Amide Rotation Research Articles

First Trifluoromethylated Phenanthrolinediamides: Synthesis, Structure, Stereodynamics and Complexation with Ln(III).

The first examples of 1,10-phenanthroline-2,9-diamides bearing CF3-groups on the side amide substituents were synthesized. Due to stereoisomerism and amide rotation, such complexes have complicated behavior in solutions. Using advanced NMR techniques and X-ray analysis, their structures were completely elucidated. The possibility of the formation of complex compounds with lanthanoids nitrates was shown, and the constants of their stability are quantified. The results obtained are explained in terms of quantum-chemical calculations.

Investigation of phosphine donor properties to vanadium(V) nitrides

Catalyst optimization has been greatly aided over the years by methods of characterizing donor and steric properties of ligands. Here, we investigated a vanadium model system, NV(NH2)2L, to determine if the enthalpic barriers associated with amide rotation are in a range that would make this a synthetic target for determining the donor ability of L experimentally, e.g., by spin saturation transfer of the amide protons in the 1H NMR. In addition to determining that the barriers to rotation should be amenable to this method, we investigated how various phosphine donor properties affected amide rotation for the d0 metal and contrasted this with a late transition metal system. The calculations suggest that some PX3 ligand features, such as lone pairs on the X substituent, may lead to increases in the high oxidation state system where they are electron withdrawing in the low oxidation state systems. The cause of this electronic difference was investigated using Natural Resonance Theory.

Amide nitrogen pyramidalization changes lactam amide spinning

Although cis-trans lactam amide rotation is fundamentally important, it has been little studied, except for a report on peptide-based lactams. Here, we find a consistent relationship between the lactam amide cis/trans ratios and the rotation rates between the trans and cis lactam amides upon the lactam chain length of the stapling side-chain of two 7-azabicyclo[2.2.1]heptane bicyclic units, linked through a non-planar amide bond. That is, as the chain length increased, the rotational rate of trans to cis lactam amide was decreased, and consequently the trans ratio was increased. This chain length-dependency of the lactam amide isomerization and our simulation studies support the idea that the present lactam amides can spin through 360 degrees as in open-chain amides, due to the occurrence of nitrogen pyramidalization. The tilting direction of the pyramidal amide nitrogen atom of the bicyclic systems is synchronized with the direction of the semicircle-rotation of the amide.

Phosphine interactions with high oxidation state metals

Phosphines and related ligands (PE3) are some of the most versatile and well-studied in the chemist’s arsenal. The vast majority of studies on these ligands have focused on their interactions with low valent transition metals. From these investigations, it is now widely accepted that there are two major electronic interactions between the PE3 ligand and a low valent metal: a σ-donor bond between the metal and phosphorus and a π-acceptor interaction, where the phosphorus accepts electron density from the metal. The π-acceptor interaction is a form of negative hyperconjugation, which becomes more significant for electron-withdrawing E groups, such as those in phosphites, P(OR)3. In this study, the bonding between a high valent transition metal, chromium(VI), and a variety of different PE3 ligands was interrogated. The Lewis acidity of the NCr(NiPr2)2+ fragment was quantified using the Gutmann method, and the acceptor number was found to be 100, similar to highly Lewis acidic SbCl5. Using calculations (DFT, Natural Resonance Theory) it was found that rarely discussed resonance forms were important for some phosphines on d0 metal centers. These alternative resonance forms included negative hyperconjugative forms that appear when aryl or heteroatom substituents are placed on the phosphorus atom, leading to increased electron density at the Lewis acidic metal center. Attempts to explore the consequences of the computational results experimentally with the [NCr(NiPr2)2PE3]+X− system were undertaken, however, due to experimental difficulties with ion pairing and solvent effects, experimental quantification of donor ability across a diverse series of phosphines was not possible. However, trialkylphosphines were fit to a simple 2-parameter model, which showed that both steric and electronic effects were extremely important in the system. While we could not reliably quantify the observation, it was noted that aryl and heteroatom substituted PE3, P(OEt)3 and PMePh2, for example, have faster amide rotation at lower temperatures than many of the trialkylphosphines. Despite experimental complications, these studies suggest that bonding to high valent metals could be more complex than simple lone pair donation, and it appears that several resonance forms may be of importance when d0 metals bond to aryl- and heteroatom substituted phosphines.

Barriers to Rotation in ortho-Substituted Tertiary Aromatic Amides: Effect of Chloro-Substitution on Resonance and Distortion.

Planarity of the amide bond represents one of the most widely recognized properties of amides. Herein, we report a combined structural and computational study on the effect of ortho-substitution on resonance and barriers to rotation in tertiary aromatic amides. We demonstrate that ortho-chloro substitution in a class of benzamides that are important from the reactivity and medicinal chemistry perspective results in increased barriers to rotation around both the N-C(O) and C-C(O) axes. The effect of steric hindrance on structures, resonance energies, barriers to rotation, and proton affinities is discussed. The present study strongly supports the use of ortho-substitution in common benzamides to strengthen amidic resonance.

Restricted amide rotation with steric hindrance induced multiple conformations

The CN bond character is dependent directly upon the resonance-contributor structure population driven by the delocalized nitrogen lone-pair of electrons. In the case of N, N-dibenzyl-ortho-toluamide (o-DBET), the molecule adopts subpopulations of conformers with distinct NMR spectral features, particularly at low temperatures. This conformational adaptation is unique to o-DBET, while the corresponding meta- and para- forms do not show such behavior. Variable-temperature (VT) NMR, two-dimensional exchange spectroscopy (EXSY), and qualitative molecular modeling studies are used to demonstrate how multiple competing interactions such as restricted amide rotation and steric hindrance effects can lead to versatile molecular adaptations in the solution state.

Peptidyl-Prolyl Model Study: How Does the Electronic Effect Influence the Amide Bond Conformation?

The triple-helical structure of collagen, the most abundant protein in animal bodies, owes its stability to post-translationally installed hydroxyl groups at position 4 of prolyl residues. To shed light on the nature of this phenomenon, we have examined the influence of the 4-substituent on the amide isomerism in peptidyl-prolyl analogues. The rigid bicyclic skeleton of 2,4-methanoprolines allowed us to follow the through-bond impact of the substituent group (electronic effect) without the side-chain conformation being affected by a stereoelectronic effect. These proline analogues were prepared by [2 + 2] photocycloaddition of (2-allylamino)acrylic acid derivatives. Subsequent pKa studies demonstrated a remarkable electronic effect of the 4-fluorine substitution, while the effect of the 4-methyl group was negligible. The trans/cis amide ratio was measured in model compounds under low temperature conditions. The observed prevalence for a trans-amide is extraordinary, and in this regard, 2,4-methanoproline is closer to primary α-amino acids than to proline. At the same time the amide rotation velocities were 3-4 orders of magnitude higher when compared to N-acetylprolyl. Finally, our results indicate that the electronic effect of the 4-substituent only affects the kinetics of the amide isomerization but not the thermodynamic prevalence for the trans-rotamer.

Amide rotation trajectories probed by symmetry.

Amide rotation of peptidyl-prolyl fragments is an important factor in backbone structure organization of proteins. Computational studies have indicated that this rotation preferentially proceeds through a defined transition-state structure (syn/exo). Here, we complement the computational findings by determining the amide bond rotation barriers for derivatives of the two symmetric proline analogues, meso and racemic pyrrolidine-2,5-dicarboxylic acids. The rotations around these residues represent syn/exo-syn/exo and anti/endo-syn/exo hybrid transition states for the meso and racemic diastereomer, respectively. The rotation barriers are lower for the former rotation by about 9 kJ mol-1 (aqueous medium), suggesting a strong preference for the syn/exo (clockwise) rotation over the anti/endo (anticlockwise) rotation. The results show that both hybrid rotation processes are enthalpically driven but respond differently to solvent polarity changes due to the different transition state dipole-dipole interactions.

The Logic behind a Physical–Organic Chemist’s Research Topics

Although my research has no common theme or defining area, a coherence connects the diverse topics insofar as one project leads logically to another. Thus, studies on mechanisms of hydrogen exchange in amides and amidines led to the influence of hydrogen bonding and to NMR methods for chemical kinetics, including 2D-EXSY spectroscopy. Another connection was the OH--catalyzed NH exchange in amines that had supported the hypothesis of stereoelectronic control. We therefore analyzed that hypothesis critically, tested it, found counterexamples, and proposed an alternative hypothesis. We next addressed one-bond NMR coupling constants in ethers and the reverse anomeric effect. The latter studies required a highly accurate NMR titration method that we developed to measure the additional steric bulk resulting from protonation of a substituent. This method is also applicable to measuring secondary isotope effects on acidity, and we could demonstrate that they arise from n-σ* delocalization, not from an inductive effect. Other studies included kinetic isotope effects for both dissociation and H exchange of aqueous NH4+, for C-N rotation in amides, and for a hydride transfer. The role of hydrogen bonding led us to the rotation of NH4+ within its solvent cage and then to the symmetry of hydrogen bonds.

Investigation of the energy barrier to the rotation of amide C[sbnd]N bonds in ACE inhibitors by NMR, dynamic HPLC and DFT

The isomerizations of Enalapril, Perindopril, Enalaprilat and Lisinopril have been investigated using NMR spectroscopic, dynamic chromatographic, unified equation and DFT theoretical calculations.The thermodynamic parameters (ΔH, ΔS and ΔG) were determined by varying the temperature in the NMR experiments. At the coalescence temperature, we can evaluate the isomerization barrier to the rotation (ΔG≠) around the amide bond. Using dynamics chromatography and an unified equation introduced by Trap, we can determine isomerization rate constants and Gibbs activation energies. Molecular mechanics calculations also provided evidence for the presence of low energy conformers for the ACE due to restricted amide rotation. With the value of barriers (ΔE) between them of the order of (20kJmol−1), which is in agreement with the dynamic NMR results and DFT calculations.

Amide Rotation Hindrance Predicts Proteolytic Resistance of Cystine-Knot Peptides.

Cystine-knot peptides have remarkable stability against protease degradation and are attractive scaffolds for peptide-based therapeutic and diagnostic agents. In this work, by studying the hydrolysis reaction of a cystine-knot inhibitor MCTI-A and its variants with ab initio QM/MM molecular dynamics simulations, we have elucidated an amide rotation hindrance mechanism for proteolysis resistance: The proteolysis of MCTI-A is retarded due to the higher free energy cost during the rotation of NH group around scissile peptide bond at the tetrahedral intermediate of acylation, and covalent constraint provided by disulfide bonds is the key factor to hinder this rotation. A nearly linear correlation has been revealed between free energy barriers of the peptide hydrolysis reaction and the amide rotation free energy changes at the protease-peptide Michaelis complex state. This suggests that amide rotation hindrance could be one useful feature to estimate peptide proteolysis stability.

Are the amide bonds inN-acyl imidazoles twisted? A combined solid-state17O NMR, crystallographic, and computational study

We report synthesis of17O-labeling and solid-state17O NMR measurements of three N-acyl imidazoles of the type R-C(17O)-Im: R = p-methoxycinnamoyl (MCA-Im), R = 4-(dimethylamino)benzoyl (DAB-Im), and R = 2,4,6-trimethylbenzoyl (TMB-Im). Solid-state17O NMR experiments allowed us to determine for the first time the17O quadrupole coupling and chemical shift tensors in this class of organic compounds. We also determined the crystal structures of these compounds using single-crystal X-ray diffraction. The crystal structures show that, while the C(O)–N amide bond in DAB-Im exhibits a small twist, those in MCA-Im and TMB-Im are essentially planar. We found that, in these N-acyl imidazoles, the17O quadrupole coupling and chemical shift tensors depend critically on the torsion angle between the conjugated acyl group and the C(O)–N amide plane. The computational results from a plane-wave DFT approach, which takes into consideration the entire crystal lattice, are in excellent agreement with the experimental solid-state17O NMR results. Quantum chemical computations also show that the dependence of17O NMR parameters on the Ar–C(O) bond rotation is very similar to that previously observed for the C(O)–N bond rotation in twisted amides. We conclude that one should be cautious in linking the observed NMR chemical shifts only to the twist of the C(O)–N amide bond.

Mechanistic Insights into Carbonyl-Directed Rhodium-Catalyzed Hydroboration: ab Initio Study of a Cyclic γ,δ-Unsaturated Amide.

A two-point binding mechanism for the cationic rhodium(I)-catalyzed carbonyl-directed catalytic asymmetric hydroboration of a cyclic γ,δ-unsaturated amide is investigated using density functional theory. Geometry optimizations and harmonic frequency calculations for the model reaction are carried out using the basis set 6-31+G** for C, O, P, B, N, and H and LANL2DZ for Rh atoms. The Gibbs free energy of each species in THF solvent is obtained based on the single-point energy computed using the PCM model at the ECP28MWB/6-311+G(d,p) level plus the thermal correction to Gibbs free energy by deducting translational entropy contribution. The Rh-catalyzed reaction cycle involves the following sequence of events: (1) chelation of the cyclic γ,δ-unsaturated amide via alkene and carbonyl complexation in a model active catalytic species, [Rh(L2)2S2]+, (2) oxidative addition of pinacol borane (pinBH), (3) migratory insertion of the alkene double bond into Rh–H (preferred pathway) or Rh–B bond, (4) isomerization of the resulting intermediate, and finally, (5) reductive elimination to form the B–C or H–C bond with regeneration of the catalyst. Free energy profiles for potential pathways leading to the major γ-borylated product are computed and discussed in detail. The potential pathways considered include (1) pathways proceeding via migratory insertion into the Rh–H bond (pathways I, I-1, and I-2), (2) a potential pathway proceeding via migratory insertion into the Rh–B bond (pathway II), and two potential competing routes to a β-borylated byproduct (pathway III). The results find that the Rh–H migratory insertion pathway I-2, followed in sequence by an unanticipated isomerization via amide rotation and reductive elimination, is the most favorable reaction pathway. A secondary consequence of amide rotation is access to a competing β-hydride elimination pathway. The pathways computed in this study are supported by and help explain related experimental results.

Modulations in restricted amide rotation by steric induced conformational trapping

The rotation around the amide bond in N,N-diethyl-m-toluamide (m-DEET) has been studied extensively and often used in laboratory instructions to demonstrate the phenomenon of chemical exchange. Herein, we show that a simple modification to N,N-diethyl-o-toluamide (o-DEET) significantly alters the dynamics of the restricted rotation around the amide bond due to steric interactions between the ring methyl group and the two N-ethyl groups. This alters the classic two-site exchange due to restricted rotation around the amide bond, to a three-site exchange, with the third conformation trapped at a higher-energy state compared to the other two. This often overlooked phenomenon is elucidated using variable-temperature NMR, two-dimensional exchange spectroscopy and molecular modeling studies.

ChemInform Abstract: Theoretical and Experimental Studies of Cycloconjugation Involving Second-Row Elements.

In a method proposed to investigate conjugative interactions between second-row elements (S, P) amd a π-electron system, barriers to amide rotation have been measured using NMR line-shape methods, for N-acetyl-4-X(hetero)-1,4-dihydropyridines (X=SO 2 , 7; P(O)OCH 3 , 13; C(CH 3 ) 2 , 6 (reference)) as well as the dihydro (8a) and tetrahydro (9) derivatives, respectively, of 7

ChemInform Abstract: Stereoelectronic Effects in the Conformational Behavior and Ring Formation of Some N,N′-Dimethyl- and N,N′-Diacetyl-1,5-dioxa-4,8- diazadecalins.

Abstract A series of 4,8-dimethyl- and 4,8-diacetyl-cis-octahydro-[1,4]oxazino[3,2-b]-1,4-oxazines (title compounds) 4 and 7 respectively, were synthesized and studied using 1H- and 13C-NMR techniques. Conformation analysis of 4 showed a strong preference for conformers possessing an anti-Nigauche-O arrays vs an anti-O/gauche-N relationship (ΔG° = 0.88 Kcal/mol). However 7b exists exclusively as an anti-O/gauche-N conformer with a free energy of activation for the amide rotation barrier of 11.6 Kcal/mol (248 K). The stereoelectronic features of the CNCOC moieties of 4 and 7 are emphasized. A general reaction pathway is also discussed.

Scission of Carbon Monoxide Using TaR3, R=(N(tBu)Ph) or OSi(tBu)3: A DFT Investigation

The experimentally known reduction of carbon monoxide using a 3-coordinate [Ta(silox)(3)] (silox=OSi(tBu)(3)) complex initially forms a ketenylidene [(silox)(3)Ta-CCO], followed by a dicarbide [(silox)(3)Ta-CC-Ta(silox)(3)] structure. The mechanism for this intricate reaction has finally been revealed by using density functional theory, and importantly a likely structure for the previously unknown intermediate [(silox)(3)Ta-CO](2) has been identified. The analysis of the reaction pathway and the numerous intermediates has also uncovered an interesting pattern that results in CO cleavage, that being scission from a structure of the general form [(silox)(3)Ta-C(n)O] in which n is even. When n is odd, cleavage cannot occur. The mechanism has been extended to consider the effect of altering both the metal species and the ligand environment. Specifically, we predict that introducing electron-rich metals to the right of Ta in the periodic table to create mixed-metal dinuclear intermediates shows great promise, as does the ligand environment of the Cummins-style 3-coordinate amide structure. This latter environment has the added complexity of improved electron donation from amide rotation that can significantly increase the reaction exothermicity.

Diverging Chemoselective Reactions of Separable Amide Rotational Isomers

Diverging chemoselective reactions of a pair of amide rotamers have been observed by separating the rotamers and then reacting them individually. Reduction of (Z)-N-allyl-2-(phenylselanyl)-N-(2,4,6-tri-tert-butylphenyl)acetamide with tributyltin hydride at room temperature provides only the product of 5-exo cyclization, 4-methyl-1-(2,4,6-tri-tert-butylphenyl)pyrrolidin-2-one. In contrast, reduction of the corresponding (E) amide rotational isomer under identical conditions provides only the reduced product, (E)-N-allyl-N-(2,4,6-tri-tert-butylphenyl)acetamide. Such diverging reactions of rotamers may be common in transformations involving reactive intermediates (carbenes, radicals, organometallic intermediates) that have low barriers to onward reactions relative to amide rotation.

Acceleration of Amide Bond Rotation by Encapsulation in the Hydrophobic Interior of a Water-Soluble Supramolecular Assembly

The hydrophobic interior cavity of a self-assembled supramolecular assembly exploits the hydrophobic effect for the encapsulation of tertiary amides. Variable-temperature (1)H NMR experiments reveal that the free energy barrier for rotation around the C-N amide bond is lowered by up to 3.6 kcal/mol upon encapsulation. The hydrophobic cavity of the assembly is able to stabilize the less polar transition state of the amide rotation process. Carbon-13 labeling studies showed that the (13)C NMR chemical shift of the carbonyl resonance increases with temperature for the encapsulated amides, which suggests that the assembly is able to favor a twisted form of the amide.

Tertiary Amide Rotation in a Nanoscale Host

AbstractA self‐assembled cylindrical capsule provides a nanoscale environment that affects the rotational barriers of tertiary amides. Measurements of the activation energies for the rotations and behaviors of the amides inside the capsule were determined by using 1H NMR spectroscopic methods in deuterated mesitylene solution. For amides 3–8, rotation rates can decrease or increase in the capsule by up to an order of magnitude from those of the free amides in solution depending on the structure of the amides. The acceleration/deceleration of the rotation results from selective destabilization/stabilization of the ground state or the transition state. In the case of compound 10, the rotation generates two isomers that are equimolar in solution but inside the capsule only one of them is observed. Accordingly, the rotation rate is slowed by several orders of magnitude inside the capsule. In the case of amide 8, a competition experiment indicates that the acceleration of the rotation inside the capsule is due to destabilization of the ground state. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)