Conformational Sampling over Transition-Metal-Catalyzed Reaction Pathways: Toward Revealing Atroposelectivity.

The Py-Conformational-Sampling (PyCoSa) technique is introduced as a systematic computational means to sample the configurational space of transition-metal-catalyzed stereoselective reactions. When applied to atroposelective Suzuki-Miyaura coupling to create axially chiral biaryl products, the results show a range of mechanistic possibilities that include multiple low-energy channels through which C-C bonds can be formed.

Uncovering the Most Kinetically Influential Reaction Pathway Driving the Generation of HCN from Oxyma/DIC Adduct: A Theoretical Study.

The combination of ethyl (hydroxyimino)cyanoacetate (Oxyma) and diisopropylcarbodiimide (DIC) has demonstrated superior performance in amino acid activation for peptide synthesis. However, it was recently reported that Oxyma and DIC could react to generate undesired hydrogen cyanide (HCN) at 20 °C, raising safety concerns for the practical use of this activation strategy. To help minimize the risks, there is a need for a comprehensive investigation of the mechanism and kinetics of the generation of HCN. Here we show the results of the first systematic computational study of the underpinning mechanism, including comparisons with experimental data. Two pathways for the decomposition of the Oxyma/DIC adduct are derived to account for the generation of HCN and its accompanying cyclic product. These two mechanisms differ in the electrophilic carbon atom attacked by the nucleophilic sp2-nitrogen in the cyclization step and in the cyclic product generated. On the basis of computed "observed" activation energies, ΔG obs ⧧, the mechanism that proceeds via the attack of the sp2-nitrogen at the oxime carbon is identified as the most kinetically favorable one, a conclusion that is supported by closer agreement between predicted and experimental 13C NMR data. These results can provide a theoretical basis to develop a design strategy for suppressing HCN generation when using Oxyma/DIC for amino acid activation.

Mechanistic Study of Diketopiperazine Formation during Solid-Phase Peptide Synthesis of Tirzepatide.

This study focused on investigating diketopiperazine (DKP) and the formation of associated double-amino-acid deletion impurities during linear solid-phase peptide synthesis (SPPS) of tirzepatide (TZP). We identified that the DKP formation primarily occurred during the Fmoc-deprotection reaction and post-coupling aging of the unstable Fmoc-Pro-Pro-Ser-resin active pharmaceutical ingredient (API) intermediate. Similar phenomena have also been observed for other TZP active pharmaceutical ingredient (API) intermediates that contain a penultimate proline amino acid, such as Fmoc-Ala-Pro-Pro-Pro-Ser-resin, Fmoc-Pro-Pro-Pro-Ser-resin, and Fmoc-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-resin, which are intermediates for both hybrid and linear synthesis approaches. During post-coupling aging, it is found that Fmoc deprotection can proceed in dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), and acetonitrile (ACN) solvents without any piperidine addition. Density functional theory (DFT) calculations showed that a peptide that has a penultimate proline stabilizes the transition state through the C-H···π interaction during Fmoc decomposition, which causes those peptides to be more prone to cascade-deprotection reactions. Pseudo-reaction pathways are then proposed, and a corresponding macrokinetics model is developed to allow accurate prediction of the TZP peptide intermediate self-deprotection and DKP formation rate. Based on those studies, control strategies for minimizing DKP formation were further investigated and an alternative to Fmoc protection was identified (Bsmoc-protected amino acids), which eliminated the formation of the DKP byproducts. In addition, the use of oxyma additives and lower storage temperature was demonstrated to markedly improve the peptide intermediate stability to DKP degradation pathways.

Substituent Effect Transmission Power of Alkyl, Alkenyl, Alkynyl, Phenyl, Thiophenyl, and Polyacene Spacers.

The transmission of substituent effect through a variety of spacers, that is to say, alkyl, alkenyl, alkynyl, phenyl, thiophenyl, and polyacene has been studied by modeling Y-G-X type molecular systems (Y: reaction center; G: spacer moiety; X: substituent) using B3LYP/6-31G(d,p) density functional theory calculations. The reaction center is always kept as a C=C double bond and the molecular electrostatic potential (MESP) minimum (Vmin ) observed for this bond showed subtle variation with respect to the changes in the spacer unit and the nature of substituent. Strong linear correlations are observed between Hammett substituent constants (σI and σp ) and Vmin , which recommend the aptness of Vmin as an electronic descriptor to quantify the substituent effect. Since Vmin offers an alternative measure of substituent effect, the correlation between Vmin and σp has been used for assessing the transmission of substituent effect through a variety of spacer moieties. The highest transmission coefficient (γ) is always observed for smaller spacer length. Among all the spacers, alkenyl showed the highest and alkyl showed the lowest transmission power. The study recommends the use of short chains of C=C double, C≡C triple or a combination of both as spacers for the effective transmission of substituent effect to the reaction center.

Correlation and Prediction of Redox Potentials of Hydrogen Evolution Mononuclear Cobalt Catalysts via Molecular Electrostatic Potential: A DFT Study.

Reduction potentials (E(0)) of six mononuclear cobalt catalysts (1-6) for hydrogen evolution reaction and electron donating/withdrawing effect of nine X-substituents on their macrocyclic ligand are reported at solvation effect-included B3P86/6-311+G** level of density functional theory. The electrostatic potential at the Co nucleus (V(Co)) is found to be a powerful descriptor of the electronic effect experienced by Co from the ligand environment. The V(Co) values vary substantially with respect to the nature of macrocycle, type of apical ligands, nature of substituent and oxidation state of the metal center. Most importantly, V(Co) values of both the oxidized and reduced states of all the six complexes show strong linear correlation with E(0). The correlation plots between V(Co) and E(0) provide an easy-to-interpret graphical interpretation and quantification of the effect of ligand environment on the reduction potential. Further, on the basis of a correlation between the relative V(Co) and relative E(0) values of a catalyst with respect to the CF3-substituted reference system, the E(0) of any X-substituted 1-6 complexes is predicted.

Nickel-catalyzed double carboxylation of alkynes employing carbon dioxide.

The nickel-catalyzed double carboxylation of internal alkynes employing carbon dioxide (CO2) has been developed. The reactions proceed under CO2 (1 atm) at room temperature in the presence of a nickel catalyst, Zn powder as a reducing reagent, and MgBr2 as an indispensable additive. Various internal alkynes could be converted to the corresponding maleic anhydrides in good to high yields. DFT calculations disclosed the indispensable role of MgBr2 in the second CO2 insertion.

The crucial roles of MgCl2 as a non-innocent additive in the Ni-catalyzed carboxylation of benzyl halide with CO2.

Ni-catalyzed carboxylation of the C(sp(3))-Cl bond with CO2 in the presence of MgCl2 was theoretically investigated. MgCl2 plays three crucial roles in stabilization of a Ni(I)-CO2 adduct and acceleration of the CO2 insertion as a non-innocent additive and the one-electron reduction process as one kind of reagent.

σ-Bond activation of small molecules and reactions catalyzed by transition-metal complexes: theoretical understanding of electronic processes.

σ-Bond activations of R1-R2 and R1-X1 (R1, R2 = H, alkyl, aromatics, etc.; X1 = electronegative group) by transition-metal complexes are classified into two main categories: σ-bond activation by a metal (M) center and that by a metal-ligand bond. The former is classified into two subcategories: concerted oxidative addition to M and stepwise oxidative addition via nucleophilic attack of M. The latter is also classified into two subcategories: heterolytic activaton by M-X2 (X2 = anion ligand) and oxidative addition to M-L (L = neutral ligand). In the concerted oxidative addition, charge transfer (CT) occurs from the M d orbital to the σ* antibonding orbital of R1-R2, the clear evidence of which is presented here. The concerted oxidative additions of Ph-CN, Me-CN, and Ph-Cl to a nickel(0) complex are discussed as examples. The stepwise oxidative addition occurs through nucleophilic attack of M to R1-X1 to form an ion-pair intermediate. In the nucleophilic attack, CT occurs from the M dσ to either the σ* orbital or empty pπ orbital of R1-X1. Solvation plays a crucial role in stabilizing the transition state and ion-pair intermediate. The oxidative addition reactions of Ph-I, CH3-Br, and Br2B(OSiH3) to platinum(0), platinum(II), and palladium(0) complexes are discussed. In the heterolytic activation of R1-R2 by an M-X2 bond, R1 and R2 are bound with M and X2, respectively, indicating that R1 becomes anion-like and R2 becomes cation-like. CT mainly occurs from the X2 ligand to the σ* antibonding orbital of R1-R2 and also from R1 to the M empty d orbital. In the oxidative addition to an M-L moiety, R1 is bound with M, R2 is bound with L, and thus-formed L-R2 is bound with M. The oxidative addition reaction of the Si-H bond of silane to Cp2Zr(C2H4) and that of the H-H bond of H2 to Ni[MesB(o-Ph2PC6H4)2] are discussed as examples. The importance of the σ-bond activation in such catalytic reactions as nickel(0)-catalyzed phenylcyanation of alkyne, nickel(0)-catalyzed carboxylation of phenyl chloride, ruthenium(II)-catalyzed hydrogenation of carbon dioxide, and the Hiyama cross-coupling reaction is discussed based on theoretical studies.

The crucial role of a Ni(I) intermediate in Ni-catalyzed carboxylation of aryl chloride with CO2: a theoretical study.

In Ni(0)-catalyzed carboxylation reaction of aryl chloride with CO2, the formation of a Ni(I) species is crucial, because the CO2 insertion into the Ni(I)-Ph bond easily occurs but that into the Ni(II)-Ph bond cannot. This is a key point of this successful carboxylation reaction.

Resonance enhancement via imidazole substitution predicts new cation receptors.

Design and development of cation receptors represent a fascinating area of research, particularly in dealing with chemical and biological applications that require fine-tuning of cation-π interactions. The electronic nature of a substituent is largely responsible for tuning the strength of cation-π interaction, and recent studies have shown that substituent resonance effect contributes significantly to such interactions. Using substituent resonance effect as a key electronic factor, we have proposed new cation-π receptors (1···M(+)-4···M(+); M(+) = Li(+), Na(+), K(+), NH4(+), and NMe4(+)). B3LYP/6-311+G(d,p) density functional theory (DFT) calculations show that by using a strategy of resonance donation from six nitrogen atoms via three substituted imidazole subunits, more than 4-fold increase in cation-π interaction energy (E(M)(+)) can be achieved for a single phenyl ring compared to benzene. The E(M)(+) (M(+) = NH4(+), NMe4(+)) of 4···M(+), wherein M(+) interacts with only one phenyl ring, is significantly higher than E(M)(+) of a known cation host with several aromatic rings (abstract figure). Our hypothesis on resonance enhancement of cation-π interaction is verified using several π-systems (5-10) containing a lone pair bearing six nitrogens and observed that a nitrogen lone pair attached to a double bond is more effective for donation than the lone pair that is directly attached to the benzenoid ring. Further, a convenient strategy to design electron rich π-systems is provided on the basis of topographical analysis of molecular electrostatic potential.

Accurate prediction of cation-π interaction energy using substituent effects.

Substituent effects on cation-π interactions have been quantified using a variety of Φ-X···M(+) complexes where Φ, X, and M(+) are the π-system, substituent, and cation, respectively. The cation-π interaction energy, E(M(+)), showed a strong linear correlation with the molecular electrostatic potential (MESP) based measure of the substituent effect, ΔV(min) (the difference between the MESP minimum (V(min)) on the π-region of a substituted system and the corresponding unsubstituted system). This linear relationship is E(M(+)) = C(M(+))(ΔV(min)) + E(M(+))' where C(M(+)) is the reaction constant and E(M(+))' is the cation-π interaction energy of the unsubstituted complex. This relationship is similar to the Hammett equation and its first term yields the substituent contribution of the cation-π interaction energy. Further, a linear correlation between C(M(+))() and E(M(+))()' has been established, which facilitates the prediction of C(M(+)) for unknown cations. Thus, a prediction of E(M(+)) for any Φ-X···M(+) complex is achieved by knowing the values of E(M(+))' and ΔV(min). The generality of the equation is tested for a variety of cations (Li(+), Na(+), K(+), Mg(+), BeCl(+), MgCl(+), CaCl(+), TiCl(3)(+), CrCl(2)(+), NiCl(+), Cu(+), ZnCl(+), NH(4)(+), CH(3)NH(3)(+), N(CH(3))(4)(+), C(NH(2))(3)(+)), substituents (N(CH(3))(2), NH(2), OCH(3), CH(3), OH, H, SCH(3), SH, CCH, F, Cl, COOH, CHO, CF(3), CN, NO(2)), and a large number of π-systems. The tested systems also include multiple substituted π-systems, viz. ethylene, acetylene, hexa-1,3,5-triene, benzene, naphthalene, indole, pyrrole, phenylalanine, tryptophan, tyrosine, azulene, pyrene, [6]-cyclacene, and corannulene and found that E(M)(+) follows the additivity of substituent effects. Further, the substituent effects on cationic sandwich complexes of the type C(6)H(6)···M(+)···C(6)H(5)X have been assessed and found that E(M(+)) can be predicted with 97.7% accuracy using the values of E(M(+))' and ΔV(min). All the Φ-X···M(+) systems showed good agreement between the calculated and predicted E(M(+))() values, suggesting that the ΔV(min) approach to substituent effect is accurate and useful for predicting the interactive behavior of substituted π-systems with cations.

Quantitative assessment of substituent effects on cation-π interactions using molecular electrostatic potential topography.

A molecular electrostatic potential (MESP) topography based approach has been proposed to quantify the substituent effects on cation-π interactions in complexes of mono-, di-, tri-, and hexasubstituted benzenes with Li(+), Na(+), K(+), and NH(4)(+). The MESP minimum (V(min)) on the π-region of C(6)H(5)X showed strong linear dependency to the cation-π interaction energy, E(M(+)). Further, cation-π distance correlated well with V(min)-π distance. The difference between V(min) of C(6)H(5)X and C(6)H(6) (ΔV(min)) is proposed as a good parameter to quantify the substituent effect on cation-π interaction. Compared to benzene, electron-donating groups stabilize the di-, tri-, and hexasubstituted cation-π complexes while electron-withdrawing groups destabilize them. In multiple substituted complexes, E(M(+)) is almost equal (∼95%) to the sum of the individual substituent contributions (E(M(+)) ≈ Σ(ΔE(M(+)))), suggesting that substituent effect on cation-π interactions is largely additive. The ΔV(min) of C(6)H(5)X systems and additivity feature have been used to make predictions on the interaction energies of 80 multiple substituted cation-π complexes with above 97% accuracy. The average mean absolute deviation of the V(min)-predicted interaction energy, E(M(+))(V) from the calculated E(M(+)) is -0.18 kcal/mol for Li(+), -0.09 kcal/mol for Na(+), -0.43 kcal/mol for K(+), and -0.67 kcal/mol for NH(4)(+), which emphasize the predictive power of V(min) as well as the additive feature of the substituent effect.

Substituent effects in cation-π interactions: a unified view from inductive, resonance, and through-space effects.

The quantification of inductive (I), resonance (R), and through-space (TS) effects of a variety of substituents (X) in cation-π interactions of the type C6H5X···Na⁺ is achieved by modeling C6H5-(Φ1)(n)-X···Na⁺ (1), C6H5-(Φ2)(n)-X···Na⁺ (2), C6H5-(Φ(2perpendicular))(n)-X···Na⁺ (2'), and C6H6 ···HX···Na⁺ (3), where Φ1 = -CH2CH2-, Φ2 = -CHCH-, Φ(2perpendicular) indicates that Φ2 is perpendicular to the plane of C6H5, and n = 1-5. The cation-π interaction energies of 1, 2, 2', and 3, relative to X = H and fitted to polynomial equations in n have been used to extract the substituent effect E0¹, E0², E0(2'), and E0³ for n = 0, the C6H5X···Na⁺ systems. E0¹ is made up of inductive (E(I)) and through-space (E(TS)) effects while the difference (E0² - E0(2')) is purely resonance (E(R)) and E0³ is attributed to the TS contribution (E(TS)) of the X. The total interaction energy of C6H5X···Na⁺ is nearly equal to the sum of E(I), E(R), and E(TS), which brings out the unified view of cation-π interaction in terms of I, R, and TS effects. The electron-withdrawing substituents contribute largely by TS effect, whereas the electron-donating substituents contribute mainly by resonance effect to the total cation-π interaction energy.

Analysis of structural water and CH···π interactions in HIV-1 protease and PTP1B complexes using a hydrogen bond prediction tool, HBPredicT.

A hydrogen bond prediction tool HBPredicT is developed for detecting structural water molecules and CH···π interactions in PDB files of protein-ligand complexes. The program adds the missing hydrogen atoms to the protein, ligands, and oxygen atoms of water molecules and subsequently all the hydrogen bonds in the complex are located using specific geometrical criteria. Hydrogen bonds are classified into various types based on (i) donor and acceptor atoms, and interactions such as (ii) protein-protein, (iii) protein-ligand, (iv) protein-water, (v) ligand-water, (vi) water-water, and (vii) protein-water-ligand. Using the information in category (vii), the water molecules which form hydrogen bonds with the ligand and the protein simultaneously-the structural water-is identified and retrieved along with the associated ligand and protein residues. For CH···π interactions, the relevant portions of the corresponding structures are also extracted in the output. The application potential of this program is tested using 19 HIV-1 protease and 11 PTP1B inhibitor complexes. All the systems showed presence of structural water molecules and in several cases, the CH···π interaction between ligand and protein are detected. A rare occurrence of CH···π interactions emanating from both faces of a phenyl ring of the inhibitor is identified in HIV-1 protease 1D4L.

Appraisal of through-bond and through-space substituent effects via molecular electrostatic potential topography.

Through-bond (TB) and through-space (TS) substituent effects in substituted alkyl, alkenyl, and alkynyl arenes are quantified separately using molecular electrostatic potential (MESP) topographical analysis. The deepest MESP point over the aromatic ring (V(min)) is considered as a probe for monitoring these effects for a variety of substituents. In the case of substituted alkyl chains, the TS effect (79.6%) clearly dominates the TB effect, whereas in the unsaturated analogues the TB effect (∼55%) overrides the TS effect.