Bifunctional iminophosphorane organocatalyst with additional hydrogen bonding: Calculations predict enhanced catalytic performance in a michael addition reaction.

A new iminophosphorane-thiourea superbase was rationally designed and investigated as an organocatalyst for the enantioselective Michael addition reaction of nitromethane to 4-phenylbut-3-en-2-one. Starting from an iminophosphorane-thiourea organocatalyst structure already known, we have used theoretical calculations to determine the structures of transition states involved in the carbon-carbon bond formation step and carried out structural modifications to accelerate the reaction rate and to increase the enantioselectivity. The effective structural modification was adding a rigid hydroxyl group able to make an additional hydrogen bond to the transition state, producing a substantial decrease of the ΔG‡ by 7 kcal mol-1. The enantiomeric excess is predicted to be above of 97% using the reliable M06-2X and ωB97M - V functionals. The determination of the complete reaction mechanism and free energy profile was followed by a detailed microkinetic analysis. The present study points out a new direction for structural modifications on this kind of organocatalyst.

Modeling the alkylation of amines with alkyl bromides: explaining the low selectivity due to multiple alkylation.

CONTEXT: Nucleophilic substitution reactions of aliphatic amines with alkyl halides represent a simple and direct mechanism for obtaining higher-order aliphatic amines. However, it is well known that these reactions suffer from low selectivity due to multiple alkylations, which is attributed to the higher reactivity of the newly formed amine. In order to provide a detailed explanation for this kind of system, we have investigated the reactivity of primary and secondary amines with 1-bromopropane and 2-bromopropane. The free energy profile in acetonitrile solution was obtained and a detailed microkinetic analysis was needed to analyze this complex reaction system. We have found that the product of the first alkylation is an ion pair corresponding to the protonated secondary amine and the bromide ion, which can transfer the proton to the reactant primary amine. Then, the newly formed secondary amine can also react, leading to a second alkylation to produce a tertiary protonated amine. Our modeling points out that both the proton transfer equilibria and the similar reactivity of the primary and secondary amines produce reduced selectivity. The proton transfer equilibria also contribute to slowing down the kinetics of the first alkylation. METHODS: The exploration of the mechanism was done by geometry optimization using the CPCM/X3LYP/ma-def2-SVP method, followed by harmonic frequency calculation at this same level of theory. A composite approach was used to obtain the free energy profile, using the more accurate ωB97X-D3/ma-def2-TZVPP level of theory for electronic energy and the SMD model for the solvation free energy. These calculations were performed with the ORCA 4 program. The detailed microkinetic analysis was done using the Kintecus program.

SN2 versus E2 reactions in a complex microsolvated environment: theoretical analysis of the equilibrium and activation steps of a nucleophilic fluorination.

The reactivity of the fluoride ion towards alkyl halides is highly dependent on the solvating environment. In polar aprotic solvents with large counter-ions is highly reactive and produces substantial E2 product, whereas in polar protic solvents leads to slow kinetics and high selectivity for SN2 reactions. The use of a more complex environment with stoichiometric addition of tert-butanol to acetonitrile solvent is able to module the reactivity and selectivity of tetrabutylammonium fluoride (TBAF). In the present work, we have performed a detailed theoretical analysis of this complex reaction system by density functional theory, continuum solvation model, and including explicit tert-butanol molecules. A kinetic model based on the free energy profile was also used to predict the reactivity and selectivity. The results indicated that the TBAF(tert-butanol) complex plays the key role to increase the SN2 selectivity, whereas higher aggregates are not relevant. The E2 product is formed exclusively via free TBAF, because the solvating tert-butanol in the TBAF(tert-butanol) complex inhibits the E2 pathway. Our analysis suggests that diols or tetraols could produce an improved selectivity.

Single-ion solvation free energy: A new cluster-continuum approach based on the cluster expansion method.

Accurate calculation of the solvation free energy of single ions remains an important goal, involving development in the dielectric continuum solvation models, and statistical mechanics with explicit solvent and hybrid discrete-continuum methods. In the last case, many of the research studies involve a quasi-chemical approach using the monomer cycle or the cluster cycle to calculate the solvation free energy of single ions. In this work, a different cluster-continuum approach based on the cluster expansion method was tested for solvation of 16 cations and 32 anions in aqueous solution. The SMD model was used for the dielectric continuum part and three explicit water molecules were introduced in the region of the solute with the highest interaction energy. Harmonic frequency calculations and molecular dynamics sampling of configurations are not required. An empirical γN parameter for cations and another for anions is introduced. The method produces a substantial improvement of the SMD model with a mean absolute deviation of 2.3 kcal mol-1 for cations and 2.9 kcal mol-1 for anions. The analysis of the correlation between theoretical and experimental data produces a linear regression line with a slope of 1.09 for cations and 1.01 for anions. The good results of this approximated cluster expansion approach suggest that the method could be further improved by including more solvent molecules and sampling the configurations.

The role of intermolecular forces in ionic reactions: the solvent effect, ion-pairing, aggregates and structured environment.

The environment enclosing an ionic species has a critical effect on its reactivity. In a more general sense, medium effects are not limited to the solvent, but involve the counter ion effect (ion pairing), formation of larger aggregates and structured environment as provided by the host in the case of host-guest complexes. In this review, a general view of the medium effect on anion-molecule reactions is presented. Nucleophilic substitution reactions of aliphatic (SN2) and aromatic (SNAr) systems, as well as elimination reactions (E2), are the focus of the discussion. In particular, nucleophilic fluorination with KF, CsF and tetraalkylammonium fluoride was used as the main model, because of the importance of this kind of reaction and the recent advances in the study of these systems. The solvent effect, ion pairing, formation of aggregates and formation of complexes with crown ethers, cryptands and calixarenes are discussed. For a deeper insight into the medium effect, many results of reliable theoretical calculations in close agreement with experiments were chosen as examples.

Nucleophilic Fluorination with KF Catalyzed by 18-Crown-6 and Bulky Diols: A Theoretical and Experimental Study.

The activation of potassium fluoride for nucleophilic fluorination of alkyl halides is an important challenge because of the high lattice energy of this salt and its low solubility in many polar aprotic solvents. Crown ethers have been used for increasing the solubilization of KF during several decades. Nevertheless, these macrocycles are not enough to produce a high reaction rate. In this work, theoretical methods were used for designing a synergic combination of bulky diols with crown ethers able to accelerate this kind of reaction. The calculations have predicted that the bulky diol 1,4-Bis(2-hydroxy-2-propyl)benzene, which has distant hydroxyl groups, is able to catalyze nucleophilic fluorination in combination with 18-crown-6 via two hydrogen bonds to the SN2 transition state. Experimental studies following the theoretical predictions have confirmed the catalytic effect and the estimated kinetic data point out that the bulky diol at 1 mol L-1 in combination with 18-crown-6 is able to produce an 18-fold increase in the reaction rate in relation to crown ether catalysis only. The reaction produces 46% yield of fluorination after 24 h at moderate temperature of 82 °C, with minimal formation of the side elimination product. Thus, this work presents an improved method for fluorination with KF salt.

Theoretical free energy profile and benchmarking of functionals for amino-thiourea organocatalyzed nitro-Michael addition reaction.

Amino-thiourea organocatalysis is an important catalytic process for enantioselective conjugate addition reactions. The interaction of the reactants with the catalyst has a substantial effect of dispersion forces and is a challenge for a reliable description when applying density functional theory. In this report, the classical addition of acetylacetone to ß-nitro-styrene catalyzed by Takemoto's catalyst in toluene was studied using the PBE functional for geometry optimization and the DLPNO-CCSD(T) benchmark method for single point energy. The complete free energy profile calculated for the reaction was able to explain all experimental observations, including the fact that the carbon-carbon bond formation step is rate-determining. The overall barrier was calculated to be 22.8 kcal mol-1 (experimental value approximately 20 kcal mol-1), and the enantiomeric excess was calculated to be 88% (experimental value in the range of 84 to 92%). Some functionals were tested for single point energy. The hybrid B3LYP presented a high mean absolute deviation (MAD) from the DLPNO-CCSD(T) benchmark method by approximately 20 kcal mol-1. The inclusion of empirical dispersion correction in the B3LYP method decreased the MAD to 6 kcal mol-1. Even the double-hybrid mPW2-PLYP and B2GP-PLYP methods had MAD values of approximately 5 kcal mol-1. The inclusion of the dispersion correction decreased the MAD to 3.6 kcal mol-1. M06-2X and ωB97X-D3 were the most accurate among the tested functionals, with MADs of 2.5 kcal mol-1 and 1.8 kcal mol-1, respectively. Additivity approximation of the correlation energy was also tested and presented a MAD of only 0.6 kcal mol-1.

Free Energy Profile of a Model Palladium Catalyzed Fluorination of Aryl Bromide with Cesium Fluoride.

Addition of fluorine to aromatic rings has increased in importance in the past decade in view of the increased role of organofluorine compounds in the design of new pharmaceuticals. Palladium catalyzed nucleophilic fluorination of unactivated aryl halides using salts such as cesium fluoride was achieved with the use of bulky biaryl monophosphine ligand. Simple monophosphine palladium complexes were not able to promote this reaction, which is attributed to the difficult reductive elimination step and the formation of dimers of the PdL(Ph)(F) intermediate. The use of theoretical methods for reliable design of new ligands requires the knowledge of the complete free energy profile of the catalyzed reaction. Otherwise, predictions may not be observed. In this work, a complete free energy profile of a model palladium catalyzed fluorination (trimethyl phosphine ligand), including the precatalyst decomposition mechanism (allylpalladium chloride), was investigated using a reliable theoretical method, the mPW2-PLYP double-hybrid functional, which was compared with the DLPNO-CCSD(T) benchmark method. The results suggest that palladium(π-cinnamyl) chloride is not a good precatalyst, while the monophosphine palladium complex bonded to an alkene should work better. The transmetalation step raises the overall barrier for the reductive elimination by 4.3 kcal mol-1 in the case of monophosphine catalyst, making the reaction difficult (ΔG⧧ = 34.1 kcal mol-1), even in the case of no dimerization of the monophosphine palladium fluoride complex. Thus, success of a ligand to promote palladium catalysis requires not only a monophosphine ligand that avoids dimerization but also a strong repulsion to both phenyl and fluorine bonded to the palladium in the PdL(Ph)(F) complex.

Free energy profile and microkinetic modeling of base-catalyzed conjugate addition reaction of nitroalkanes to α,ß-unsaturated ketones in polar and apolar solvents.

Michael reactions involving nitroalkanes and enones are important carbon-carbon bond formation reactions. These reactions are base-catalyzed, and during the past 15 years, the asymmetric version using bifunctional amino-thiourea organocatalyst has been developed. In this work, the reaction of nitromethane and 4-phenyl-3-buten-2-one, catalyzed by the methoxide ion and piperidine as bases, was investigated by theoretical calculations. We obtained the theoretical free energy profile and did a microkinetic analysis of the catalytic cycle. The direct reaction of the CH2NO2- ion and the enone is very favorable, with a free energy of activation of 21.1 kcal mol-1 in methanol solvent. However, the generated MS2 product works like an inhibitor of the catalysis, and the effective barrier in the catalytic cycle becomes 25.5 kcal mol-1, leading to slow kinetics at room temperature. In the case of the reaction in apolar solvent (toluene), we found a pathway involving isomerization from the CH3NO2 reactant to the CH2NO2H species, and the latter makes a nucleophilic attack on the enone. Piperidine works like a bifunctional catalyst. In this case, the barrier is very high (32.5 kcal mol-1), indicating the importance of the polar environment to accelerate the reaction in the catalytic cycle. Graphical abstract Base-catalyzed conjugate addition reaction of nitroalkanes to α,ß-unsaturated ketones.

Potassium fluoride activation for the nucleophilic fluorination reaction using 18-crown-6, [2.2.2]-cryptand, pentaethylene glycol and comparison with the new hydro-crown scaffold: a theoretical analysis.

Activation of potassium fluoride salt for selective and fast nucleophilic fluorination requires its solubilization and stabilization of the respective transition state. This goal can be achieved through control of the nano-environment around the reactants via cation or ion-pair binding catalysis. In this work, six different species were theoretically investigated as promoters and catalysts for nucleophilic fluorination: tri-tert-butanolamine, 18-crown-6, pentaethylene glycol, [2.2.2]-cryptand, and two new hydroxylated crown ethers (hydro-crowns). Calculations using the PBE functional and the LPNO-CEPA method, as well as the SMD continuum model, were carried out for the SN2 reaction of KF with ethyl bromide in toluene solution as a model system. The present study points out that [2.2.2]-cryptand is the most effective promoter of the reaction when using stoichiometric quantities. In the case of a catalytic process, the new DB18C6-4OH is the most effective molecule considering only a 1 : 1 complex. The hydroxyl groups are important for the solubilization of potassium fluoride and for the catalytic cycle. Nevertheless, the DB18C6-4OH hydro-crown can form a 2 : 2 complex and is needed to add bulk groups close to the hydroxyls to avoid dimerization. The calculated overall free energy of activation for reactions promoted by 18-crown-6, pentaethylene glycol, and [2.2.2]-cryptand is in good agreement with the experimental data.

Infinite dilution activity coefficient from SMD calculations: accuracy and performance for predicting liquid-liquid equilibria.

Prediction of liquid-liquid phase equilibria is an important goal in the physical chemistry of solutions. Quantum chemistry methods, combined with a dielectric continuum description of the solvent, has received attention as a first principle approach. In this work, the performance of the continuum solvation model based on density (SMD) for prediction of γ∞ in binary liquid mixtures, using 46 values of γ∞, was evaluated. We found the mean uncertainty of RTln γ∞ to be 0.92 kcal mol-1. Based on the calculated γ∞ and the two parameters of the Redlich-Kister expansion, we calculated the liquid-liquid phase equilibria. Based on 26 values of solubility, an uncertainty of 0.66 was found in the logarithm of molar fraction of the smallest component in each phase. Our results suggest this approach can be used for fast and semi-quantitative prediction of phase behavior. More reliable predictions could be obtained with improvements in the SMD model. Graphical abstract Prediction of liquid-liquid phase equilibriaᅟ.

Cluster expansion of the solvation free energy difference: Systematic improvements in the solvation of single ions.

The cluster expansion method has been used in the imperfect gas theory for several decades. This paper proposes a cluster expansion of the solvation free energy difference. This difference, which results from a change in the solute-solvent potential energy, can be written as the logarithm of a finite series. Similar to the Mayer function, the terms in the series are related to configurational integrals, which makes the integrand relevant only for configurations of the solvent molecules close to the solute. In addition, the terms involve interaction of solute with one, two, and so on solvent molecules. The approach could be used for hybrid quantum mechanical and molecular mechanics methods or mixed cluster-continuum approximation. A simple form of the theory was applied for prediction of pKa in methanol; the results indicated that three explicit methanol molecules and the dielectric continuum lead to a root of mean squared error (RMSE) of only 1.3 pKa units, whereas the pure continuum solvation model based on density method leads to a RMSE of 6.6 pKa units.

Mechanism of the Piperidine-Catalyzed Knoevenagel Condensation Reaction in Methanol: The Role of Iminium and Enolate Ions.

The free energy profile of the piperidine catalyzed Knoevenagel condensation reaction of acetylacetone with benzaldehyde has been obtained by theoretical calculations. The carbinolamine formation step involves catalysis by methanol solvent, and its decomposition takes place via hydroxide ion elimination without a classical transition state, leading to the iminium ion. Hydroxide ion deprotonates the acetylacetone, forming an enolate that attacks the iminium ion and leads to an addition intermediate. The final step involves elimination of piperidine catalyst. Our analysis suggests the iminium ion formation has the highest barrier and the catalytic effect of piperidine is facilitating the elimination step rather than activation of the benzaldehyde electrophile. Experimental measures of the kinetics lead to an observed free energy barrier of 20.0 kcal mol-1, in good agreement with the theoretical value of 21.8 kcal mol-1 based on the free energy profile.

CMIRS Solvation Model for Methanol: Parametrization, Testing, and Comparison with SMD, SM8, and COSMO-RS.

The new continuum solvation model, composite method for implicit representation of solvent (CMIRS), proposed by Pomogaeva and Chipman and implemented in GAMESS was parametrized for methanol solvent, with the aim of using it for ionic reactions in solution. The model was tested for predicting single-ion solvation free energy, pKa of acids and protonated bases, and the activation free-energy barriers of SN2 and SNAr reactions in methanol. A comparison was performed with other continuum models, such as SMD, SM8, and COSMO-RS. For a prediction of pKa and free-energy barriers, the order of performance was CMIRS > COSMO-RS > SMD > SM8. In particular, the CMIRS model is much superior to the other continuum models for predicting pKa of acids (without empirical corrections) and is able to evenly describe hard ions like methoxide and charge-dispersed ions like 2,4,6-trinitrophenol. On the basis of our results, we suggest that the field-extremum contribution, present in CMIRS, should be included in continuum solvation models, which can result in substantial improvement in the modeling of ionic reactions in solution.

Theoretical Design and Calculation of a Crown Ether Phase-Transfer-Catalyst Scaffold for Nucleophilic Fluorination Merging Two Catalytic Concepts.

Fluorinated organic molecules are playing an increased role in the area of pharmaceuticals and agrochemicals. This fact demands the development of efficient catalytic fluorination processes. In this paper, we have designed a new crown ether with four hydroxyl groups strategically positioned. The catalytic activity of this basic scaffold was investigated with high levels of electronic structure theory, such as the ONIOM approach combining MP4 and MP2 methods. On the basis of the calculations, this new structure is able to solubilize potassium fluoride in toluene solution much more efficiently than 18-crown-6 (18C6). In addition, the strong interaction of the new catalyst with the SN2 transition state leads to a very important catalytic effect, with a predicted free energy barrier of 23.3 kcal mol(-1) for potassium fluoride plus ethyl bromide reaction model. Compared with experimental data and previous theoretical studies, this new catalyst is 10(4) times more efficient than 18C6 for nucleophilic fluorination of alkyl halides. The catalysis is predicted to be selective, leading to 97% of fluorination and only 3% of elimination. Catalytic fluorination of the aromatic ring has also been investigated, and although the catalyst is less efficient in this case, our analysis has indicated further development of this strategy can lead to more efficient catalysis.

Cluster-continuum quasichemical theory calculation of the lithium ion solvation in water, acetonitrile and dimethyl sulfoxide: an absolute single-ion solvation free energy scale.

Absolute single-ion solvation free energy is a very useful property for understanding solution phase chemistry. The real solvation free energy of an ion depends on its interaction with the solvent molecules and on the net potential inside the solute cavity. The tetraphenyl arsonium-tetraphenyl borate (TATB) assumption as well as the cluster-continuum quasichemical theory (CC-QCT) approach for Li(+) solvation allows access to a solvation scale excluding the net potential. We have determined this free energy scale investigating the solvation of the lithium ion in water (H2O), acetonitrile (CH3CN) and dimethyl sulfoxide (DMSO) solvents via the CC-QCT approach. Our calculations at the MP2 and MP4 levels with basis sets up to the QZVPP+diff quality, and including solvation of the clusters and solvent molecules by the dielectric continuum SMD method, predict the solvation free energy of Li(+) as -116.1, -120.6 and -123.6 kcal mol(-1) in H2O, CH3CN and DMSO solvents, respectively (1 mol L(-1) standard state). These values are compatible with the solvation free energy of the proton of -253.4, -253.2 and -261.1 kcal mol(-1) in H2O, CH3CN and DMSO solvents, respectively. Deviations from the experimental TATB scale are only 1.3 kcal mol(-1) in H2O and 1.8 kcal mol(-1) in DMSO solvents. However, in the case of CH3CN, the deviation reaches a value of 9.2 kcal mol(-1). The present study suggests that the experimental TATB scale is inconsistent for CH3CN. A total of 125 values of the solvation free energy of ions in these three solvents were obtained. These new data should be useful for the development of theoretical solvation models.

The role of ammonia oxide in the reaction of hydroxylamine with carboxylic esters.

Theoretical calculations indicate that hydroxylamine can exist in both neutral and zwitterionic (ammonia oxide) forms in aqueous solution, the former being 3.5 kcal mol(-1) more stable. In this report, we have studied the reaction mechanism of hydroxylamine with phenyl acetate and analyzed the role of the zwitterionic isomer. We have observed that the main reaction pathway takes place through the zwitterionic form with a concerted mechanism, not involving the classical tetrahedral intermediate. Attack by the nitrogen atom (via neutral isomer) has a minor contribution and it is also a concerted process. The activation free energy barriers in aqueous solution were calculated at the MP4/TZVPP + diff level for gas phase energies, CPCM for optimization and frequencies, and through single point calculation of the solvation free energy using the SM8 method. Our theoretically predicted barriers are 20.8 and 23.8 kcal mol(-1) for O and N attack, respectively, in very good agreement with the experimental values of 20.4 and 22.3 kcal mol(-1), respectively. Our results support the view that hydroxylamine is a very special nucleophile and the reactivity of this functional group should be further investigated.

Performance of the SMD and SM8 models for predicting solvation free energy of neutral solutes in methanol, dimethyl sulfoxide and acetonitrile.

The continuum solvation models SMD and SM8 were developed using 2,346 solvation free energy values for 318 neutral molecules in 91 solvents as reference. However, no solvation data of neutral solutes in methanol was used in the parametrization, while only few solvation free energy values of solutes in dimethyl sulfoxide and acetonitrile were used. In this report, we have tested the performance of the models for these important solvents. Taking data from literature, we have generated solvation free energy, enthalpy and entropy values for 37 solutes in methanol, 21 solutes in dimethyl sulfoxide and 19 solutes in acetonitrile. Both SMD and SM8 models have presented a good performance in methanol and acetonitrile, with mean unsigned error equal or less than 0.66 and 0.55 kcal mol(-1) in methanol and acetonitrile, respectively. However, the correlation is worse in dimethyl sulfoxide, where the SMD and SM8 methods present mean unsigned error of 1.02 and 0.95 kcal mol(-1), respectively. Our results point out the SMx family of models need be improved for dimethyl sulfoxide solvent.

Theoretical prediction of pKa in methanol: testing SM8 and SMD models for carboxylic acids, phenols, and amines.

Methanol is a widely used solvent for chemical reactions and has solvation properties similar to those of water. However, the performance of continuum solvation models in this solvent has not been tested yet. In this report, we have investigated the performance of the SM8 and SMD models for pKa prediction of 26 carboxylic acids, 24 phenols, and 23 amines in methanol. The gas phase contribution was included at the X3LYP/TZVPP+diff//X3LYP/DZV+P(d) level. Using the proton exchange reaction with acetic acid, phenol, and ammonia as reference species leads to RMS error in the range of 1.4 to 3.6 pKa units. This finding suggests that the performance of the continuum models for methanol is similar to that found for aqueous solvent. Application of simple empirical correction through a linear equation leads to accurate pKa prediction, with uncertainty less than 0.8 units with the SM8 method. Testing with the less expensive PBE1PBE/6-311+G** method results in a slight improvement in the results.

Revisiting the mechanism of neutral hydrolysis of esters: water autoionization mechanisms with acid or base initiation pathways.

The mechanism of neutral hydrolysis of ester has long been explored by theoretical studies. However, reliable theoretical calculations show that the usual bifunctional catalysis mechanism reported by different authors cannot explain the experimental kinetics. An important advance was recently reported by Gunaydin and Houk, suggesting that ions are involved in the mechanism and the process initiates by water autoionization followed by protonation of the ester (W(AI)A mechanism). However, this mechanism does not explain the hydrolysis of activated esters. In this work, we have used ab initio calculations, continuum solvation models, and intrinsic reaction coordinate method to support the W(AI)A mechanism for normal ester. In the case of activated esters, the process can also be viewed as water autoionization with formation of hydroxide ion aided by a second water molecule acting as a general base (W(AI)B mechanism). This is the mechanism that was proposed by Jencks and Carriuolo 50 years ago. Our analysis point out that the usual method for exploring mechanisms, searching for saddle points, may not work for problems like the present one, since there are no saddle points on the reaction pathway. Rather, the formation of a pair of ions from a neutral species may have an asymptotic barrier. The approach used in this paper allows the calculation of the free energy profile and enable us to explain the mechanism and kinetics of the neutral hydrolysis of normal (methyl acetate) and activated (methyl trifluoroacetate) esters. In addition, the present study suggests that formation of a pair of ions should always be considered in reactions in aqueous solution.