Flexible Organic Molecules Research Articles

A Robust and Cost-Efficient Scheme for Accurate Conformational Energies of Organic Molecules.

Several standard semiempirical methods as well as the MMFF94 force field approximation have been tested in reproducing 8 DLPNO-CCSD(T)/cc-pVTZ level conformational energies and spatial structures for 37 organic molecules representing pharmaceuticals, drugs, catalysts, synthetic precursors, industry-related chemicals (37conf8 database). All contemporary semiempirical methods surpass their standard counterparts resulting in more reliable conformational energies and spatial structures, even though at significantly higher computational costs. However, even these methods show unexpected failures in reproducing energy differences between several conformers of the crown ether 1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-6). Inexpensive force field MMFF94 approximation groups with contemporary semiempirical methods in reproducing the correct order of conformational energies and spatial structures, although the performance in predicting absolute conformational energies compares to standard semiempirical methods. Based on these findings, we suggest a two-step strategy for reliable yet feasible conformational search and sampling in realistic-size flexible organic molecules: i) geometry optimization/preselection of relevant conformers using the MMFF94 force field; ii) single-point energy evaluations using a contemporary semiempirical method. We expect that developed database 37conf8 is going to be useful for development of semiempirical methods.

Crystal Nucleation of Tolbutamide in Solution: Relationship to Solvent, Solute Conformation, and Solution Structure.

The influence of the solvent in nucleation of tolbutamide, a medium-sized, flexible and polymorphic organic molecule, has been explored by measuring nucleation induction times, estimating solvent-solute interaction enthalpies using molecular modelling and calorimetric data, probing interactions and clustering with spectroscopy, and modelling solvent-dependence of molecular conformation in solution. The nucleation driving force required to reach the same induction time is strongly solvent-dependent, increasing in the order: acetonitrile<ethyl acetate<n-propanol<toluene. The combined DFT and MD modelling results show that in acetonitrile, ethyl acetate and n-propanol the nucleation difficulty is a function of the strength of solvent-solute interaction, with emphasis on the interaction with specific H-bonding polar sites of importance in the crystal structure. A clear exception from this rule is the most difficult nucleation in toluene despite the weakest solvent-solute interactions. However molecular dynamics modelling predicts that tolbutamide assumes an intramolecularly H-bonded conformation in toluene, substantially different from and more stable than the conformation in the crystal structure, and thus presenting an additional barrier to nucleation. This explains why nucleation in toluene is the most difficult and why the relatively higher propensity for aggregation of tolbutamide molecules in toluene solution, as observed with FTIR spectroscopy, does not translate into easier nucleation. Thus, our combined experimental and molecular modelling study suggests that the solvent can influence on the nucleation not only via differences in the desolvation but also through the influence on molecular conformation.

Crystal structure prediction of flexible pharmaceutical-like molecules: density functional tight-binding as an intermediate optimisation method and for free energy estimation.

Successful methodologies for theoretical crystal structure prediction (CSP) on flexible pharmaceutical-like organic molecules explore the lattice energy surface to find a set of plausible crystal structures. The initial search stages of CSP studies use relatively simple lattice energy approximations as hundreds of thousands of minima have to be considered. These generated crystal structures often have poor molecular geometries, as well as inaccurate lattice energy rankings, and performing reasonably accurate but computationally affordable optimisations of the crystal structures generated in a search would be highly desirable. Here, we seek to explore whether semi-empirical quantum-mechanical methods can perform this task. We employed the dispersion-corrected tight-binding Hamiltonian (DFTB3-D3) to relax all the inter- and intra-molecular degrees of freedom of several thousands of generated crystal structures of five pharmaceutical-like molecules, saving a large amount of computational effort compared to earlier studies. The computational cost scales better with molecular size and flexibility than other CSP methods, suggesting that it could be extended to even larger and more flexible molecules. On average, this optimisation improved the average reproduction of the eight experimental crystal structures (RMSD15) and experimental conformers (RMSD1) by 4% and 23%, respectively. The intermolecular interactions were then further optimised using distributed multipoles, derived from the molecular wave-functions, to accurately describe the electrostatic components of the intermolecular energies. In all cases, the experimental crystal structures are close to the top of the lattice energy ranking. Phonon calculations on some of the lowest energy structures were also performed with DFTB3-D3 methods to calculate the vibrational component of the Helmholtz free energy, providing further insights into the solid-state behaviour of the target molecules. We conclude that DFTB3-D3 is a cost-effective method for optimising flexible molecules, bridging the gap between the approximate methods used in CSP searches for generating crystal structures and more accurate methods required in the final energy ranking.

Charge-transport properties of 4-(1,2,2-tri-phenyl-vinyl)-aniline salicylaldehyde hydrazone: tight-packing induced molecular 'hardening'.

Based on first-principles calculations, the relationship between molecular packing and charge-transport parameters has been investigated and analysed in detail. It is found that the crystal packing forces in the flexible organic molecule 4-(1,2,2-triphenylvinyl)-aniline salicylaldehyde hydrazone (A) can apparently overcome the dynamic intramolecular rotations and the intramolecular steric repulsion, effectively enhancing the molecular rigidity and decreasing the internal reorganization energy. The conducting properties of A have also been simulated within the framework of hopping models, and the calculation results show that the intrinsic electron mobility in A is much higher than the corresponding intrinsic hole mobility. These theoretical investigations provide guidance for the efficient and targeted control of the molecular packing and charge-transport properties of organic small-molecule semiconductors and conjugated polymeric materials.

A series of terpyridine containing flexible amino diethylacetate derivatives with large two-photon action cross-sections for effective mitochondrial imaging in living liver cancerous cells

Small molecules possess large two-photon action cross sections (Φσ) are highly demanded for biological purpose. Herein, three novel terpyridine containing flexible amino diethylacetate organic small molecules (A1, A2 and A3) were rationally designed and their photophysical properties were investigated both experimentally and theoretically. The results revealed that the three chromophores possess large Φσ and remarkable Stokes' shift in high polar solvents, which are particularly benefit for further biological imaging application. One chromophore (A1) displayed an effective intracellular uptake against lung cancerous living cells A549. Colocalization studies suggested the internalized subcellular compartment was mitochondria. Consequently, chromophore A1 provides a promising platform to directly monitor mitochondria in living cells under two-photon confocal laser scanning microscopy.

Interfacial Design in Dielectric Nanocomposite Using Liquid-Crystalline Polymers

The interfacial region plays a critical role in determining the electrical properties of dielectric nanocomposites. The current state-of-the-art interfacial modification is predominantly based on utilizing flexible organic molecules, which are random polymer coils and generally collapse on the surface of any modified nanoparticles. This work focused on engineering the interfacial region between Na2Ti3O7 nanofibers and polymer matrix and, for the first time, utilized the liquid-crystalline polymer poly{2,5-bis[(4-methoxyphenyl)oxycarbonyl]styrene} (PMPCS) to modulate the interface where the rigid polymer was forced to form a straight conformation. Owing to the rigidity and orientation of PMPCS, a series of core–shell structured Na2Ti3O7@PMPCS nanofibers with finely tuned shell thickness were prepared. The prepared Na2Ti3O7@PMPCS/P(VDF-HFP) nanocomposites showed significantly different permittivity from 10.7 to 69.6 at 1 kHz with the gradient thicknesses of PMPCS shell. These results effectively proved that...

Conformational Effect of Polymorphic Terfluorene on Photophysics, Crystal Morphologies, and Lasing Behaviors

Molecular conformation is an important factor in flexible organic molecules and deeply influences their physical and chemical properties. Here, a model fluorene trimer, 2,2′:7′,2″-ter(9,9-dimethylfluorene) (TDMeF), was designed and synthesized to investigate the effect of conformational diversity of oligofluorene on the morphologies of microcrystals and photophysical properties. Single crystal X-ray diffraction analysis indicates that TDMeF has four polymorphs with different molecular conformations, and crystalline polymorphism is first observed in oligofluorenes. Moreover, the slight change in molecular conformation leads to form different crystal morphologies, namely, ribbon and rodlike microcrystals, in virtue of different intermolecular interactions. Finally, although both microcrystals display deep blue lasing behaviors, the rodlike microcrystal shows a threshold of 114 W/cm2, which is twice times lower than that of the ribbon-like one due to the effect of molecular orientation and optical microcavity.

Conformational Studies of Triazole Based Flexible Molecules: A Comparative Analysis of Crystal Structure and Optimized Structure for DNA Binding Ability

AbstractThe present studies deal with design and synthesis of triazole based flexible molecules, their conformational analysis and DNA binding ability. The conformational studies were carried out in solid state through crystal structure and in gaseous state through theoretical calculation. The obtained conformations, found from either crystal structure or optimized most stable conformation from theoretical calculation have been screened for DNA binding ability to find importance of conformation in flexible organic molecules.

Cross-linking Zr-based metal-organic polyhedra via postsynthetic polymerization.

Metal organic polyhedra (MOPs) have potential as supramolecular building blocks, but utilizing MOPs for postsynthetic polymerization has not been explored. Although MOPs with flexible organic moieties have been recently reported to target enhanced processability, permanent porosity has not been demonstrated. Here, a novel synthetic strategy involving the cross-linking of MOPs via a covalent bond is demonstrated by exploiting a condensation reaction between the MOP and flexible organic linkers. An amine-functionalized Zr-based MOP is cross-linked with acyl chloride linkers in the crystalline state to form cross-linked MOPs. The condensation reaction results in a cross-linked system without significant changes to the structure of the Zr-based MOP. Such cross-linked MOPs provide a microporous tetrahedral cage based on gas sorption analysis. This cross-linking strategy highlights the potential of MOPs as building blocks and provides access to a new class of porous material.

Multiconformation, Density Functional Theory-Based pKa Prediction in Application to Large, Flexible Organic Molecules with Diverse Functional Groups.

We consider the conformational flexibility of molecules and its implications for micro- and macro-pKa. The corresponding formulas are derived and discussed against the background of a comprehensive scientific and algorithmic description of the latest version of our computer program Jaguar pKa, a density functional theory-based pKa predictor, which is now capable of acting on multiple conformations explicitly. Jaguar pKa is essentially a complex computational workflow incorporating research and technologies from the fields of cheminformatics, molecular mechanics, quantum mechanics, and implicit solvation models. The workflow also makes use of automatically applied empirical corrections which account for the systematic errors resulting from the neglect of explicit solvent interactions in the algorithm's implicit solvent model. Applications of our program to large, flexible organic molecules representing several classes of functional groups are shown, with a particular emphasis in illustrations laid on drug-like molecules. It is demonstrated that a combination of aggressive conformational search and an explicit consideration of multiple conformations nearly eliminates the dependence of results on the initially chosen conformation. In certain cases this leads to unprecedented accuracy, which is sufficient for distinguishing stereoisomers that have slightly different pKa values. An application of Jaguar pKa to proton sponges, the pKa of which are strongly influenced by steric effects, showcases the advantages that pKa predictors based on quantum mechanical calculations have over similar empirical programs.

Modeling the Emission Spectra of Organic Molecules: A Competition between Franck-Condon and Nuclear Ensemble Methods.

The emission spectra of flexible and rigid organic molecules are theoretically investigated in the framework of the Franck-Condon (FC) and nuclear ensemble (NE) approaches, both of which rely on results from density functional theory but differ in the way vibrational contributions are taken into account. Our findings show that the emission spectra obtained using the NE approach are in better agreement with experiment than the ones produced by FC calculations considering both rigid and flexible molecules. Surprisingly, the description of a suitable balance between the vibronic progression and the emission spectra envelope shows dependency on the initial sampling for the NE calculations which must be judiciously selected. Our results intend to provide guidance for a better theoretical description of light emission properties of organic molecules with applications in organic electronic devices.

Structural analysis of rigid and flexible small organic molecules assisted by residual dipolar couplings

Structural analysis of rigid and flexible small organic molecules assisted by residual dipolar couplings

Simulating "soft" electronics.

Simulating electronic devices built from flexible organic molecules requires both adequate conformational sampling and a reliable quantum mechanical description of the electronics of the system. The former is best achieved using classical (force field) molecular-dynamics simulations, from which individual geometries (“snapshots”) can be used for subsequent quantum mechanical calculations. As the repeating unit in the classical simulations typically involves thousands of atoms, the quantum mechanical techniques must also be able to handle many thousands of atoms quickly and effectively on modern parallel hardware. The newly developed EMPIRE program has been used in such a scheme to perform simulations on self-assembled-monolayer field-effect transistors (SAMFETs). Calculations of the size needed require novel interpretation and post-processing techniques based on local properties calculated on grids, rather than the more traditional population analyses. The results of simulations using the techniques described above will be presented and the algorithms and parallelization strategies implemented to be able to calculate as many as 100,000 atoms on 1,024 cores.

Which conformations make stable crystal structures? Mapping crystalline molecular geometries to the conformational energy landscape

Flexible organic molecules often do not adopt their lowest energy conformer in crystal structures. We find that there is a preference for molecules to crystallise with high surface area conformers.

Turn the Molecule This Way for a Faster Reaction

Molecular beams and ultracold atom-trapping methods resolve the different reaction rates of the cis and trans conformers of a flexible organic molecule. [Also see Report by Chang et al. ]

Conformational Distribution oftrans-Stilbene in Solution Investigated by Liquid Crystal NMR Spectroscopy and Compared within VacuoTheoretical Predictions

The basic question about the structure and the conformational distribution of a π-conjugated, flexible organic molecule (interesting in itself, in relation to the balance of forces determining its torsional equilibrium) becomes a really intriguing problem in the case of trans-stilbene (t-St), a "fundamental" molecule from a chemical point of view, as well as the prototype fragment of a series of derivatives endowed with several important biological and technological properties. As a matter of fact, the problem of t-St planarity when the molecule is isolated or in solution is a particularly debated question. In the present paper we studied the conformational distribution of t-St in solution, by resorting to the powerful technique of liquid crystal NMR spectroscopy (LXNMR), and we compared the obtained experimental results with accurate theoretical calculations carried out in vacuo, by using the MP2/6-31G** method (allowing for bond lengths and angles relaxation every 3° torsional steps). Our theoretical and experimental outcomes agree in indicating the nonplanarity of the molecule which, on the contrary, exhibits the coexistence of four stable rotamers, two by two symmetry related. In particular, we have found a couple of global minima corresponding to propeller-like C(2) symmetry conformations, where both the rings are "disrotated", with respect to the vinyl group, of about 17° in solution and of 27° in vacuo (theoretical value). Besides this, the presence of a couple of C(i) local minima, with both the rings "conrotated" of 17° (fluid phase) or of 27° (MP2/6-31G** calculations for the isolated molecule) has been determined.

Hydrothermal synthesis and crystal structure of (H2bpp)3[Mo5P2O23]·H2O: a twofold interpenetrating 3D supramolecular architecture constructed of Standberg-type polyoxometalate

A novel three-dimensional (3D) supramolecular assembly of Standberg-type polyoxometalate and flexible organic molecule (H2bpp)3[Mo5P2O23]·H2O (1) [bpp = 1,3-bis(4-pyridyl)propane] has been hydrothermally synthesized and structurally characterized by single-crystal X-ray diffraction, IR spectra, elemental analysis and thermogravimetric analysis (TGA). X-ray analyses show that compound 1 represent a twofold interpenetrating 3D supramolecular architecture constructed of Standberg-type polyoxometalate and bpp molecular through the hydrogen bonds as well as electrostatic interactions.

Experimental and Predicted Crystal Energy Landscapes of Chlorothiazide

An experimental search for physical forms of the thiazide diuretic compound chlorothiazide comprising 402 different crystallizations identified one nonsolvated form and ten crystalline solvates. There are five distinct conformations in the experimental crystal structures which are in good agreement with the conformational minima found by ab initio optimization of the isolated molecule structure. An approximate rigid-body crystal energy landscape using these five conformations produced a diverse range of low energy crystal structures, with the anhydrous structure among the most stable. Inspection of the molecular packing adopted in both the experimental and predicted structures highlighted a number of chlorothiazide···chlorothiazide motifs that result from packing the different conformers. Specifically, four bimolecular face-to-face motifs were observed in most of the predicted structures and all of the experimental structures. The role of these robust intermolecular packing motifs and of the organic solvent molecules in stabilizing the experimental solvate structures of chlorothiazide is discussed. The results highlight the value of the approximate crystal energy landscape for flexible organic molecules in assisting with the interpretation of solid-state diversity in chlorothiazide crystal structures and identifying key stabilizing packing features.

Crystal packing predictions of the alpha-amino acids: methods assessment and structural observations

Crystal structure prediction calculations are performed for four hydrophobic amino acids (alanine, valine, leucine and isoleucine), to test the computational methods that have been developed for flexible organic molecules. Specific focus is placed on the final energy minimisation and optimisation of the molecular conformations in the computer-generated crystal structures. Overall, the results are very encouraging. The observed crystal structures are usually found as the lowest energy predicted structures, demonstrating that crystal packing is predictable by computational methods, even for fairly challenging systems. In addition to the assessment of the computational methods, comparison of the hypothetical with the observed crystal structures provides insight into the balance between hydrogen bonding and hydrophobic side-chain packing that determines the crystal structures of these biologically important molecules.

On the Treatment of Conformational Flexibility when Using Residual Dipolar Couplings for Structure Determination

Mission possible! The motional averaging of NMR spectroscopic data complicates the determination of conformation and relative configuration in flexible organic molecules. Two alternative routes are discussed for the treatment of conformational equilibrium in a moderately flexible compound (see the superposition of the two conformers of the butyrolactone studied) when residual dipolar couplings are used.