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Mechanism of Piperidine-Catalyzed Knoevenagel Condensation Reaction in Methanol: The Role of Iminium and Enolate Ions Ellen Vasconcelos Dalessandro, Hugo Paul Collin, Luiz Gustavo L. Guimarães, Marcelo Siqueira Valle, and Josefredo Rodriguez Pliego J. Phys. Chem. B, Just Accepted Manuscript • Publication Date (Web): 04 May 2017 Downloaded from http://pubs.acs.org on May 5, 2017

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The Journal of Physical Chemistry

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

Ellen V. Dalessandro, Hugo P. Collin, Luiz Gustavo L. Guimarães, Marcelo S. Valle and Josefredo R. Pliego Jr.†,*

†

Departamento de Ciências Naturais, Universidade Federal de São João del-Rei

36301-160, São João del-Rei, MG, Brazil.

* [email protected]

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Abstract

The free energy profile of 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 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 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.


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Introduction In the past fifteen years, aminocatalysis has emerged as a powerful approach in the catalysis of aldol and related reactions.1-8 In the landmark paper on proline catalyst of asymmetric aldol reaction in 2000 by List, Lerner and Barbas,9 the authors have proposed a mechanism involving iminium and enamine intermediates in the reaction of acetone with 4-nitrobenzaldehyde. A similar proposal of iminium ion formation was also done by Ahrendt, Borths and MacMillan in a seminal paper on organocatalytic Diels-Alder reaction.10 The perception of the importance and utility of this kind of reaction has induced a lot of both theoretical and experimental research on the mechanism.11-17 In particular, the role of theoretical methods to understand catalytic processes has become more and more important.18-24 Many of the theoretical studies on aminocatalysis are not complete and are usually limited to specific aspects of the reactions. For example, following the experimental work of List et al.,9 theoretical studies have investigated the C-C bond formation step involving the enamine intermediate.25-28 More complete investigation of the reaction pathways was done by Rankin et al..29 Nevertheless, the free energy profile was not calculated and the authors have not found a reaction pathway (with low activation barrier) able to explain the formation of enamine. The critical step was the formation of carbinolamine intermediate, a problem previously reported in the methylamine reaction with acetaldehyde.30 In the same year, a theoretical study by Hall and Smith has indicated the role of water (hydroxyl group) in the catalysis of this step.31 Patil and Sunoj have also found that methanol molecule catalyzes this addition reaction.32 The step of iminium ion formation is more difficult to describe by theoretical calculations (continuum solvation) because there is formation of charged species33 and it is possible that no transition state exists for this process. This possibility can lead to a flaw of standard computational approaches based on transition state searching.34 Thus, previous studies on carbinolamine decomposition have included explicit methanol molecule in the transition state, leading directly to enamine intermediate.32 Experimental kinetic studies aimed to provide reaction and activation barriers of key steps and intermediates are important contributions to our understand of the reaction.35-38 Furthermore, experimental determination of a complete free energy profile 3 ACS Paragon Plus Environment


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and all-step kinetic model is a challenge, although is very useful for a deep understand of the mechanism, reaction rate and product ratio.13, 39-40 Thus, recently Orlandi et al. have reported a very interesting combination of experimental and theoretical data to proposed a complete all-step (or multiple transition state approach) kinetics and thermodynamics description of proline catalyzed aldol reaction.13 In special, they have observed that the Curtin-Hammett principle is not adequate for these reactions because backward equilibrium is important and can lead to wrong theoretical prediction of stereoselectivity. The Knoevenagel condensation reaction is a variant of aldol condensation and only more recently an asymmetric version has been reported.41-42 Theoretical studies of this reaction have been limited to gain insights on the reaction. For example, Frapper et al. have reported a theoretical study of a Knoevenagel condensation reaction catalyzed by water.43 However, they have found high free energy barriers, which can be partially attributed to use of B3LYP functional. In fact, some authors have found that B3LYP is inaccurate for aldol reactions.44-45 Our recent study also confirms this finding.46 Despite the several studies along the years, a complete theoretical free energy profile and related kinetic model for aldol and similar reactions, able to explain semi-quantitatively the experimental kinetics, rarely has been reported.13,

46

Thus, the aim of this work is to

provide a reliable free energy profile and a kinetics analysis of a classical Knoevenagel condensation reaction, presented in Scheme 1.

Scheme 1: Piperidine catalyzed Knoevenagel condensation reaction investigated in this work.


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Theoretical methods We have used a composited approach for studying the reaction indicated in Scheme 1. The potential of mean force surface of the reaction was investigated using the X3LYP functional47 with the 6-31(+)G(d) basis set (no diffuse functions on carbon atoms) and CPCM solvation model (CPCM with 240 tesserae),48-52 which corresponds to CPCM/X3LYP/6-31(+)G(d) level of theory. Geometry optimization was followed by harmonic frequency calculations to obtain the vibrational, rotational and translational contributions to the free energy (Gvrt). The electronic energy (Eel) was determined by single point energy calculation using the M08-HX functional53 with the Ahlrichs TZVPP basis set54 augmented with sp diffuse functions (TZVPP + diff). The M08-HX functional has presented a good performance for aldol related reactions46 and has been reported to be one of the most accurate functionals for reaction energies.55 The “gas phase” free energy was obtained from:

= +

(1)

The solvent effect was included through single point energy calculation using the SMD method (240 tesserae)56 and the X3LYP/6-31(+)G(d) electronic density. The SMD model is reliable for solvation of neutrals in methanol57 and has a relatively good performance for ion-molecule reactions.33, 58 The free energy in solution was obtained from:

= + ∆

(2)

We have used the standard state of 1 mol L-1 in reporting free energies. All the calculations were performed using the GAMESS program.59-60 Following the calculation of the free energy profile, a complete kinetics analysis was done by numerical integration of the system of ordinary differential equations. The integration was done with the Kintecus program.61



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Results and Discussion Iminium ion formation The complete mechanism of acetylacetone reaction with benzaldehyde catalyzed by piperidine is presented in Scheme 2 and some key optimized structures are presented in Figure 1. The reaction initiates by formation of the iminium ion and this process takes place in two steps. Step (1) is the formation of the carbinolamine intermediate (MS1). We have found three transition states for this step, corresponding to TS1a,

TS1b and TS1c. The free energy barriers are in Table 1. The pathway via TS1a corresponds to direct attack of pireridine to benzaldehyde, leading to a very high barrier of 30.6 kcal mol-1. The second mechanism involves participation of one methanol solvent molecule, resulting in a favorable barrier of only 19.6 kcal mol-1. The third mechanism involves a second piperidine molecule, with a free energy barrier of 23.6 kcal mol-1. Therefore, our results indicate that methanol catalyzes this step. Considering that the methanol concentration is around 24.6 mol L-1, we can predict an observed second order rate constant of 0.04 L mol-1 s-1 for this step, suggesting a quick process. We can also extrapolate our result to aprotic solvents. In this case, the second piperidine molecule could catalyzed the process and even the carbinolamine intermediate could promote an autocatalytic process. The calculations have indicated that the carbinolamine (MS1) is only 3.2 kcal mol-1 above of the reactants. The second reaction step is the elimination of hydroxide ion from MS1. This step involves the formation of two charged species, including the highly solvated hydroxide ion.62 Such process cannot be accurately described by the continuum model SMD.33 However, it is possible to obtain the free energy of the reaction through combination of reactions that have the same number of ions on both of sides of the reaction, minimizing the error.34, 46 Thus, we have used the processes I and II of Table 1 to obtain the process III, which corresponds to step (2) of Scheme 2. The free energy of this step is only 13.6 kcal mol-1. Considering that MS1 is 3.2 kcal mol-1 above of the reactants, the relative free energy of iminium + OH− state is 16.8 kcal mol-1.


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Scheme 2: Reaction steps of the mechanism of piperidine-catalyzed Knoevenagel condensation reaction in methanol solvent investigated in this work.



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Step (2) has a free energy barrier, although does not have a transition state on the potential of mean force surface leading to separated iminium and hydroxide ions. Thus, the inverse process is diffusion controlled. This kind of process is very fast and has a free energy barrier around 5 kcal mol-1. Summing this value to the free energy of “iminium + OH− ” leads to a free energy barrier of 21.8 kcal mol-1 for step (2) in relation to benzaldehyde and piperidine reference point. We can anticipate that based on our calculations, this is the rate-determining-step of the overall reaction.

Deprotonation of acetylacetone Steps (3) and (4) are acid-base equilibrium and are related to pKa of acetylacetone, piperidine and water in methanol. 44, 60-61 The respective pKa values and free energies are in Table 2. Combining steps (1) to (4) leads to formation of iminium cation, enolate (deprotonated acetylacetone) and water with a free energy of 6.9 kcal mol-1 above of the reactants. We have used the pKa data in methanol46, 62-63 to determine this free energy aimed to reduce the error in continuum solvation calculation. In addition, we consider these equilibria are rapid processes.

Nucleophilic attack of the enolate Once the enolate and the iminium ions were formed, the next step is the nucleophilic attack of enolate to iminium. The transition state is presented in Figure 1 (TS2) and the free energy barrier for this step is calculated to be 13.7 kcal mol-1. Thus, this transition state is 20.6 kcal mol-1 above of the initial reactants (acetylacetone, benzaldehyde and pireridine). The formed intermediate (MS2) is only 7.5 kcal mol-1 above of these initial reactants.


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TS1a

TS1b

TS1c

TS2

TS3 Figure 1: Transition states indicated in Scheme 2.



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Table 1: Reaction and activation thermodynamic properties for acetylacetone reaction with benzaldehyde catalyzed by piperidine.a ∆E (M08)b

∆Ggc

∆∆Gsolvd

∆Gsole

TS1a

24.30

34.52

-3.88

30.64

TS1b

-1.69

20.93

-1.37

19.56 (17.66)f

TS1c

5.12

27.35

-3.79

23.56 21.79g

TSOH MS1

-11.87

0.96

2.25

−

3.21

iminium + OH

16.79

iminium + enolate + H2O

6.85

TS2

15.18

28.63

-8.02

20.61

MS2

-7.01

7.84

-0.35

7.49

MS2z

12.10

29.69

-17.41

12.28

TS3

14.47

29.96

-8.40

21.56

PD + H2O + piperidine

0.57

2.49

-6.50

-4.01

∆E (M08)

∆Gg

∆∆Gsolv

∆Gsol

2.68

-10.67

8.22

-2.45

processes +

(I) MS1 + (CH3)3NH → iminium + (CH3)3N + H2O (II) H2O + (CH3)3N → OH− + (CH3)3NH+

16.03h

(III) MS1 → iminium + OH−

13.58i

a – Units of kcal mol-1 and standard state of 1 mol L-1. Values in relation to acetylacetone, benzaldehyde and piperidine reference. Geometries and frequencies obtained at CPCM/X3LYP/6-31(+)G(d) level. b – Electronic energy obtained at M08-HX/TZVPP+diff level of theory. c – “Gas phase” free energy. d – Solvation contribution to the free energy, obtained at SMD/X3LYP/6-31(+)G(d) level, methanol solvent. e – Solution phase free energy. f – Value in parenthesis corresponds to correction for methanol concentration or standard state of pure methanol solvent. g – See text. h - Obtained from pKa values in methanol. See Table 2. i – From combination of processes (I) and (II).


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Table 2: Compiled pKa data in methanol. Process

pKa

∆G (kcal mol-1)

(CH3)3NH+ → (CH3)3N + H+

9.80a

13.37

21.55b

29.39

acetylacetone → enolate + H+

14.26b

19.45

piperidineH+ → piperidine + H+

11.07a

15.10

H2O

→ OH− + H+

a – Experimental data taken from ref. 64. b – theoretical prediction from ref. 46.

Elimination of the piperidine catalyst The last step of the mechanism is the elimination of piperidine catalyst, which is regenerated. This process takes place in two steps from MS2 (reactions (6) and (7)). First, occurs an isomerization from MS2 to MS2z, a zwitterion of MS2. This process takes place via proton exchange with the medium and we consider this to be a rapid event. The species MS2z is 12.3 kcal mol-1 above of the initial reactants. The elimination of piperidine (TS3 in Figure 2) has an overall free energy barrier of 21.6 kcal mol-1, staying only 9.3 kcal mol-1 above of MS2z. In this point, it is worth to observe that this barrier is slight below of the barrier of step (2), 21.8 kcal mol-1. The final product (PD) is stable by 4.0 kcal mol-1.

Free Energy Profile The free energy profile of the most favorable reaction pathway is presented in Figure 2. It is evident that the elimination of hydroxide ion from MS1 intermediate is the rate-determining step with a free energy of 21.8 kcal mol-1. However, the free energy for TS3, elimination of pireridine, and even for TS2 are close, 21.6 and 20.6 kcal mol-1, respectively. Although higher level of theory could change the relative barriers, we have found a favorable reaction pathway with low barriers, in agreement with experimental observations of effective catalysis by piperidine. Comparing the 11 ACS Paragon Plus Environment


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present finding with our previous report on methoxide-catalyzed Knoevenagel reaction, we can see the main effect of piperidine is to decrease the barrier of the elimination step leading to the final product. Thus, the leaving piperidine can be eliminated much more easily than the highly reactive hydroxide ion. In fact, taking the MS2 intermediate as reference, the elimination of piperidine has a barrier of 14.1 kcal mol-1, while elimination of hydroxide ion has a barrier of 23.4 kcal mol-1 from MS1b (see reference 46). On the other hand, the attack of the enolate to iminium ion has a barrier of 13.7 kcal mol-1, while the same attack of the enolate to acetaldehyde has a free energy barrier of 15.6 kcal mol-1, very close to iminium-enolate pair. Therefore, an important consequence of these studies is that the piperidine catalysts works by facilitating the elimination step rather activation of the benzaldehyde electrophile via iminium ion formation, as usually believed.65 This is an important change in our vision of this reaction.

Figure 2: Free energy profile for acetylacetone reaction with benzaldehyde catalyzed by piperidine. Units in kcal mol-1. Standard state of 1 mol L-1 for solutes and pure solvent for methanol.


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Experimental Kinetics Observing Figure 2 and assuming that the rate-determining step involves only benzaldehyde and piperidine, the rate law should be:

[] = − [][] 3 where BZ is benzaldehyde, PP is piperidine and kI is the second-order rate constant. Because piperidine is a catalyst and its concentration remains close to the initial value, we can define the pseudo first-order rate constant k by the relation:

= [] 4 The reaction was accomplished by absorption spectroscopy, measuring the absorbance at 380 nm (experimental details in the supporting Information). The experimental absorbance was fitted to the equation 5:

=

!

+ " 5

The fitted curve is presented in Figure 3, resulting in k = 0.07108 min-1. Based on equation 4, we can obtain that kI = 0.0141 L mol-1 s-1, leading to experimental ∆G‡ = 20.0 kcal mol-1. We can observe that the fitting process leads to a curve in excellent agreement with the experimental data, suggesting that step 2 of Scheme 2 is indeed the ratedetermining step, as indicated by the calculated free energy profile (Figure 2). In addition, the experimental free energy barrier of 20.0 kcal mol-1 is also close to the theoretically calculated value of 21.8 kcal mol-1.



4

3 Absorbance

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2

1

0 0

10

20

30

t (min)

Figure 3: Reaction of benzaldehyde (0.81 mol L-1) with acetylacetone (0.81 mol L-1) catalyzed by piperidine (0.084 mol L-1) in methanol solvent at 25 oC. The absorbance (circles) was measured at 380 nm. The continuum line is a fit to equation 5 and the obtained parameters are A∞ = 3.38038, B = -2.61293, k = 0.07108 min-1.

Kinetics Analysis Using Theoretical Data. The mechanism of the investigated reaction has several steps with similar free energy barriers. Thus, a simple kinetics analysis based on identifying the ratedetermining step may not be accurate. Therefore, we have done a kinetics analysis using all the reaction steps in Figure 2. In the kinetics model, steps 3 and 4 are summed, becoming a rapid equilibrium step: OH− + acetylacetone → enolate + H2O simulated with high forward and backward rate constants (kf = 1 x 109 L mol-1 s-1 and kb = 5.18 x 101 L mol-1 s-1), with values restricted to the equilibrium constant of this step. The used rate constants are presented in Table 3. The full kinetics problem was resolved by numeric integration of the system of ordinary differential equations using the Kintecus program. A comparison was done with the rate-determining step approach (RDS). In this case, the rate law is given by equation 3 and kI is related to the free energy barrier of 21.79 kcal mol-1. Thus, considering that [PP] = 0.084 mol L-1 and kI = 14 ACS Paragon Plus Environment

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6.6 x 10-4 L mol-1 s-1, the theoretical rate constant for pseudo-first-order decay of benzaldehyde is 5.6 x 10-5 L mol-1 s-1. The related curve is also presented in Figure 4.

Table 3: Kinetics and thermodynamics data used in the kinetics analysis.a Process in scheme 2

∆G

∆G‡

knb

k-nc

Kn d

1

3.21

17.66

0.704

1.59E+2

4.44E-3

2

13.58

18.58

0.149

1.34E+9

1.11E-10

3+4

-9.94

(1E9)e

(51.8)e

1.93E7

5

0.64

5.00E2

1.47E+3

6

4.80

7

-16.29

13.77

e

9.28

(1E5)

(3.27E8)

9.79E+5

1.12E-6

e

3.40E-1 3.06E-4 8.74E+11

-1

a – Units of kcal mol , and mol, L and s. b – rate constant for the forward reaction. c – rate constant for the backward reaction. d – equilibrium constant. e – Values used for steps considered be equilibrium.

The results of kinetics modeling in Figure 4 indicates that just considering the overall barrier of step (2) for predicting the reaction kinetics is not accurate. This model predicts that in 10 hours of reaction, the conversion is 87%. The complete kinetics analysis indicates a meaningful decrease of the reaction rate, with 68% of conversion. Although this deviation must be taken into account when analyzing concentration, the effect on the observed activation barrier is small due to exponential dependence on the rate constant with the free energy barrier. Thus, the calculated experimental barrier must provide a reliable estimate of the real free energy barrier.



1.0 0.8

[BZ] (mol/L)

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0.6 0.4 Full kinetics

0.2

RDS

0.0 0

5

10

15

Time (h)

Figure 4: Concentration of benzaldehyde along the time, based on full kinetics analysis and rate-determining step (RDS) approximation (see text). Initial concentrations of benzaldehyde, acetylacetone and piperidine are 0.81 mol L-1, 0.81 mol L-1 and 0.084 mol L-1, respectively.

Conclusion The Knoevenagel condensation reaction of acetylacetone with benzaldehyde catalyzed by piperidine in methanol solvent takes place via carbinolamine, iminium and enolate intermediates. The step of iminium ion formation is the rate-determining one and involves elimination of hydroxide ion from carbinolamine intermediate. This hydroxide ion deprotonates acetylacetone, leading to enolate, which attacks the iminium to form the intermediate MS2. This intermediate isomerizes to MS2z and eliminates the piperidine catalyst, forming the final product. Steps involving enolate attack and piperidine elimination have also high barriers, close to iminium ion formation. Therefore, a full kinetics analysis has been performed in this study. We have also observed that the main effect of piperidine is to decrease the barrier of the elimination step leading to the final product. The nucleophilic attack of the enolate to the iminium ion and to benzaldehyde have similar activation barriers, suggesting that iminium ion


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formation does not increase substantially the nucleophilicity of benzaldehyde in methanol solvent.

Supporting Information Details of the experimental procedure, NMR spectra, IV spectra, and the coordinates of the optimized structures are available.

Acknowledgments The authors thank the agencies CNPq, FAPEMIG, and CAPES for support. This work is a collaboration research project of members of the Rede Mineira de Química (RQ-MG) supported by FAPEMIG (Project: CEX - RED-00010-14).

References (1) Govender, T.; Arvidsson, P. I.; Maguire, G. E. M.; Kruger, H. G.; Naicker, T., Enantioselective Organocatalyzed Transformations of β-Ketoesters. Chem. Rev. 2016. (2) Bertelsen, S.; Jorgensen, K. A., Organocatalysis After the Gold Rush. Chem. Soc. Rev. 2009, 38, 2178-2189. (3) MacMillan, D. W. C., The Advent and Development of Organocatalysis. Nature 2008, 455, 304-308. (4) Dondoni, A.; Massi, A., Asymmetric Organocatalysis: From Infancy to Adolescence. Angew. Chem. Int. Ed. 2008, 47, 4638-4660. (5) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B., Asymmetric Enamine Catalysis. Chem. Rev. 2007, 107, 5471-5569. (6) Erkkilä, A.; Majander, I.; Pihko, P. M., Iminium Catalysis. Chem. Rev. 2007, 107, 5416-5470. (7) Notz, W.; Tanaka, F.; Barbas, C. F., Enamine-Based Organocatalysis with Proline and Diamines: The Development of Direct Catalytic Asymmetric Aldol, Mannich, Michael, and Diels−Alder ReacDons. Acc. Chem. Res. 2004, 37, 580-591. (8) List, B., Proline-Catalyzed Asymmetric Reactions. Tetrahedron 2002, 58, 5573-5590.



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