Thiourea Derivatives as Brønsted Acid Organocatalysts

Transcription

1 Supporting Information Thiourea Derivatives as Brønsted Acid Organocatalysts Ádám Madarász, Zsolt Dósa, Szilárd Varga, * Tibor Soós, Antal Csámpai, Imre Pápai * Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, H-1117 Budapest, Magyar tudósok körútja 2, Hungary Institute of Chemistry, Eötvös Loránd University, P. O. B. 32, H-1518 Budapest-112, Hungary adresses: varga.szilard@ttk.mta.hu, papai.imre@ttk.mta.hu Contents S.1 Test calculations... S2 S.2 Reference state ternary complexes... S3 S.3 Conformational analysis of thiourea 1... S3 S.4 Ion-pair intermediate associated with TS BA-2... S4 S.5 MeOH-catalyzed tautomerization of 1... S5 S.6 Direct BA pathway... S6 S.7 Adduct formation... S6 S.8 Extended molecular model... S7 S.9 Total energy data... S9 S.10 Cartesian coordinates of the optimized geometries... S10 S.11 Experiments... S46 S1

2 S.1 Test calculations The computational methodology applied in our present work includes a number of approximations regarding the exchange-correlation functional, the basis set, the estimation of thermal and entropic contributions, as well as the solvent effects. To assess the uncertainty of our energy predictions arising from these approximations, we performed test calculations employing two additional functionals (B3LYP- D3 and M06-2X-D3) 1 that are frequently used in current theoretical mechanistic studies. The test calculations were carried out for transition states TS HB-1, TS HB-2 and TS BA-1 as representatives of HB and BA type transition states. In all cases, we used the same protocol as described in the Computational Details section of the paper (geometry optimizations, vibrational analysis, and the estimation of solvent effects were performed with the 6-311G(d,p) basis set; plus additional single-point energy calculations with the G(3df,3pd) basis set). We estimated the effect of geometry optimization in the solvent phase, i.e. allowing to relax the geometry of transition states by switching on the implicit solvent model during the optimization procedure. The results of our test calculations are collected in Table S1. Table S1: Relative energies of TS HB-1 and TS HB-2 transition states (with respect to TS BA-1 ) as computed by different methods. a entry method TS HB-1 energy difference (in kcal/mol) TS HB-2 1 G sol (ωb97x-d) G o (ωb97x-d) E o (ωb97x-d) E o (ωb97x-d) G sol-opt (ωb97x-d) c E sol-opt (ωb97x-d) c G sol (B3LYP-D3) G o (B3LYP-D3) E o (B3LYP-D3) G sol (M06-2X-D3) n/a b G o (M06-2X-D3) n/a b E o (M06-2X-D3) n/a b 10.2 a Notation: E o and E o refer to electronic energies computed with 6-311G(d,p) and G(3df,3pd) basis sets; G o and G sol denote gas-phase and solution-phase Gibbs free energies. b Transition states corresponding to TS HB-1 with the M06-2X-D3 functional could not be located. The TS structures found in these calculations describe proton shift from MeOH to DHP coupled with deprotonation of the catalyst (proton shift from 1 to MeO ). c Geometries of transition states were reoptimized with the implicit solvent model (PCM) using THF as a solvent. As indicated in the manuscript, the most favored transition state located for the BA mechanism (TS BA-1 ) using our standard protocol is 6.5 and 7.5 kcal/mol more stable than TS HB-1 and TS HB-2 (entry 1 in Table S1, highlighted in red). The energy differences are somewhat smaller in terms of gas-phase Gibbs free energies (entry 2). In other words, the solvent effects are found to enhance the preference of TS BA-1 (they likely induce more stabilization for BA type transition states). In line with this, computations involving solution-phase geometry optimizations predict even larger energy separations (entries 5 and 6). The preference of TS BA-1 is about 8 kcal/mol in gas-phase electronic energies, and the effect of basis set expansion (from 6-311G(d,p) to G(3df,3pd)) appears only fairly small (entries 3 and 4). Although S2

3 the B3LYP-D3 and M06-2X-D3 functionals give slightly different relative stabilities ranging from 5.2 to 10.2 kcal/mol, the trend of having clearly favored TS BA-1 remains (entries 7-12). These results demonstrate that the conclusion drawn in our paper regarding the relevance of Brønsted acid catalysis in the investigated reaction remains valid at all levels of theory. S.2 Reference state ternary complexes The conformational analysis of catalyst-meoh-dhp ternary complexes involved an initial Monte Carlo sampling using the OPLS_2005 force field, 2 which was then followed by DFT calculations. The most stable forms of the ternary complexes relevant to the investigated systems (catalyst = 1, 4 and 5) are depicted in Figure S1. The solution-phase Gibbs free energies of these structures served us as reference levels to estimate the reaction barriers. Figure S1: The most stable forms of catalyst-methanol-dhp ternary complexes S.3 Conformational analysis of thiourea 1 Three different conformers of thiourea 1 could be identified computationally, which differ in the orientation of the N-H groups (Figure S2). The present computational approach predicts the E,Z structure to be the most stable form, however, the Z,Z isomer is only 2.2 kcal/mol less stable. 3 The third form, the E,E conformer, is computed to be at +3.6 kcal/mol in free energy, and it displays an intramolecular arylaryl contact. The iminothiol tautomeric form of 1 is notably less stable as it is computed to be at +8.3 kcal/mol. S3

4 Figure S2: Computationally identified conformers of thiourea 1. Relative Gibbs free energies are shown in parenthesis (in kcal/mol; with respect to the most stable form). S.4 Ion-pair intermediate associated with TS BA-2 The transition state corresponding to the proton transfer from the E,Z form of catalyst 1 to the β-side of DHP is computed to be at kcal/mol (see TS BA-2-init in Figure S3). IRC calculations in the forward direction (towards the product state) lead to a local energy minimum, and the obtained structure is characterized as a trimolecular ion-pair species involving the deprotonated catalyst ([1 dp ] ), the protonated DHP (DHPH + ), and an MeOH molecule bound to the thiourea S atom (see [1 dp ] DHPH + MeOH in Figure S3). This species is predicted to be at kcal/mol with respect to the reference level. The addition of MeOH to DHPH + takes place in a separate step, i.e. via TS BA-2, which represents a barrier of 29.2 kcal/mol on this BA pathway. The ion-pair species can be regarded as a transient reaction intermediate, and the low barriers defined by transition states TS BA-2-init and TS BA-2 imply that this reaction pathway is a borderline between a two-step and a concerted/asynchronous mechanisms. S4

5 Figure S3: Formation of the transient ion-pair intermediate and the subsequent addition of MeOH. Relative stabilities (in kcal/mol; with respect to the reference state) are given in parenthesis. Our calculations indicate that the [1 dp ] DHPH + MeOH ion-pair can easily undergo structural rearrangements (see section S.6), and even the dissociation of the ions might be feasible at the experimental reaction conditions. For instance, the dissociation of [1 dp ] DHPH + MeOH into [1 dp ] MeOH and DHPH + (in THF) is predicted to be endergonic only by 1.9 kcal/mol (dissociated species are depicted in Figure S4). Figure S4: Optimized structures of [1 dp ] MeOH and DHPH + ions. The geometries of the [1 dp ] DHPH + MeOH ion-pair and the adjacent transition states (TS BA-2-init and TS BA-2 ) have been reoptimized in the presence of the implicit solvent (THF) as well. As expected from the ionic (or partially ionic) nature of these structures, we found slight stabilization for all these species. The computed relative free energies in this model are 27.1, 25.5 and 27.7 kcal/mol for TS BA-2-init, [1 dp ] DHPH + MeOH and TS BA-2, respectively (values corresponding to gas-phase optimizations are 27.8, 26.9 and 29.2 kcal/mol, as shown in Figure S3). S.5 MeOH-catalyzed tautomerization of 1 Calculations were carried out to explore the energetics of methanol-assisted tautomerization of thiourea 1. The results indicate that even a single alcohol molecule opens a kinetically feasible pathway for this process (see Figure S5). In particular, the 1-tau 1-E,Z isomerization has a very low barrier (6 kcal/mol) suggesting that the original form of catalyst 1 can be easily regenarated from the iminothiol tautomer formed along the BA pathways represented by transition states TS BA-1 - TS BA-4 (see Figure 2 of the paper). S5

6 Figure S5: Methanol-assisted tautomerization of thiourea 1. Relative stabilities (in kcal/mol; with respect to 1- E,Z MeOH) are given in parenthesis). S.6 Direct BA pathway Structural rearrangements of the [1 dp ] DHPH + MeOH ion-pair species were examined, and we found that methanol migration to form a hydrogen bond with the N atom of the [1 dp ] anion has a low barrier (see Figure S6; TS rearr lies only 2.3 kcal/mol above [1 dp ] DHPH + MeOH). This new form of the ion-pair intermediate ([1 dp ] DHPH + MeOH rearr in Figure S6) allows an alternative MeOH addition pathway that regenerates 1 directly as the proton is shifted to the thiourea N atom. The overall barrier of this BA pathway (29.2 kcal/mol) is comparable to those represented by transition states TS BA-1 - TS BA-4. Figure S6: Structural rearrangement of the ion-pair species followed by methanol addition that regenerates the original form of catalyst 1. Relative stabilities (in kcal/mol; with respect to the reference state) are given in parenthesis. S.7 Adduct formation The potential energy surface has been scanned with respect to the C-N bond distance for the [1 dp ] DHPH + MeOH ion-pair (see Figure S7). Based on these calculations, the barrier of C-N type adduct formation is less than 1 kcal/mol from the ion-pair species. Nucleophilic attack of the S atom in [1 dp ] is also feasible. One possible transition state is depicted in Figure S7 (TS C-S ), which represents an overall barrier of 29.7 kcal/mol for the C-S type adduct formation. S6

7 Figure S7: Formation of 1-DHP adducts. Left: Potential energy scan from the ion-pair towards C-N type adduct (scanned C-N distance is highlighted in blue). Right: transition state located for the formation of C-S type adduct. Relative stabilities (in kcal/mol; with respect to the reference state) are given in parenthesis. S.8 Extended molecular model The trimolecular 1/DHP/MeOH model used throughout our computational study has been augmented by an additional MeOH molecule and the most favored HB and BA type transition states (i.e. TS HB-1 and TS BA-1 ) were reoptimized with this model as well. We assumed that the additional methanol molecule acts as a H-bond donor by coordinating either to the oxygen of the reacting methanol, or to the sulphur of thiourea 1. The most favored transition states 4 located for this extended model are depicted in Figure S8 along with the computed relative stabilities. The calculations reveal that transition states corresponding to H-bond formation with the reacting methanol (TS BA-1 MeOH-1 and TS HB-1 MeOH-1) are notably more favored (by 3.5 kcal/mol) than those involving S HO-Me type H-bonds (TS BA-1 MeOH-2 and TS HB-1 MeOH-2). This is actually not surprising as the O-H bond of the reacting methanol is polarized in the transition state (oxygen bears partial negative charge). However, it is also apparent that the free energy difference between the BA and HB type transition states (6.2 kcal/mol) is very close to that found with the trimolecular model (6.5 kcal/mol), so the higher feasibility of the of Brønsted acid mechanism is borne out with the extended model as well. S7

8 Figure S8: Transition states identified with the extended model. Relative Gibbs free energies with respect to the most stable structure (TS BA-1 MeOH-1) are given in parenthesis (in kcal/mol). S8

9 S.9 Total energy data The energy data computed for the ωb97xd/6-311g(d,p) optimized geometries of the structures discussed in the manuscript and in the Supporting Information are listed in Table S1 (in the order as they are discussed in the main text and then in the SI). Table S2: Energy data (in atomic units) computed for ωb97xd/6-311g(d,p) optimized structures. a structures E o G o G sol E o G TS HB TS HB TS BA TS BA TS BA TS BA TS BA add CN add CS TS BA (4) TS BA (5) MeOH DHP MeOH DHP MeOH DHP E,Z Z,Z E,E tau TS BA-2-init [1 dp ] DHPH + MeOH [1 dp ] MeOH DHPH E,Z MeOH TS tau tau MeOH TS rearr [1 dp ] DHPH + MeOH rearr TS BA [1 dp ] DHPH + MeOH PS TS add TS C-S TS BA-1 MeOH TS BA-1 MeOH TS HB-1 MeOH TS HB-1 MeOH a Notation: E o and E o refer to electronic energies computed at ωb97xd/6-311g(d,p) and ωb97xd/ g(3df,3pd) level of DFT; G o and G sol denote gas-phase and solution-phase Gibbs free energies obtained from ωb97xd/6-311g(d,p) calculations. The last column is obtained as G = E o + (G o - E o) + (G sol - E o) and the relative energies discussed in the manuscript and in the SI are obtained from these values. The value a.u. corresponds to concentration correction to the free energy when switching from p = 1 atm (ideal gas standard state) to c = 1mol/dm 3 (standard concentration in solution phase). S9

10 S.10 Cartesian coordinates of the optimized geometries Cartesian coordinates of ωb97xd/6-311g(d,p) optimized geometries are given below in standard XYZ format (units are in Å). First line indicates total number of atoms, second line shows the notation of the molecule (as defined above, see also Table S1). 60 TS HB-1 C S N H N H C C C C C H H H H H H O H H O H C H H H C C C C H C H C H C C C C H C H C H C C S10

11 C C F F F F F F F F F F F F TS HB-2 C S N H N H C C C C C H H H H H H O H H O H C H H H C C C C H C H C H C C C S11

12 C H C H C H C C C C F F F F F F F F F F F F TS BA-1 C S N H N C C C C H C H C H C C C C H C H C H C C F F F F F S12

13 F C C F F F F F F H C C C C C H H H H H H O H H C H H H O H TS BA-2 C S N H N C C C C H C H C H C C C C H C H C S13

14 H C C F F F F F F C C F F F F F F H C C C C C H H H H H H O H H C H H H O H TS BA-3 C S N H N C C C C H C H C H S14

15 C C C C H C H C H C C F F F F F F C C F F F F F F H C C C C C H H H H H H O H H C H H H O H TS BA-4 C S N H N C S15

16 C C C H C H C H C C C C H C H C H C C F F F F F F C C F F F F F F H C C C C C H H H H H H O H H C H H H O H S16

17 60 TS BA-5 C S N H N C C C C H C H C H C C C C H C H C H C C F F F F F F C C F F F F F F H C C C C C H H H H H H O H S17

18 H C H H H O H add CN C S N H N C C C C H C H C H C C C C H C H C H C C F F F F F F C C F F F F F F H C C C C C S18

19 H H H H H H O H H add CS S C N N C C C C C C C C C C C C C C C C O C C F F F C F F F C F F F C F F F H H H H H S19

20 H H H H H H H H H H H TS BA (4) C S N H N C C H C C C C C H H H H H H O H H C H H H O H C H H O TS BA (5) C S N N C C S20

21 C C H C H C H C C C C H C H C H C C F F F F F F C C F F F F F F H C C C C C H H H H H H O H H C H H H O H C H S21

22 H H MeOH DHP C S N N C C C C H C H C H C C C C H C H C H C C F F F F F F C C F F F F F F H C C C C C H H H H H H S22

23 O H H C H H H O H H MeOH DHP C S N H N C C H C C C C C H H H H H H O H H C H H H O H C H H O MeOH DHP C S N N C C C S23

24 C H C H C H C C C C H C H C H C C F F F F F F C C F F F F F F H C C C C C H H H H H H O H H C H H H O H C H H S24

25 H E,Z C S N H N H C C C C H C H C H C C C C H C H C H C C C C F F F F F F F F F F F F Z,Z C S N N C C C C S25

26 C C C C C C C C C C F F F F F F C C F F F F F F H H H H H H H H E,E C S N H N H C C C C H C H C H C C C C H S26

27 C H C H C C C C F F F F F F F F F F F F tau C S N H N C C C C H C H C H C C C C H C H C H C C F F F F F F C S27

28 C F F F F F F H TS BA-2-init C S N H N C C C C H C H C H C C C C H C H C H C C F F F F F F C C F F F F F F H C C C C S28

29 C H H H H H H O H H C H H H O H [1 dp ] DHPH + MeOH C S N H N C C C C H C H C H C C C C H C H C H C C F F F F F F C C F F F S29

30 F F F H C C C C C H H H H H H O H H C H H H O H [1 dp ] MeOH C S N H N C C C C H C H C H C C C C H C H C H C C F F F S30

31 F F F C C F F F F F F C H H H O H DHPH + H C C C C C H H H H H H O H H E,Z MeOH C S N H N C C C C H C H C H C C C S31

32 C H C H C H C C F F F F F F C C F F F F F F H C H H H O H TS tau C S N H N C C C C H C H C H C C C C H C H C H S32

33 C C F F F F F F C C F F F F F F H C H H H O H tau MeOH C S N H N C C C C H C H C H C C C C H C H C H C C F F F F S33

34 F F C C F F F F F F H C H H H O H TS rearr C S N H N C C C C H C H C H C C C C H C H C H C C F F F F F F C C F F S34