Arkajyoti Sengupta

Electrostatic and Allosteric Cooperativity in Ion-Pair Binding: A Quantitative and Coupled Experiment-Theory Study with Aryl-Triazole-Ether Macrocycles.

Cooperative binding of ion pairs to receptors is crucial for the manipulation of salts, but a comprehensive understanding of cooperativity has been elusive. To this end, we combine experiment and theory to quantify ion-pair binding and to separate allostery from electrostatics to understand their relative contributions. We designed aryl-triazole-ether macrocycles (MC) to be semiflexible, which allows ion pairs (NaX; X = anion) to make contact, and to be monocyclic to simplify analyses. A multiequilibrium model allows us to quantify, for the first time, the experimental cooperativity, α, for the equilibrium MC·Na(+) + MC·X(-) ⇌ MC·NaX + MC, which is associated with contact ion-pair binding of NaI (α = 1300, ΔGα = -18 kJ mol(-1)) and NaClO4 (α = 400, ΔGα = -15 kJ mol(-1)) in 4:1 dichloromethane-acetonitrile. We used accurate energies from density functional theory to deconvolute how the electrostatic effects and the allosteric changes in receptor geometry individually contribute to cooperativity. Computations, using a continuum solvation model (dichloromethane), show that allostery contributes ∼30% to overall positive cooperativity. The calculated trend of electrostatic cooperativity using pairs of spherical ions (NaCl > NaBr > NaI) correlates to experimental observations (NaI > NaClO4). We show that intrinsic ionic size, which dictates charge separation distance in contact ion pairs, controls electrostatic cooperativity. This finding supports the design principle that semiflexible receptors can facilitate optimal electrostatic cooperativity. While Coulombs law predicts the size-dependent trend, it overestimates electrostatic cooperativity; we suggest that binding of the individual anion and cation to their respective binding sites dilutes their effective charge. This comprehensive understanding is critical for rational designs of ion-pair receptors for the manipulation of salts.

Anions Stabilize Each Other inside Macrocyclic Hosts

Contrary to the simple expectations from Coulombs law, Weinhold proposed that anions can stabilize each other as metastable dimers, yet experimental evidence for these species and their mutual stabilization is missing. We show that two bisulfate anions can form such dimers, which stabilize each other with self-complementary hydrogen bonds, by encapsulation inside a pair of cyanostar macrocycles. The resulting 2:2 complex of the bisulfate homodimer persists across all states of matter, including in solution. The bisulfate dimers OH⋅⋅⋅O hydrogen bonding is seen in a 1 H NMR peak at 13.75 ppm, which is consistent with borderline-strong hydrogen bonds.

Flexibility Coexists with Shape-Persistence in Cyanostar Macrocycles

Shape-persistent macrocycles are attractive functional targets for synthesis, molecular recognition, and hierarchical self-assembly. Such macrocycles are noncollapsible and geometrically well-defined, and they are traditionally characterized by having repeat units and low conformational flexibility. Here, we find it necessary to refine these ideas in the face of highly flexible yet shape-persistent macrocycles. A molecule is shape-persistent if it has a small change in shape when perturbed by external stimuli (e.g., heat, light, and redox chemistry). In support of this idea, we provide the first examination of the relationships between a macrocycles shape persistence, its conformational space, and the resulting functions. We do this with a star-shaped macrocycle called cyanostar that is flexible as well as being shape-persistent. We employed molecular dynamics (MD), density functional theory (DFT), and NMR experiments. Considering a thermal bath as a stimulus, we found a single macrocycle has 332 accessible conformers with olefins undergoing rapid interconversion by up-down and in-out motions on short time scales (0.2 ns). These many interconverting conformations classify single cyanostars as flexible. To determine and confirm that cyanostars are shape-persistent, we show that they have a high 87% shape similarity across these conformations. To further test the idea, we use the binding of diglyme to the single macrocycle as guest-induced stimulation. This guest has almost no effect on the conformational space. However, formation of a 2:1 sandwich complex involving two macrocycles enhances rigidity and dramatically shifts the conformer distribution toward perfect bowls. Overall, the present study expands the scope of shape-persistent macrocycles to include flexible macrocycles if, and only if, their conformers have similar shapes.

Application of the generalized connectivity-based hierarchy to biomonomers: enthalpies of formation of cysteine and methionine.

Computational challenges toward an accurate determination of the enthalpies of formation of amino acids are partly due to the nonavailability of systematic error-canceling thermochemical procedures for such biomonomers. Recently, we developed the connectivity-based hierarchy (CBH) to accurately compute the enthalpies of formations of organic molecules composed of main group elements. Advancing the applicability of CBH to biologically relevant molecules, we have computed the enthalpies of formation of the naturally occurring sulfur-containing amino acids cysteine and methionine which act as fertile testing grounds for the error-canceling ability of thermochemical schemes for biomolecules. We establish herein using the sophisticated error-canceling isoatomic scheme (CBH-2) that relatively inexpensive computational methods with modest basis sets can be used to accurately obtain the enthalpies of formations of the amino acids. Overall, we recommend the use of the isoatomic scheme over the currently popular isodesmic bond separation scheme in future applications in theoretical thermochemistry.

Prediction of Accurate Thermochemistry of Medium and Large Sized Radicals Using Connectivity-Based Hierarchy (CBH).

Accurate modeling of the chemical reactions in many diverse areas such as combustion, photochemistry, or atmospheric chemistry strongly depends on the availability of thermochemical information of the radicals involved. However, accurate thermochemical investigations of radical systems using state of the art composite methods have mostly been restricted to the study of hydrocarbon radicals of modest size. In an alternative approach, systematic error-canceling thermochemical hierarchy of reaction schemes can be applied to yield accurate results for such systems. In this work, we have extended our connectivity-based hierarchy (CBH) method to the investigation of radical systems. We have calibrated our method using a test set of 30 medium sized radicals to evaluate their heats of formation. The CBH-rad30 test set contains radicals containing diverse functional groups as well as cyclic systems. We demonstrate that the sophisticated error-canceling isoatomic scheme (CBH-2) with modest levels of theory is adequate to provide heats of formation accurate to ∼1.5 kcal/mol. Finally, we predict heats of formation of 19 other large and medium sized radicals for which the accuracy of available heats of formation are less well-known.

Accurate and computationally efficient prediction of thermochemical properties of biomolecules using the generalized connectivity-based hierarchy.

In this study we have used the connectivity-based hierarchy (CBH) method to derive accurate heats of formation of a range of biomolecules, 18 amino acids and 10 barbituric acid/uracil derivatives. The hierarchy is based on the connectivity of the different atoms in a large molecule. It results in error-cancellation reaction schemes that are automated, general, and can be readily used for a broad range of organic molecules and biomolecules. Herein, we first locate stable conformational and tautomeric forms of these biomolecules using an accurate level of theory (viz. CCSD(T)/6-311++G(3df,2p)). Subsequently, the heats of formation of the amino acids are evaluated using the CBH-1 and CBH-2 schemes and routinely employed density functionals or wave function-based methods. The calculated heats of formation obtained herein using modest levels of theory and are in very good agreement with those obtained using more expensive W1-F12 and W2-F12 methods on amino acids and G3 results on barbituric acid derivatives. Overall, the present study (a) highlights the small effect of including multiple conformers in determining the heats of formation of biomolecules and (b) in concurrence with previous CBH studies, proves that use of the more effective error-cancelling isoatomic scheme (CBH-2) results in more accurate heats of formation with modestly sized basis sets along with common density functionals or wave function-based methods.

Solving the Density Functional Conundrum: Elimination of Systematic Errors To Derive Accurate Reaction Enthalpies of Complex Organic Reactions

The failure of available density functional methods to compute accurate reaction enthalpies of common organic reactions is well documented. Herein, we demonstrate that the disparate results from different functionals stem from the systematic errors in the underlying elementary reactions that represent the changes in the bonding environment between reactants and products. We develop a rigorous protocol to correct for these systematic errors and obtain dramatically improved results with deviations of only 1-2 kcal/mol for most functionals.

Breaking a bottleneck: Accurate extrapolation to “gold standard” CCSD(T) energies for large open shell organic radicals at reduced computational cost

Open Shell organic radicals are principal species involved in many diverse areas such as combustion, photochemistry, and polymer chemistry. Computational studies of such species with an accurate method like coupled‐cluster with single and double and perturbative triple (CCSD(T)) may be restricted to systems of modest size due to the steep computational scaling of the method. Herein, we assess the accuracy of extrapolated CCSD(T) energies determined using the connectivity‐based hierarchy (CBH) method on medium to large sized radicals. In our method, an MP2 calculation on the target radical is coupled with CCSD(T) energies of fragments determined uniquely by our hierarchy to perform accurate extrapolations. A careful assessment is done with a robust CBH‐rad49 test set comprising of 49 diverse cyclic and acyclic radicals with a variety of functional groups. We demonstrate that the extrapolation method with CBH‐2 or CBH‐3 is sufficient to obtain sub‐kcal accuracy. ROMP2 and PMP2 calculations with both Pople‐style and Dunning‐style basis‐sets resulted in mean absolute errors for CCSD(T) extrapolation (full CCSD(T)—extrapolated CCSD(T)) within 0.5 kcal/mol. Further speedup for such CCSD(T) extrapolations are obtained with ROHF‐based RI‐MP2 calculations. Challenging systems with (a) high ring strain, (b) delocalized character, and (c) spin contamination are identified and analyzed in detail. Finally, we apply our extrapolation method on 10 larger radicals containing 10−15 heavy atoms, where accurate CCSD(T) energies are obtained at a fractional cost of full CCSD(T) calculations.

Accurate Thermochemistry for Organic Cations via Error Cancellation using Connectivity-Based Hierarchy

Connectivity-Based Hierarchy (CBH) is an effective error-cancellation scheme for the determination of chemically accurate thermochemical properties of a variety of organic and biomolecules. Neutral molecules and open-shell radicals have already been treated successfully by this approach utilizing inexpensive computational methods such as density functional theory. Herein, we present an extension of the method to a new class of molecules, specifically, organic cations. Because of the presence of structural rearrangements involving hydrogen migrations as well as unusual structures such as bridged cations, the application of the standard CBH protocol to a test set of 25 cations leads to significant errors due to ineffective bond-type matching. We propose an adjusted protocol to overcome such limitations to achieve highly effective error cancellation. The modified CBH methods, in conjunction with a wide range of density functionals, reproduce G4 energies for the test set of organic cations accurately within 1-2 kcal/mol at a reduced computational cost.

Anion-Binding Macrocycles Operate Beyond the Electrostatic Regime: Interaction Distances Matter

Anion recognition impacts many areas of chemistry and often relies on receptors with multiple hydrogen-bond donors. Previous studies of these donors in small molecules have long promoted the idea that electrostatic interactions alone correlate with association strength, yet this correlation has not been critically evaluated in the framework of larger, macrocyclic receptors. Here, we provide that assessment by evaluating how much electrostatics contributes to the gas-phase binding energy of macrocyclic receptors with various anions. Whereas small-molecule complexes behave as expected, we find that electrostatic interactions fail to accurately describe total binding energies of many common macrocyclic receptors: calix[4]pyrroles, dipyrrolyldiketones, indolocarbazoles, amido-pyrroles, triazolophanes, and cyanostars. This deviation arises from the fact that most macrocycles have multiple points of contact with the anion. Whereas the hydrogen-bond donors collectively stabilize the anion, the interaction distances are typically larger than equilibrium values seen with small molecules. This leads to increases in the relative contributions of the attractive components such as induction (e.g., induced dipoles) and dispersion, which are found to be as high as 32 % for CH-donor based tricarbazole triazolophane complex with large polarizable ClO4- . This study augments previous observations of the importance of dispersion and induction towards anion binding of macrocyclic receptors in solution.