A DFT Approach to the Mechanistic Study of Hydrozone Hydrolysis

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A DFT Approach to the Mechanistic Study of Hydrozone Hydrolysis Ibrahim Yildiz J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.6b02882 • Publication Date (Web): 02 May 2016 Downloaded from http://pubs.acs.org on May 15, 2016

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The Journal of Physical Chemistry

A DFT Approach to the Mechanistic Study of Hydrozone Hydrolysis Author(s): Ibrahim Yildiz* *Assistant Professor, Applied Mathematics & Sciences, Khalifa University, PO Box 127788, Abu Dhabi, UAE Tel: +971 (0)2 401 8208, Fax: +971 (0)2 447 2442, e-mail:[email protected]

Abstract Hydrazone chemistry is widely utilized in biomedical field as a means of bioconjugation protocol, especially in drug delivery field due to pH labile nature of this linkage. In the light of kinetic studies, the generally accepted mechanism for the hydrolysis of hydrazones involves two main steps, namely nucleophilic addition of water molecule to the hydrazone molecule to form carbinolamine intermediate and subsequent decomposition of this intermediate into the hydrazine and aldehyde/ketone moieties. Hydrolysis of hydrazones are catalyzed in the acidic environments and are thought to proceed through several proton transfer steps. To the best of our knowledge, in the literature no detailed theoretical study has been reported related to the mechanism of hydrolysis. In this study, we evaluated the proposed mechanism with DFT calculations with M06-2X functional at the 6-311+g(d,p) level including CPCM solvation model. We also analyzed possible proton transfer pathways, and assessed energetics of each step.

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1. Introduction Molecules and polymers bearing hydrazone functional group(s) have garnered long-standing interest in various fields due to the unique features imparted to materials by the presence of this multi-modular chemical functionality.1

They were employed in the applications such as

molecular switches 2-3, sensors4-6, dynamic combinatorial libraries7-8; they have shown biological activity against a number of disorders 9; and hydrazone linkage was utilized in biomedical field as a stable and bio-orthogonal conjugation handle

10-13

. Besides, the pH labile nature of the

hydrazone bond led to the formation of smart materials capable of responding extra- and intracellular pH changes. This features have been used to generate stimuli responsive drug delivery platforms for a variety of applications.14-17 Mechanistic interpretation of formation as well as hydrolysis of hydrazones bear utmost importance in biomedical applications. It could help to design and synthesize novel constructs that can have optimum properties such as stability for bio-conjugation reactions, and tunable hydrolysis rates for drug delivery systems. The reversible nature of hydrazone formation and hydrolysis reactions provide mechanistic insights. A variety of catalysts have been found to accelerate the rate of hydrazone formation both in neutral and acidic solutions.18-21 Furthermore, it was found that groups that have acidic/basic features form hydrazones with faster kinetics without the use of catalyst.22-24 The generally accepted hydrolysis/formation mechanism of hydrazones--as well as of chemically similar imine functionalities such as oximes, and carbazones--with slight variations has been based on the early kinetic studies by Jencks

25-27

, and others

28-34

. Under acidic conditions, the

hydrolysis reaction starts with the protonation of nitrogen, N1, of hydrazone, 1, yielding 2 (Step 1), followed by H2O addition to C1 to form carbinolamine intermediate, 3 (Step 2). (Figure 1) In the following step, a proton is lost from positively charged oxygen, O1, to yield intermediate 4 (Step 3a) which decomposes into corresponding hydrazine (5) and aldehyde/ketone (6) species (Step 4a). In some studies, in an alternative pathway, a proton from O1 position at 3 is internally transferred to N1 to form 4’ (Step 3b) followed by the decomposition of 4’ into same products through loss of a proton from O1 to presumably to a suitable Lewis base (step 4b).28, 30 The rate of hydrolysis has been shown to depend on both the pH of the buffer solutions and the substituents at C1 and N2 positions.29-30, 35 It was found that the rate of hydrazone formation 1 ACS Paragon Plus Environment

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shows bell-shaped pH dependence, at near or above neutrality nucleophilic attack of hydrazine to carbonyl carbon (Step 4, reverse reaction) is assumed to be the rate determining step, whereas the dehydration of carbinolamine intermediate 3 is assumed to be the rate determining step at low pH values (Step 2, reverse reaction).33, 36 Kinetic studies of the hydrolysis reactions revealed that the hydrolysis mechanism follows the same trends similar to formation mechanism, that is to say, at low pH values the rate determining step corresponds to the decomposition of neutral carbinolamine intermediate (Step 4), whereas in neutral solutions, attack of water molecules to the C1 position of hydrazone (step 1) becomes the rate determining step.27, 37

Figure 1. The proposed mechanism for the hydrolysis of hydrazones

As the utilization of hydrazone functionality has become widespread in drug delivery systems, studies have been directed to understand how to control the hydrolysis rate in order to formulate platforms that display minimal hydrolysis during circulation in body, and that display enhanced hydrolysis rates in more acidic regions, i.e. extracellular tumor tissues or in organelles such as endosome and lysosome.38 Hydrazones formed from an acyl hydrazine (hydrazide) derivative and three different carbonyl compounds, which includes an aliphatic aldehyde, an aliphatic ketone, and aromatic ketone, the hydrazone derived from aromatic ketone has shown the most stability against hydrolysis at pH 7.4 and 5.0, while the aliphatic aldehyde derivative has shown the least stability.39 It was argued that conjugation of C1=N1 π bond with aromatic π system increases the stability of the hydrazone towards hydrolysis. Similarly, hydrazones formed from aromatic aldehydes exhibited better hydrolytic stability at pH 7.4 and 5.5 than aliphatic ones.35 In another study, hydrazones derived from hydrazines that have electron withdrawing groups at N2 position have shown enhanced hydrolysis rates in neutral water.34 This phenomenon was 2 ACS Paragon Plus Environment


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ascribed to the electrophilicity increase at C1 position which facilitates the attack of water molecules (Step 1, Figure 1) to initiate hydrolysis reaction.

Kalia et al. have reported a

comprehensive study in which they evaluated the hydrolytic stabilities of isostructural alkyl/acyl hydrazones and an oxime at pH 5-9 interval.29 They showed that in this pH range oxime linkage has shown the highest stability against hydrolysis. This phenomenon was attributed to resistance of N1 atom to the protonation (Figure 1, Step 1) due to replacement of N2 atom with a more electronegative oxygen atom. This finding has been corroborated with a recent study in which triazine-based hydrazones showed better stability than their isostructural acetylhydrazones at low pH due to the decrease of proton affinity of N1 atom.30 2. Computational Details and Methodology In this study, we evaluated the proposed hydrolysis mechanism for the hydrolysis of a model hydrazone compound, 1-Ethylidene-2-methylhydrazine (7 in Figure 2), to methyl hydrazine and acetaldehyde with M06-2X40 DFT functional at the 6-311+g(d,p) level using Gaussian 09 package41. The geometries of reactants, transition states, intermediates, and products were optimized in water using conductor-like polarizable continuum solvation model (CPCM).42 Frequency calculations were run to validate the reactants/products without negative frequencies and the transition states with only one imaginary frequency, and to calculate thermodynamic quantities at 25 °C and 1 atm. IRC (intrinsic reaction coordinate) calculations were run to confirm the reaction pathways connecting reactants and products through the located transition states.43 Transition states were estimated through potential energy scans (PES) using either optimized reactants or products by scanning bond coordinates, and then were optimized using Berny algorithm 44. In order to test the reliability of M06-2X as a model DFT functional to probe the hydrolysis mechanism, we have run some selected calculations with B3LYP45 and wB97XD46 functionals with the same basis set. The optimized geometries and energetics of selected steps did not differ considerably from M06-2X, and for the sake of simplicity only M062X calculations were reported here. Furthermore, since no detailed experimental results are available for the energetics of hydrolysis reaction, we did not consider as necessary to report the results of each functional and compare them.

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Figure 2. Structures of model compounds used in calculations

3.

Results and Discussions

3.1 Hydazone Protonation (Step 1) According to the proposed mechanism, the hydrolysis reaction starts with the protonation of N1 position. (Figure 1, Step 1) In order to shed light on the potential energy profile of this step, we have run a PES using 7 and H3O+ ion separated by a distance in which 7 and H3O+ practically could be thought of two separate molecules. (Figure S1) The distance between H atom (H1) in H3O+ ion and N1 atom in 7 was decreased over a number of steps. A downhill process without any energy barrier was observed for the proton transfer step from H3O+ ion to N1. Furthermore, it has to be regarded that hydrazones might exist in several geometrical isomeric forms in solution due to the presence of imine double bond (C1=N1) and N1-N2 bond. To take into account this factor, we performed a conformational search on the model protonated hydrazone, 8, to find the most stable protonated conformer. The Z isomer based on C1=N1 bond has been found to be more stable than E isomer, however due to the rotation about N1-N2 bond a number of Z isomers with very small energy differences are also possible. In further calculations, we have employed the Z conformer (8 in Figure S1 or RC1 excluding H2O in Figure 3) that can yield to the transition states and products in the successive steps without too much conformational changes. This structure also was obtained from PES calculations.



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Figure 3. Three-step hydrazone hydrolysis process based on the reaction of one H2O molecule with the model compound 8 through Pathway 2. In Step 1, concerted C1-O1 bond formation and proton transfer from O1 to N2 lead to the formation of carbinolamine intermediate termed as RC1-PC1 (product complex1-reactant complex2). After the inversion of N2 (Step 2), carbinolamine decomposes into corresponding products through a second proton (H2) transfer process to N1 (Step 3).

Some studies attribute the stability of hydrazones and oximes against hydrolysis to the resistance of N1 atom towards protonation.29-30 Since no energy barrier was observed in our model for the protonation step (Figure S1), we have calculated the proton affinity of N1 as the Gibbs free energy difference between the product (protonated hydrazone - H2O complex) and the reactant (separated hydrazone and H3O+). To test whether there is a correlation between calculated N1 proton affinities and the experimental hydrolysis half-lives, we have calculated the proton affinity of N1 for the three model compounds (7, 9, and 10 in Figure 2) which are structurally similar to those reported by Kalia et. al29. The rationale for selecting these three model compounds is that 7 represents an alkyl hydrazone which has a relatively shorter hydrolysis halflife, 9 represents an oxime derivative which is resistant to the hydrolysis, and 10 represents a positively charged hydrazone derivative which does not hydrolyze appreciably under ambient conditions. According to our calculations, model compound 10, a hydrazone derivative carrying a positive charge on N2, has the lowest and the model compound 7 has the highest calculated proton affinities which are in good correlations with the experimental results. It is expected that the positive charge on N2 in 10 will discourage N1 protonation due to first the electrostatic repulsion with incoming hydronium ion and second the decrease of electron density on N1. Model oxime compound 9 is expected to have less electron density on N1 than 7 as a result of an adjacent O atom (in place of N2) being more electronegative than nitrogen (N1). Kalia et al.29 also discussed the protonation site of the first step which is assumed to be N1 by most reports. According to the NMR studies, they have reached the conclusion that the possible protonation site for alkyl hydrazones is N2. However, based on the hydrolytic stabilities of different hydrazones and an oxime, N1 protonation is more plausible. The apparent logic behind this reasoning was that N1 protonation makes C1 position more electrophilic towards H2O attack (Step 2, Figure 1). In this regard, we envisaged that the computed proton affinities of N1 and N2 positions could be used to elucidate the likely protonation site. We have evaluated proton 5 ACS Paragon Plus Environment

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affinities of model compounds 7, 9, and 11 (Figure 2) using M06-2X functional. 7(alkyl hydrazone) showed almost a negligible proton affinity difference between N1 and N2 positions. However, 9(oxime) and 11(acyl hydrazone) showed pronounced proton affinities for N1 position in comparison with N2 position by 13.50 kcal/mol and 16.85 kcal/mol respectively. If the hydrolysis reaction commences with the initial N2 protonation, according to our calculations (not reported here), there is a considerable increase in the activation energy of subsequent hydrolysis steps. These indirect results suggest that N1 is the more likely protonation site for the initial step. 3.2 Water Addition – Carbinolamine Formation (Step 2 & 3) 3.2.1

One H2O Molecule as Reactant

After the initial protonation step, it is proposed that in the following two steps, one H2O molecule attacks to the electrophilic C1 position forming a protonated carbinolamine intermediate and this step is followed by an internal proton transfer from O1 to N1 position. (Step 2 and Step 3 in Figure 1) In order to locate a possible TS structure for Step 2, we have run a PES between 8 (protonated model hydrazone) and H2O by decreasing the distance between C1 at 8 and O1 at H2O. (Figure S2) We also expected to obtain an intermediate structure corresponding to the product of Step 2 (3 in Figure 1). Interestingly, the highest energy point in PES (TS in Figure S2), after optimization, corresponded to a transition state (TS) (TS1 in Figure 3) structure that belongs to a concerted mechanism in which H2O addition and the proton transfer steps occur in a single step simultaneously. Following the IRC path, we optimized the structure corresponding to the reactant complex (RC1 in Figure 3) which consisted of 8 and H2O. However, both TS and IRC calculations showed that proton was transferred to N2 position rather than to N1 as proposed. (PC1 in Figure 3) We have analyzed the corresponding energy profile, and the activation energies for the forward and reverse steps were calculated. (Figure 3) In order to compare the energetics of proton transfer from H2O either to N1 (Path 1 in Figure 4) or N2 (Path 2 in Figure 4), we located another TS structure corresponding to the reaction in which the proton transfer occurs to N1 position. To this end, we have used another PES using the product of Path 1 (13 in Figure 4), which was generated placing OH to the C1 position and H to N1. In this scan, the distance between O1 and H (connected to N1) was decreased over a number of steps to locate the TS structure for the proton transfer step. (Figure S3) Similarly, the optimized



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TS structure corresponded to a concerted mechanism in which C1-O1 and N1-H bond formations occur simultaneously. (TS1 in Figure 5) The energetics of this path was summarized in Table S1 and Figure 5. It is evident that Path 2 requires a considerable lower activation barrier than Path 1 for carbinolamine formation process. (1 H2O for both path in Table S1) The analysis of the TS structures reveals that cabinolamine formation for Path 1 proceeds through a 4-membered ring TS structure (TS-1H2O-N1 in Figure 6) whereas at Path 2 it proceeds through a less strained 5membered ring TS structure (TS-1H2O-N2 in Figure 6).

Figure 4. Two possible carbinolamine formation pathways through addition of H2O to C1 and concurrent proton transfer to either N1 (Pathway 1) or N2 (Pathway 2)

Figure 5. Three-step hydrazone hydrolysis process based on the reaction of one H2O molecule with the model compound 8 through Pathway 1. In Step 1, concerted C1-O1 bond formation and proton transfer from O1 to N1 lead to the formation of carbinolamine intermediate termed as RC1-PC1 (product complex1-reactant complex2). In the following step carbinolamine decomposes into corresponding products through a second proton (H2) transfer process to N2 (Step 2). 7 ACS Paragon Plus Environment

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Figure 6. Transition state (TS) structures corresponding to carbinolamine formation through Pathway 1(N1) and Pathway 2 (N2) for the reaction of model compound 8 with one, two, and three H2O molecules.

3.2.2

Two H2O Molecules as Reactant

The high activation barriers obtained for both paths especially for Path 1 seem incompatible with the experimental observations since alkyl hydrazones readily hydrolyze at room temperature.

29

For hydrolysis reactions, it is found that inclusion of more H2O molecules in the calculations as reactants lowers the activation barriers for proton transfer steps. 47-48 Extra H2O molecules could act as carriers of proton from one site to another and they can lower the activation barrier through forming high-membered-ring TS structures with less ring strain. To this end, we envisaged that introduction of another water molecule as reactant might act as a courier to relay the transfer of proton from H2O, which is attacking C1 position, either to N1 (Path 1) or N2 (Path 2). (Figure 4) This process, which is generally termed as water (solvent) assisted proton transfer, indeed lowered the activation barrier for both Path 1 and Path 2 considerably. (Table S1 and S2) For Path 1 with one H2O molecule as reactant, M062X functional estimated a one-step-reaction 8 ACS Paragon Plus Environment


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for carbinolamine formation in which water addition and proton transfer steps occurs simultaneously. (Figure 3) However, M062X calculation yielded a three-step-reaction pathway for carbinolamine formation with two H2O molecules as reactant. (Figure 7) The TS structure (TS1 in Figure 3) was modified to include the second H2O molecule as reactant and the resulting preliminary structure was reoptimized. The resultant TS structures (TS3 in Figure 7) corresponded to the protonation step of N1. By following IRC coordinate, the optimized reactant, PC2, corresponded to a carbinolamine in which one H2O molecule covalently attached to C1. This finding accords with the proposed mechanism in which carbinolamine formation and proton transfer steps are consecutive not concurrent steps. (Figure 1) In order to locate a TS structure for the initial carbinolamine formation (formation of C1-O1 bond) we have run a PES using PC2 by increasing C1-O1 bond distance in a number of steps. Surprisingly, we were able to locate two TS structures using maximum energy points from PES. In the first step, reaction of two H2O molecules results in the addition of one H2O molecule to C1 position of 8 and this process proceeds without proton transfer and produces an intermediate, PC1-RC2 (Figure 7). At PC1, the second H2O molecule has H bonding interaction with the newly attached O1. The second located TS structure (TS2 in Figure 7) corresponds to the inversion step for N1 atom which makes the subsequent water assisted proton transfer feasible. Without the inversion step, proton transfer seems not possible since the inversion process could bring the nitrogen lone pair electrons into proper orientation. The activation barriers for the inversion of N1 and proton transfer steps were calculated to be very low. (Step 2 and Step 3 in Figure 7) The overall barrier for the three-step carbinonamine formation process is lower than one-step carbinonamine formation.


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Figure 7. Four-step hydrazone hydrolysis process based on the reaction of two H2O molecules with the model compound 8 through Pathway 1. In Step 1, C1-O1 bond formation lead to the formation of initial carbinolamine intermediate termed as RC1-PC1 (product complex1-reactant complex2). After the inversion of N1 (Step 2), an internal proton (H1) transfer occurs to N1 position (Step 3). The resultant carbinolamine decomposes into corresponding products through a second proton (H2) transfer process to N2 (Step 4).

For Path 2, similar to Path 1, M06-2X functional estimated a single step reaction comprising both initial carbinolamine formation and proton transfer step for one H2O molecule as reactant, whereas for two water molecule a successive two-step-reaction pathway was estimated. (Path 2 in Table S2, and Figure 8) In path 2 for carbinolamine formation process, no initial inversion step is required since N2 has proper orientation for proton transfer process. Water assisted carbinolamine formation has indeed ≈ 9 kcal/mol less activation barrier. (Path 2, 1H2O vs 2H2O 10 ACS Paragon Plus Environment


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for Step 1 in Table S2) Analysis of TS structures for water assisted (TS-N2-2H2O in Figure 6) and direct proton transfer step (TS-N2-1H2O in Figure 6) reveals that the first one proceeds through a seven membered ring TS structure whereas the latter one proceeds through five membered TS structure. This observation might help in explaining the lower barrier for the water assisted proton transfer step. Furthermore, water assisted Path 2 has lower activation barrier than water assisted Path 1 presumably as a result of less strained TS structure for proton transfer step to N2 (TS-N2-2H2O in Figure 6, 7-membered ring TS structure) as compared to proton transfer step to N1 (TS-N1-2H2O in Figure 6, 6-membered ring TS structure).

Figure 8. Four-step hydrazone hydrolysis process based on the reaction of two H2O molecules with the model compound 8 through Pathway 2. In Step 1, C1-O1 bond formation lead to the formation of initial carbinolamine intermediate termed as RC1-PC1 (product complex1-reactant complex2). An internal proton (H1) transfer (Step 2) occurs to N2 position which is followed by the inversion of N1 (Step 3). The resultant carbinolamine decomposes into corresponding products through a second proton (H2) transfer process to N1 (Step 4).


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3.2.3

Three H2O Molecules as Reactant

In addition to the two water molecules involved in water assisted proton transfer step, we envisaged that inclusion of more water molecules might shed more light on the hydrolysis mechanism on the ground that the calculations could portray the hydrolysis process more accurately. To this end, N1 and N2 atoms in aqueous environment could, in principle, form H bonding with water molecules. With this reasoning, it could be thought that three H2O molecules could act as combined-reactant for hydrolysis reaction and each H2O molecule could have an individual as well as common functions. For path 1, two H2O molecules could be involved in the initial carbinolamine formation and water assisted proton transfer to N1 while the third water molecule, that has H bonding interaction with these two H2O molecules, could have H bonding with N2. (TS-N1-3H2O in Figure 6) Similarly, for path 2, 2H2O molecules could be involved in the carbinolamine formation and water assisted proton transfer to N2 and the third one could have H bonding with N1. (TS-N2-3H2O in Figure 6) Since solvation models inherently don’t recognize specific solvent solute/reactant interactions such as H bonding and solvent assisted proton transfer features, it is reasonable to include explicit solvent molecules for calculations without increasing computational cost considerably. For Path 1, M06-2X functional estimated a stepwise mechanism for the formation of carbinolamine intermediate through initial carbinolamine formation, inversion of N1, and H2O assisted proton transfer step. (Path 1, 3H2O in Table S1 and Figure S4) The inversion of N1 have been calculated with a relatively small barrier (≈1 kcal/mol) with respect to other steps (Step 2 in Figure S4). The energy barrier for water assisted proton transfer to N1 was found to be 4.57 kcal/mol (Step 3 in Figure S4). Inclusion of extra water molecules as reactants in the carbinolamine formation step dramatically decreased the total activation barrier. For Path 1, the barrier with one H2O molecule (1-stepreaction) is 34.56 kcal/mol, with two H2O molecule (3-step-reaction) is 17.00 kcal/mol, and with 3 H2O molecule (3-step-reaction) is 11.64 kcal/mol. The activation barrier for two and three H2O molecules as reactant is assumed to be the Gibbs free energy difference between TS of Step 3 (TS3) and the reactant complex of Step 1 (RC1) (Figure 7 and Figure S4) considering very low activation barriers for reverse reactions for Step 1 and Step2 (Table S1). It is reasonable to conclude that two H2O molecules leads to water assisted proton transfer step and it goes through 12 ACS Paragon Plus Environment


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a less strained TS structure (TS-N1-2H2O in Figure 6) with respect to one H2O molecule as reactant. If we analyze the results of M062X functional, it is possible to say that adding the third H2O molecule decreases the overall barrier for the carbinolamine formation through stabilization of TS structure of initial carbinolamine formation (TS1 in Figure S4) by H bonding interaction. (Table S1, the activation barrier for Path1 for Step 1 is 14.37 kcal/mol for two H2O molecules, and 8.69 kcal/mol for three H2O molecules) The barrier for N1 inversion step (Path 1, 2H2O and 3H2O, Step 2 in Table S1) is very small for both two H2O and three H2O molecules, whereas the barrier for water assisted proton transfer step is relatively higher for three H2O molecule (Path 1, 2H2O and 3H2O, Step 3 in Table S1; 1.70 kcal/mol vs 4.57 kcal/mol). If we analyze the TS structures for Step 3 both for 2H2O (TS3 in Figure 7) and 3H2O systems (TS3 in Figure S4), it could be seen that the TS structure is very similar to a two-fused ring structure for 3H2O and this situation might result in an increase in the energy of the TS structure due to ring stain. This situation could be corroborated by analyzing dihedral angles for atoms around C1-N1 bond for both transition states. (Figure S5) However, the stabilization of step 1 through H bonding might overwhelm the extra instability posed by ring strain, and as a result three H2O molecule as reactant is energetically more favorable than two H2O as reactant. For Path 2, M06-2X functional estimated a two-step-reaction for the formation of carbinolamine intermediate from the reaction of 8 with the three water molecules. (Path 2 in Table S1 and Figure S6) As it can be seen from Table S1, increasing the number of water molecules steadily and considerably decreases the activation barrier for the reaction. Reaction of 8 with one H2O molecule has 19.68 kcal/mol, with two H2O molecules has 10.65 kcal/mol, and with three H2O molecules 9.14 kcal/mol activation barriers. The reason for the considerable decrease of activation barrier with two H2O molecule is the stabilization of TS structure (TS1 in Figure 8) by means of less strained and more membered ring formation. The third water molecule has H bonding interaction with N1 and this interaction presumably lowers the activation barrier further. (TS1 in Figure S6 or TS-N2-3H2O in Figure 6) In the first step C1-O1 bond formation occurs, and in the subsequent step water assisted proton transfer process proceeds to form the carbinolamine intermediate. For both two and three H2O molecule systems, the proton transfer steps have very small activation barriers and are very exergonic processes. (Path 2 in Table S1) It is reasonable to conclude that initial C1-O1 bond formation affect the rate of overall carbinolamine formation process. Comparison of one, two and three water molecule systems for 13 ACS Paragon Plus Environment

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Path 2 clearly indicates that water assisted proton transfer step and H bonding interaction of the third water molecule with N1 considerably lowers the activation barrier for the formation of carbinolamine intermediate. (Path 2 in Table S1) Which Pathway (1 or 2) is favorable in hydrolysis reaction? If we consider activation barriers for one, two, and three water molecules as reactants for both pathways, it is reasonable to say that Path 2 requires less energy barrier. For Path 1 and 2, even though multiple steps might be required for carbinolamine formation process, it is reasonable to use an overall activation barrier taking into account the energy difference between the initial product complex of the first step and the TS structure of the last step. Since almost all the first steps are very endergonic and the next step(s) has/have very low activation barriers, this assumption will be valid. Although Path 2 seems more favorable, the energetic of the last step corresponding to decomposition of carbinolamine intermediate into final products has to be evaluated. 3.3 Carbinolamine Decomposition (Step 4) According to the proposed mechanism, the hydrolysis reaction ends with the decomposition of carbinolamine intermediate into the corresponding aldehyde/ketone and hydrazine molecules. (Figure 1, Step 4a/4b) In this step, C1-N1 bond breaking and loss of a proton from O1 occur. In the reported mechanisms, there is no clear pathway for the loss of proton, presumably it is meant to be transferred to a surrounding water molecule or any other suitable Lewis base. In order to locate possible TS structure(s) for the carbinolamine decomposition step, we have utilized PES calculations. In the PES calculations, the C1-N1 bond length was increased stepwise and possible TS structures were optimized both for Pathway 1 and 2. For PES calculations for Pathway 1, we have used the carbinolamine structures obtained from the reaction of 8 with one water molecule (PC1-RC2 in Figure 5, and it will be termed as P1-CA-1H2O), two water molecules (PC3-RC4 in Figure 7, and it will be termed as P1-CA-2H2O), and three (PC3-RC4 in Figure S4, and it will be termed as P1-CA-3H2O) water molecules. We also expected that the inclusion of more water molecules might possibly highlight the possibility proton transfer from carbinolamine O1 to one of H2O molecules acting as Lewis base. For Pathway 1, the PES for P1-CA-1H2O yielded a TS structure in which the C1-N1 bond breaking occurs simultaneously with the transfer of a proton from O1 to N2. (TS2 in Figure 5 or 14 ACS Paragon Plus Environment


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P1-CA-TS-1H2O in Figure 9) Basically, N2 is found to be acting as a Lewis base for this step. The TS structure corresponding to the decomposition of the P1-CA-2H2O is very similar to the TS structure for the P1-CA-1H2O. Again C1-N1 bond breaking accompanied by the proton transfer from O1 to N2. (TS4 in Figure 7 or P1-CA-TS-2H2O in Figure 9) The function of H2O molecule during the decomposition of P1-CA-2H2O TS appears to be that O2 atom in H2O has H bonding interactions with N1 and N2 hydrogens. (TS4 in Figure 7) The decomposition of P1CA-3H2O resulted in a slightly different TS structures in which one water molecule mediates the transfer of proton from O1 to N2. It is as if a water molecule acts as a Lewis base and accepts the proton from carbinolamine O1 and at the same time the resultant hydronium ion protonates N2 position. (TS4 in Figure S4 or P1-CA-TS-3H2O in Figure 9) A closer look at the TS structures belonging to decomposition of P1-CA-1H2O, P1-CA-2H2O, and P1-CA-3H2O (all P2-TSs in Figure 9) will reveal that the C1-N1 distance during the TS of P1-CA-3H2O (TS4 in Figure S4) is considerably longer than the C1-N1 distance in P1-CA-1H2O and P1-CA-2H2O. For P1-CA3H2O, the decomposition process appears to occur via C1-N1 bond breaking and subsequently water assisted proton transfer step. The other water molecule, particularly O2, is in H bonding interaction with the N1 and N2 hydrogens. The activation barrier for the decomposition of carbinolamine increases slightly (1.46 kcal/mol more for 2 H2O than for 1 H2O and 2.87 kcal/mol more for 3 H2O than for 2 H2O) (Path 1, Step 1 in Table2) upon inclusion of more water molecules. For the TS structure for P1-CA-2H2O decomposition, the water molecule simply acts as H bonding agent and is not involved directly in bond formation/breaking process. However, for the P1-CA-3H2O decomposition the second water molecule act as intermediary for the proton transfer step.


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Figure 9. Transition state (TS) structures corresponding to carbinolamine decomposition step through Pathway 1 (P1) and Pathway 2 (P2) for the carbinolamines obtained from reaction of model compound 8 with one, two and three water molecules.

For Pathway 2, PES calculations using C1-N1 bond did not furnish any potential candidate for a possible TS structure for the carbinolamine decomposition process. We envisaged that since Pathway 1 involved protonation of N1 in the carbinolamine formation step and protonation of N2 in the cabinolamine decomposition step, for Pathway 2 protonation of N1 could be a driving force for the decomposition step. To this end, we have run PES calculations in which we decreased the distance between the H (bonded to O1) and N1. In PES, we were able to locate two TS structures, one is for the inversion of N1, and second one is for the proton transfer step to N1. The inversion step is necessary for the proton transfer step since it brings N1 into a proper geometry for proton transfer step. For PES calculations, we have used the carbinolamine structures obtained from reaction of 8 with one water molecule (PC1 in Figure 3, and it will be termed as P2-CA-1H2O), two water molecules (PC2-RC3 in Figure 8, it will be termed as P2CA-2H2O), three water molecules (PC2-RC3 in Figure S6, and it will be termed as P2-CA3H2O). For P2-CA-3H2O, the protonation of N1 is water assisted proton transfer from O1 to N1. 16 ACS Paragon Plus Environment


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(TS4 in Figure S6 or P2-CA-TS-3H2O in Figure 9) For both TS structures corresponding to the decomposition of P2-CA-2H2O (TS4 in Figure 8 or P2-CA-TS-2H2O in Figure 9) and P2-CA3H2O (TS4 in Figure S6 or P2-CA-TS-3H2O in Figure 9), N2 has H bonding interaction with one of the water molecule. The inversion of N1 was estimated to have an energy barrier in the range of 3.8-6.09 kcal/mol for the three three systems. (Path 2, Step 1in Table S2) After the inversion step, the proton transfer from O1 to N1 triggers the decomposition of the carbinolamine intermediate. The activation barrier for this process for both P2-CA-1H2O, P2CA-2H2O are calculated to be around 42 kcal/mol. (Path 2, Step 2 in Table S2) Since the protonation of N1 is caused by the proton transfer from O1 to N1 and for both P2-CA-1H2O, P2-CA-2H2O this process involves direct proton transfer. The accompanying TS structures are highly strained four membered rings which might highlight the unusually high activation barriers. (P2-CA-TS-1H2O and P2-CA-TS-2H2O in Figure 9) However, if the proton transfer process is operative via solvent assisted fashion as in the case of decomposition of P2-CA3H2O, the activation barrier is found to be around 24.5-26.5 kcal/mol. The accompanying TS structure is similar to a six membered ring and this explains the considerable decrease in the activation barrier relative to both P2-CA-1H2O and P2-CA-2H2O. (P2-CA-TS-3H2O in Figure 9) Even though there is a considerable decrease for the activation barrier, among all steps involved in Pathway 1 and Pathway 2, this process has the highest barrier, and Pathway 2 becomes energetically less favorable. In addition to three water molecules as reactant system for Pathway 1, we have tested four and five water molecules considering that N1 and N2 atoms are polar and they might interact with surrounding water molecules through H bonding. According to our calculations—which were not reported in this study—the values of total activation barriers for carbinolamine formation and decomposition steps with four and five water molecules as reactant system were very similar to the three water molecules as reactant system. Therefore, it is reasonable to assume that threewater-molecule system is a good model system for the hydrolysis reaction and the rest of water molecules could be approximated as continuum of solvent. 4. Conclusion The comparison of the two possible pathway for the hydrolysis reaction suggests that Pathway 1 is energetically more favorable than Pathway 2. According to our model and calculations, 17 ACS Paragon Plus Environment

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carbinolamine decomposition is the rate determining step. However, as discussed before, to a great extent the rate of hydrolysis was found to depend on the ease of protonation of N1 position and this was invoked to explain the relative stability order of hdyrazone and oxime derivatives. Even though we could not find any energy barrier for the protonation of hydrazones in our model system in which a hydazone derivative accepts a proton from a hydronium ion, the computed proton affinity values correlated with the experimental results. Furthermore, for both carbinolamine formation and decomposition steps proton transfer processes have more favorable energetics through solvent (water) assisted mechanism. It is largely due to formation of less strained TS structures by inclusion of one water molecule.

Furthermore, a second water

molecule can decrease the activation barrier further through H bonding interaction and presumably as a result of decrease in the strain in the TS structure. With the inclusion of more water molecules as part of the reactant system, we were able to obtain activation barriers in the range of 8-20 kcal/mol with M06-2X functional and these barriers could be overcome at room temperature for the hydrolysis reaction. In our model, we haven’t placed any other Lewis acid/base other than H2O, H3O+ and the hydrazone molecule. It is a fact that reactions are carried in buffer conditions, and buffer components and reactant, product and intermediate molecules might act as Lewis acids/bases. In future calculations, we are planning to include model Lewis acids/bases for the hydrolysis reaction and will probe the activation barriers for each step. By this way, the energetics of Step 3b and 4b could be studied computationally. Potentially, further calculations with different hydrazone derivatives might increase our understanding with respect to mechanism and it might help to design materials with controlled properties. ASSOCIATED CONTENT Supporting Information Figures associated with PES calculations (Figure S1-S3); a figure associated with four-step hydrazone hydrolysis process based on the reaction of three H2O molecules with the model compound 8 through Pathway 1 (Figure S4); list of dihedral angles for the TS structures corresponding to the proton transfer step to N1 for Pathway 1 for two and three H2O molecule systems (Figure S5); four-step hydrazone hydrolysis process based on the reaction of three H2O molecules with the model compound 8 through Pathway 2 (Figure S6); Tables (Table S1-S8) associated with Gibbs Free Energy of activation for forward and reverse steps, Gibbs free 18 ACS Paragon Plus Environment


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energy, enthalpy, zero-point corrected electronic energies of each species in both pathways; and Cartesian coordinates of all species. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author e-mail:[email protected] Notes The author declares no competing financial interest. ACKNOWLEDGEMENTS This work is supported by Khalifa University Internal Research Fund (KUIRF) Level 1 Award (Award # 210080). The author is grateful to Dr. Serdal Kirmizilatin, Assistant Professor of Chemistry, NYU Abu Dhabi, for the training in various software. The author also acknowledges the contribution of High Performance Computing Facility (BUTINAH Cluster) at NYU Abu Dhabi.

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A DFT Approach to the Mechanistic Study of Hydrozone Hydrolysis

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