Green Catalytic Method for Hydrothiolation of Allylamines: An External Electric Field.

Based on the idea of environmental friendliness, we first studied the hydrothiolation reactions of thiophenol with allylamine using a green catalyst-an external electric field (EEF). The hydrothiolation reactions could occur through Markovnikov addition (path M) and anti-Markovnikov addition (path AM) pathways. The calculation results demonstrated that when the EEF was oriented along F -X , F -Y , and F +Z directions, path M was accelerated. However, it is favorable for path AM only when the EEF is oriented along the +X and -Y-axes. In addition, the introduction of the EEF further increased and lowered the differences of the reaction barrier as the EEF was oriented along F -X , F -Y , and F +X directions. The solvent effects were also considered in this work. Hopefully, this unprecedented and green catalytic method for the hydrothiolation reactions of allylamine may provide guidance in the lab.

Introduction

Hydrothiolation reactions are of great importance in organic chemistry; the formed organosulfur compounds are not only common synthetic intermediates[1] but also this method features the most direct and 100% atom economy.[2] In general, hydrothiolation reactions can occur through two possible pathways (Scheme ): Markovnikov addition and anti-Markovnikov addition, in which the former formed the branched C–S bond and the latter formed the linear C–S bond. The anti-Markovnikov hydrothiolation reaction of thiyl radicals with alkynes and alkenes was probed since the first report in 1905.[3] However, Markovnikov additions were difficult because of the C-radical stability. Efforts have been made to achieve this type of addition through Lewis and Brønsted acid-mediated strategies[4] with some drawbacks, such as selectivity, limited functional group tolerance, etc. Later, transition metal catalysts came into the highlight and were tried to be employed in the catalysis of hydrothiolation reactions.[5] However, the development of the metal-mediated hydrothiolation reactions of the unsaturated carbon–carbon bonds is particularly challenging, especially the hydrothiolation addition of alkenes, due to the sulfur’s strong coordination to metal that results in the catalyst’s deactivation[6] and the low coordination ability of alkenes to metal.[7]

Scheme 1

Possible Pathways of Hydrothiolation Reactions of Allylamine

By now, various systems, including alkynes,[8] allenes,[9] diene,[10] and alkenes,[11] have been studied for the hydrothiolation reactions of both Markovnikov and anti-Markovnikov additions. Among these reports, hydrothiolation of electronically unactivated allylamines is relatively underexplored. In 2016, Hull et al.[12] reported rhodium-catalyzed regiodivergent hydrothiolation of allylamines, delivering branched and linear thioethers. Following this, two research groups further elucidated this study by density functional theory calculations.[13] In these studies, the reaction mechanisms and the impact of ligands on the regioselectivity of Rh-catalyzed hydrothiolation of allylamine were probed in detail. Despite a reliable regulator of the regioselectivity of the reaction, the preparation of the different ligands is complicated and costly. The visible light is also employed in the hydrothiolation reactions in the presence of a photocatalyst.[14]

Growing focus on the environment and energy use has spurred extensive interest to make organic syntheses greener and more sustainable. An external electric field (EEF), as a green and smart catalyst, has been introduced in the chemical processes. Since Shaik et al. reported that the EEF controls the selectivity of iron-oxo porphyrin with propene,[15] relevant literature studies gradually sprung up in theory and the experiment.[16] Upon perusal of this work, we were inspired and tried to explore hydrofunctionalization reactions (such as hydroboration,[17] hydrohydrazination,[18] and hydrosilyation[19]) by EEF as an “invisible” catalyst. According to this precedent, we first studied the EEF-mediated allylamine hydrothiolation reaction in this manuscript. We expect that this work would provide new insights into the hydrothiolation reaction of allylamines and may guide the future design of the new related reactions.

Results and Discussion

Hydrothiolation Reactions

According to Scheme , hydrothiolation reactions could occur in Markovnikov addition (path M) and anti-Markovnikov addition (path AM) pathways. We first fully optimized the stationary points along the potential energy surfaces in the gas phase, and the structures with key bond parameters are shown in Figure a. Then, IRC analyses (Figure b) were performed based on the optimized transition states to confirm the true connectivity of the transition states with their forward and backward minima. Lastly, the relative energies (Figure c) of the geometries in the two pathways were calculated at the B3LYP/6-311++G(d,p)//B3LYP/6-31G(d,p) level of theory.

Figure 1

(a) Structures (bond lengths are given in Å) along the potential energy surface in the hydrothiolation reaction (the terminal carbon is denoted C1, the internal carbon is denoted C2; gray: C; white: H; blue: N; and yellow: S, the same as the other figures). (b) IRC analysis of the transition states in path AM and path M. (c) Profile of the relative energies of two pathways in which the geometries of two transition states are shown on the right.

From Figure a, it can be seen that when thiophenol interacted with allylamine through a sulfur atom approaching the terminal carbon atom in allylamine, the anti-Markovnikov addition occurred with a transition state (TSa) formed. The bond lengths of the S–H and C–C bonds in TSa are elongated obviously by 0.443 and 0.077 Å as compared with those of the reactants, respectively, and the distances of S–C1 and C2–H in TSa are 2.763 and 1.250 Å, respectively. IRC (Figure b, the left) revealed that, as the reaction progressed, the bond lengths of S–H and C–C are gradually elongated, while the distances of S–C1 and C2–H are shortened. When the interaction between thiophenol and allylamine was further enhanced, S–C1 and C2–H bonds were formed and the S–H bond broke, and the linear product (Pa) was eventually generated. From Figure c, the relative energy of TSa is found to be 41.9 kcal/mol; thus, the barrier height of path AM is 41.9 kcal/mol. The relative energy of the product is −12.0 kcal/mol, indicating that this anti-Markovnikov hydrothiolation is an exothermic reaction.

When thiophenol interacted with allylamine via a sulfur atom approaching the internal carbon atom in allylamine (Figure a), the Markovnikov addition occurred with the formation of a transition state (TS). In TS, the respective bond lengths of S–H and C–C bonds are also stretched by 0.477 and 0.082 Å, respectively, implying that the former tended to rupture, while the latter would become a single bond. The distances of S–C2 and C1–H are 2.868 and 1.229 Å, respectively. IRC (Figure b, the right) verified that the changes of S–H, C–C, S–C2, and C1–H along the reaction path are correct. This path M would produce a branched C–S bond (P) at last. As shown in Figure c, the relative energy of TS is 38.7 kcal/mol; therefore, the reaction barrier of path M is 38.7 kcal/mol. The relative energy of P is −13.7 kcal/mol; consequently, Markovnikov hydrothiolation is also an exothermic reaction.

On comparing path AM and path M, one can see that path M had a lower barrier height, and this pathway also released more heat. In general, the sulfur atom that attacked the internal carbon atom would encounter more hindrance, that is, the Markovnikov addition. However, Markovnikov hydrothiolation of thiophenol with allylamine is more possible to occur because of a smaller reaction barrier. Why and what contributed to this result? We first analyzed the atom charges (Figure a, the left) of thiophenol and allylamine molecules, as well as their electrostatic potentials (Figure a, the right). Upon inspection of these values, we found that the C1 atom has a more negative charge than the C2 atom, and the H atom has a more positive charge than the S atom. As a result, the H atom was prone to attach to the terminal C1 atom, while the S atom interacted with the internal C2 atom. It is consistent with the Markovnikov addition mode. In addition, from the point of view of the electrostatic potential maps, the same conclusion could be drawn. Further, we studied the atom charges of two transition states and their absolute energies (Figure b). One can speculate that, in TSa, the charges of C1 and H atoms decreased and the charges of C2 and S atoms increased. A similar phenomenon is found in TS, where the charges of C2 and H atoms decreased and the charges of C1 and S atoms increased. These results demonstrate that the charges in the H atom transferred to the C atom, while the charges of the C atom transferred to the S atom; see the arrows in Figure b. The crucial difference is that the C atom passed more charges to the S atom in TS, which may contribute to the Markovnikov reaction. In addition, the absolute energy of TS is lower than that of TSa by 0.0057 au (approximately 3.6 kcal/mol). This means the TS is more stable, which led to a lower barrier height.

Figure 2

(a) Atom charges (the left) of thiophenol and allylamine molecules and the corresponding electrostatic potential at the 0.001 au isosurface of electron density (the right). (b) Atom charges of TSa and TS, with their absolute energies (au) given below.

Hydrothiolation Reactions in EEF

Inspired by the previous work, we tried to introduce an external electric field as a green catalyst in the hydrothiolation reactions of thiophenol with allylamine. All of the structures were optimized in the presence of the EEF (their direction refers to Scheme ), see Figure a, and their relative energies were also recalculated (Table ). To compare the catalytic effect of various directional EEFs, both the reaction barriers of path M and path AM are summarized in Figure b.

Scheme 2

Directions of the External Electric Field

Figure 3

(a) Structures (bond lengths are given in Å, the values in the negative field directions are given in brackets, from up to down: X, Y, and Z-axes) along the potential energy surface in the hydrothiolation reaction by the action of the external electric field (field strength (fs) is equal to 25 (×10–4) au). (b) Reaction barriers of the hydrothiolation reaction under different directions of EEFs.

Table 1

Relative Energies (kcal/mol) of Stationary Points along Potential Energy Surfaces under Different Directions of EEFs (fs = 25 (×10–4) au)

	F+X	F–X	F+Y	F–Y	F+Z	F–Z
R1 + R2	0.0	0.0	0.0	0.0	0.0	0.0
TSa	41.5	42.5	42.8	40.3	41.8	41.9
Pa	–12.9	–11.3	–15.3	–13.6	–12.3	–17.1
TS	39.7	37.7	40.2	35.9	38.5	39.0
P	–12.7	–14.9	–12.4	–15.0	–13.5	–13.7

From Figure a, we can conclude that the geometries in the EEF changed little when compared with those of EEF-free. From an inspection of the barrier heights shown in Figure b or Table , a clear difference can be observed. For path M, the EEF reduced the reaction barriers when it was oriented along the directions of −X, −Y, and +Z-axes. Especially, the barrier heights lowered to 1.0 and 2.8 kcal/mol when the EEF was oriented along the F– and F–. For path AM, only when the EEF was oriented along the +X and −Y-axes, the barrier heights were reduced. The biggest reduction in the reaction barrier was found at about 1.6 kcal/mol as the EEF oriented the F–. Consequently, the EEF generated an opposite influence on path M and path AM when it was oriented along the C=C bond, while it produced the same influence when it was oriented perpendicular to the C=C bond.

To explain the possible reasons, we first analyzed the atom charge of a carbon atom in allylamine; see Table . One can see that the atom charges changed obviously only when the EEF was oriented along the X-axis because this direction is considered as the direction of the “bond axis”.[20] To be specific, the EEF oriented along the +X-axis induced the C1 atom charge to decrease, which is unfavorable for path M. Thus, the barrier height of path M increased as EEF oriented along F+. Whereas, when the EEF was oriented along the −X-axis, the atom charge of C1 increased, therefore, path M was accelerated. Therefore, the F+ EEF catalyzed path AM, while the F– EEF catalyzed path M. In addition, we can also conclude the same conclusion from the changes in the dipole moment (Table and Figure ). For μ, when the EEF was oriented along the −X-axis, its value even became positive. This means that the C1 atom accumulated more charges, and thus path M was promoted. As for the F and F+, especially the Y-axis is usually known as the direction of the “reaction axis”;[20] their dipole moments are increased, which catalyze the hydrothiolation reaction.

Table 2

Charges of C1 and C2 Atoms and Dipole Moments of the Allylamine Molecule under Different EEFs (fs = 25 (×10–4) au)

	C1	C2	μX	μY	μZ
0	–0.442	–0.227	–0.349	0.184	–1.248
F+X	–0.430	–0.238	–0.787	0.185	–1.184
F–X	–0.454	–0.217	0.092	0.183	–1.310
F+Y	–0.442	–0.227	–0.347	–0.042	–1.265
F–Y	–0.442	–0.228	–0.350	0.410	–1.229
F+Z	–0.444	–0.225	–0.287	0.168	–1.517
F–Z	–0.440	–0.229	–0.413	0.203	–0.978

Figure 4

Direction of dipole moments of the allylamine molecule.

Except for the abovementioned changes, the reaction selectivity of the hydrothiolation was also influenced by the action of EEF. In the absence of EEF, the difference of the barrier heights of path AM and path M is 3.2 kcal/mol (ΔE = EAM – EM); see Table . On the one hand, once the EEF was introduced, we can see that the differences in barrier heights were expanded by 4.7, 4.3, and 3.3 kcal/mol when EEF was oriented along the −X, −Y, and +Z-axes. Further, we enlarged the field strength to 50 (×10–4) au to observe these differences, and the calculated results are shown in Figure a. Compared to the barrier heights, one can conclude that for path M, they are lowered gradually with the increase in the field strength when EEF is oriented along F–, and F–, while it is increased and reduced for path AM when EEF is oriented along F–, and F–, respectively. It coincides with the abovementioned conclusions. At the same time, the differences of reaction barriers of path AM and path M are also augmented to be 6.5 and 5.7 kcal/mol when F– and F– are equal to 50 (×10–4) au. It means the selectivity of a hydrothiolation reaction is higher when the EEF is oriented along the abovementioned directions. On the other hand, the differences in reaction barriers are reduced when the EEF are oriented along F+, F+, and F–, which means the selectivity becomes worse, especially for the F+ direction. For the +X direction, we also enlarged the field strength to explore a possibility of the reversal of reaction selectivity; see Figure b. As we predicted, the differences in the barrier heights of path AM and path M are decreased with the increase in the field strength. When F+ = 60 (×10–4) au, this difference shrinks to only 0.1 kcal/mol, which means the two pathways of the hydrothiolation reactions of thiophenol with allylamine became an almost equally competitive reaction. However, when we tried to enlarge the +X-axis field strength so much as to get an anti-Markovnikov addition product, path AM cannot be obtained.

Table 3

Differences in Reaction Barriers (kcal/mol) of Two Pathways at Various Directions of EEF (fs = 25 (×10–4) au)

ΔE	F+	F–
0	3.2
X	1.8	4.7
Y	2.6	4.3
Z	3.3	2.9

Figure 5

(a) Differences in reaction barriers of two pathways when F– and F– are equal to 25 and 50 (×10–4) au. (b) Differences in reaction barriers of two pathways when F+ is equal to 60 (×10–4) au.

Solvent Effects

To examine the solvent effects on these hydrothiolation reactions of thiophenol with allylamine, we employed three different solvents: toluene, acetonitrile, and water. The structures on the potential energy surfaces were reoptimized in solvents at the same level of theory, and their relative energies were recalculated as well. Further, the external electric field was also considered when the solvents were present. All of the results in different solvents are shown in Figure and Table . From Figure a, we can see that the geometries changed little when the solvents were employed. In addition, one can see that from Figure b, the introduction of solvents produced an obvious influence on the hydrothiolation reactions. On the one hand, the solvents reduced the barrier heights of both path M and path AM. On the other hand, with the increase in dielectric constants of the solvent, the reaction barriers became increasingly lower. In addition, when the external electric field was used, the barrier heights decreased much more in most of the directions of the EEF. Consequently, combining the external electric field and the solvents would be a nice catalytic method for the hydrothiolation reactions.

Figure 6

(a) Structures (bond lengths are given in Å) along the potential energy surface in the hydrothiolation reaction in toluene, acetonitrile, and water solvents (from up to down). (b) Reaction barriers of two pathways in toluene, acetonitrile, and water solvents. (c) Profile of the reaction barriers of two pathways in toluene, acetonitrile, and water solvents, as well as the external electric field (fs = 25 (×10–4) au).

Table 4

Relative Energies (kcal/mol) of Stationary Points along Potential Energy Surfaces in Different Solvents (fs = 25 (×10–4) au)abc

	EEF-free			FX		FY		FZ
	toluene	acetonitrile	water	25	–25	25	–25	25	–25
R1 + R2	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0	0.0
TSa	41.6	40.6	39.6	42.4	40.5	41.0	42.6	42.8	40.7
				42.0	38.4	39.4	41.9	42.0	39.2
				41.0	37.6	38.5	41.0	41.2	38.2
Pa	–11.4	–11.6	–13.0	–16.7	–14.9	–16.7	–14.9	–13.5	–18.1
				–16.4	–15.8	–18.9	–13.2	–13.6	–18.7
				–17.9	–17.0	–20.4	–14.5	–14.8	–20.1
TS	37.8	33.2	31.9	34.2	40.4	35.6	39.9	39.1	36.4
				26.2	39.4	31.7	35.1	35.5	31.2
				24.8	38.4	30.6	33.7	34.3	30.0
P	–12.8	–12.2	–13.6	–17.5	–16.3	–17.1	–16.7	–16.9	–17.2
				–17.2	–15.5	–16.7	–15.9	–16.2	–16.7
				–18.7	–16.7	–18.2	–17.1	–17.6	–18.1

Values were calculated in the toluene solvent.

Values were calculated in the acetonitrile solvent.

Values were calculated in the water solvent, and the rules were the same as those of F–, F+, F–, F+, and F–.

Conclusions

In the present paper, the hydrothiolation reactions of thiophenol with allylamine were first studied on the basis of the B3LYP/6-31G(d,p) level of theory. The calculated results demonstrated that two possible pathways could be found in the hydrothiolation reaction, in which the Markovnikov addition (path M) is easier to occur. Although a bigger hindrance occurred when thiophenol approached the allylamine molecule in path M, this channel had a lower reaction barrier because of the charge distribution. Once an external electric field (EEF) as a green catalyst was introduced in the hydrothiolation reaction, the barrier heights changed variously due to the oriented directions of EEF. To be specific, for path M, the EEF reduced the reaction barriers when it was oriented along the directions of −X, −Y, and +Z-axes, while for path AM, only when the EEF was oriented along the +X and −Y-axes, the barrier heights reduced. In addition, the selectivity of the hydrothiolation reactions was also changed by the action of EEF. The F– and F– EEF increased the difference in barrier heights of two pathways, which means that path M took place easily. Even when the F+ EEF decreased the difference in reaction barriers, the selectivity of the hydrothiolation reaction could not be reversed. In addition, the solvent effects were also considered, and the results demonstrated that the solvents accelerated the reactions, especially when the EEF also existed in some directions. In summary, from an environment and energy point of view, the employment of EEF is greener and more sustainable.

Computational Methods

All of the calculations of the hydrothiolation reactions of allylamine were performed with the Gaussian16 program.[21] The stationary points along the potential energy surfaces were fully optimized at the level of 6-31G(d,p) by means of B3LYP.[22] Harmonic vibrational frequencies were simultaneously calculated to affirm that all of the structures had no imaginary frequency, except the transition state had only one negative value of frequency. Further, the transition states were verified by IRC (intrinsic coordinate reaction)[23] calculations to confirm that they correctly connected the former and the latter when necessary. To improve the accuracies of the results, the single-point energies of all of the structures were further calculated at the level of 6-311++G(d,p) by the same method. Electrostatic potentials of the reactant molecules and NBO (natural bond orbital) analyses were also carried out at the B3LYP/6-31G(d,p) level, and the NBO was analyzed with the keyword NBO included in Gaussian16. To consider the solvent effects, toluene, acetonitrile, and water were used in the hydrothiolation reactions. The keyword “Field = M ± N”, which defines the direction and the magnitude of EEF (external electric field), was employed in the calculations to examine the catalysis of EEF in the hydrothiolation reactions. The oriented directions of the EEF are shown in Scheme .