups. Molecular components in 4 are arranged as zigzag tapes of O–H⋯N hydrogen bonds and acid⋯amide heterodimers. Supramolecular synthesis with phenol–isonicotinamide adducts expands the versatility of isonicotinamide as a co-crystallizing agent in crystal engineering.

Ligand exchange reactions of proton bound dimers of carboxamides models for protonated proteins

The kinetics of the ligand exchange reaction of the proton bound homodimer of primary amides propionamide (PPA) and pivalamide (PVA), of the tertiary amide N, N-dimethylformamide (DMF), and of the mixed proton bound heterodimer of DMF with n-propyl amine using 14 reactants were investigated by FT-ICR spectrometry. The proton bound dimers of the amides undergo sequential exchange of both ligands if a more basic amide or another strongly polar reactant is used. With amines and other reactants of small polarity the exchange of only one amide ligand is observed. The proton bound heterodimer of DMF with n-propyl amine exhibits role specificity for the two different ligands: the DMF ligand is selectively exchanged by polar reactants while the n-propyl amine is selectively exchanged by a more basic amine. This behavior is understood by a “solvation model” for the structure of such heterodimers. The reaction efficiency of an exothermic ligand exchange by a polar reactant is always large. This is explained by a profound electrostatic activation of the initial encounter complex which drives the exchange reaction. Exothermic ligand exchanges of the proton bound dimers of primary amides by amines are moderately efficient, while the same exchanges of the proton bound dimer of the tertiary DMF are slow and inefficient processes. This different behavior is explained by different mechanisms of the ligand exchange. In the case of dimers of primary amides the incoming amine is initially bonded to an acidic H atom of the amino group of the amide, and the exchange proceeds by a proton shift via a relay mechanism, while in the case of dimers of tertiary amides the exchanging amine has to approach the proton of the proton bridge directly in a perpendicular mode. This mechanism explains the severe steric hindrance observed for the ligand exchanges. The significance of these results for the reaction of protonated proteins in the gas phase is briefly discussed.

Density Functional Theory Vibrational Frequencies of Amides and Amide Dimers

Infrared spectra of amides and polypeptides can provide detailed information on conformation. An understanding of the amide group in model compounds is a vital step toward a deeper insight into the vibrational spectra of proteins. We show that in contrast to MP2 and the popular B3LYP functional, which overestimate amide I frequencies by 20−80 cm-1, the recently developed empirical density functional, EDF1, yields unscaled harmonic vibrational frequencies of monoamides in close agreement with experimental data, even using the relatively small 6-31+G* basis set. New calculations on several hydrogen-bonded amide dimers and the experimental data available for these dimers also support the conclusion that EDF1 yields frequencies in better agreement with experiment than MP2 or B3LYP. We present calculated minimum-energy structures and vibrational spectra of N-acetylglycine-N‘-methylamide and N-acetyl-l-alanine-N‘-methylamide at the EDF1/6-31+G* and B3LYP/6-31+G* levels.

Chelate Ring Size Controls the Formation of Mixed Complexes Involving Butyllithium and Sodium Amides

NMR spectroscopic studies on the sodium and lithium adducts of four tridentate amines, 1−4, are reported. The lithium and sodium amides of amines 1 and 2 can only form five-membered ring chelates with the alkali metals. The lithium and sodium amides of amines 3 and 4 can form both five- and six-membered chelates with the alkali metals. It is shown that addition of butyllithium (n-BuLi) to sodium amide dimers Na-3 and Na-4 in THF solution results in the formation of mixed 1:1 dimer complexes between n-BuLi and sodium amide. No such mixed complexes containing one lithium and one sodium are found from the amines 1 and 2. On the basis of 6Li,1H HOESY experiments it is found that lithium prefers the five-membered chelate while sodium prefers the six-membered chelate in these mixed complexes.

An engineered N–H⋯π interaction: crystal structure of 4-tritylbenzamide–p-xylene (2∶1)

The title host–guest crystal structure is designed to contain an N–H⋯π interaction. The crystal structure is stabilised by an N–H⋯O hydrogen-bonded amide dimer and weak N–H⋯π and C–H⋯O hydrogen bonds. The phenyl rings of triphenylmethyl groups interact via the edge-to-face herringbone T-motif.

Homo- and heterocomplexes of sodium and lithium amides--structures in solution.

Addition of the chiral amine (S)-methyl(1-phenyl-2-pyrrolidinoethyl)[15N]amine (1) to a large excess of nBuNa resulted in the formation of a mixed sodium amide/nBuNa complex. This is the first observation of such a complex. Addition of nBuLi to the chiral sodium amide dimer 3 gave a new mixed lithium/sodium amide 5. The use of 15N,6Li coupling constants showed that the lithium in 5 occupied the tetracoordinated site. The use of chiral sodium amide 3 in the desymmetrization of cyclohexene oxide gave a modest enantiomeric excess (ee) of 37%. The corresponding lithium amide gave an ee of 70% of the same enantiomer. This is the first example of the comparison of asymmetric induction by sodium as cation with that of lithium.

Crystalline Glycylglycine Bolaamphiphile Tubules and Their pH-Sensitive Structural Transformation

The assembled structure of the heptane bolaamphiphile, bis(N-α-amido-glycylglycine)-1,7-heptane dicarboxylate, displays a sensitivity to the acidity of a solution. At pH 4, the heptane bolaamphiphile grows to a crystalline tubule in two weeks. At pH 8, a helical ribbon structure is formed in one week. The degree of carboxylic acid protonation was used to control the final assembled structures since the structures are determined by the strengths of the amide−amide and carboxylic acid dimer hydrogen bonds. Direct structural transformation between tubules and helical ribbons was also confirmed as a function of pH using optical microscopy and Raman microscopy. Conversion from the helical ribbons to the tubules occurs within one day, while the reverse conversion, from the tubules to the helical ribbons, is ten times slower.

Synthesis of Amide-Linked [(3′)CH2CO-NH(5′)] Nucleoside Analogues of Small Oligonucleotides

We report syntheses of new amide-linked (di-penta)nucleoside analogues of antisense oligonucleotide components. Solution-phase coupling of 3′-(carboxymethyl)-3′-deoxy- and 5′-amino-5′-deoxynucleoside derivatives provides amide dimers. Activated [3′-(carboxymethyl)-3′-deoxy] units with a 5′-azido-5′-deoxy function provide “masked” 5′-amino-5′-deoxy residues for chain extension, and a 5′-O-DMT-protected unit provides the 5′-terminus for attachment to a phosphodiester linkage.

Amide-Linked Ribonucleoside Dimers Derived from 5'-Amino-5'-deoxy- and 3'-(Carboxymethyl)-3'-deoxynucleoside Precursors(1).

Treatment of tert-butyldimethylsilyl (TBDMS) derivatives of 3'-keto(adenosine or uridine) with [(ethoxycarbonyl)methylene]triphenylphosphorane gave exocyclic alkenes that underwent stereoselective hydrogenation to give 3'-deoxy-3'-[(ethoxycarbonyl)methyl](Ado or Urd) analogues. Saponification provided the 3'-(carboxymethyl)-3'-deoxy(Ado and Urd) derivatives 37 and 38. Treatment of 37 or 38 with DCC and 5'-amino-2',3'-bis-O-TBDMS-5'-deoxynucleosides gave the amide-linked dimers (74-82%). Activation of 37 or 38 with 4-nitrophenol/DCC, and direct coupling of the 4-nitrophenyl esters with 5'-amino-5'-deoxy(Ado or Urd) in pyridine also produced amide dimers efficiently (65-70%). Analogous activation of a 5'-O-DMT-protected carboxylate, and its coupling with 5'-amino-5'-deoxy-2'-O-methyladenosine gave the amide dimer in good yield (74%). Coupling (DCC) of a 5'-azido-2'-O-TBDMS-3'-(carboxymethyl)-3',5'-dideoxyuridine intermediate with 5'-amino-5'-deoxynucleosides gave amide-linked dimers (72-78%) that can serve as masked (azide reduction) 5'-amino dimers for analogous synthesis of extended amide-linked oligomers.