Ligand Exchange Reaction of Au(I) R-N-Heterocyclic Carbene

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Ligand Exchange Reaction of Au(I) R-NHeterocyclic Carbene Complexes with Cysteine Helio F. Dos Santos, Marisa A. Vieira, Giset Y. Sánchez Delgado, and Diego Paschoal J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.6b01052 • Publication Date (Web): 24 Mar 2016 Downloaded from http://pubs.acs.org on March 27, 2016

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The Journal of Physical Chemistry

Ligand Exchange Reaction of Au(I) R-N-heterocyclic Carbene Complexes with Cysteine

H. F. Dos Santos,1,* M. A. Vieira,1 G. Y. Sánchez Delgado,1 D. Paschoal1,2

1

NEQC: Núcleo de Estudos em Química Computacional, Federal University of Juiz de Fora,

Department of Chemistry, Campus Universitário Martelos, 36.036-900, Juiz de Fora – BRAZIL 2

Federal University of Rio de Janeiro – Campus Macaé, 27.930-560, Macaé - BRAZIL

____________ *Corresponding author: H. F. Dos Santos – E-mail: [email protected]

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ABSTRACT

The chemotherapy with gold complexes has been attempted since the 90s after the clinical success of auranofin, a gold(I) coordination complex. Currently, the organometallics compounds have shown promising in cancer therapy, mainly those complexes containing N-heterocylic carbenes (NHC) as ligand. The present study shows a kinetic analysis of the reaction of six alkylsubstituted NHC with cysteine (Cys), which is taken as an important bio-nucleophile representative. The first and second ligand exchange processes were analyzed with the complete description of the mechanism and energy profiles. For the first reaction step, which is the ratelimiting step of the whole substitution reaction, the activation enthalpy follows the order: 1/Me2 < 2/Me,Et < 4/n-Bu2 < 3/i-Pr2 < 6/Cy2 < 5/t-Bu2, which is fully explained by steric and electronic features. From a steric point of view, the previous reactivity order is correlated with the r(Au-S) calculated for the transition state structures where S is the sulphur ligand from the Cys entering group. This means that longer r(Au-S) leads to higher activation enthalpy and is consistent with the effectiveness of gold shielding from nucleophile attack by bulkier alkyl-substituted NHC ligand. When electronic effect was addressed we found that higher activation barrier was predicted for strongly electron-donating NHC ligand, represented by the eigenvalue of σ-HOMO orbital of the free ligands. The molecular interpretation of the electronic effects is that strong donating NHC forms strong metal-ligand bond. For the second reaction step, similar structurereactivity relationships were obtained, however the activation energies are less sensitive to the structure.


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INTRODUCTION

Following the clinical success of cisplatin, cis-[Pt(NH3)2Cl2], the search for other metal complexes with improved therapeutic properties has been continuously active.1 In this new scenario, the gold complexes, mainly those of Au(I), are promising compounds following the leader molecule known as auranofin (AF), widely used in the treatment of rheumatoid arthritis.2 Besides, auranofin has also been successful tested against several types of leukemia, and carcinoma.3 The AF metabolism has so far hindered the rational design of gold metallodrugs and therefore, the development of more stable gold complexes is of particular interest.4 In addition, previous structure-activity relationship (SAR) studies about AF indicated that the phosphine ligand might play a major role for the biological potency than the thioglucose moiety.5 Different from Pt-complexes, for which the main target is the DNA, the Au-complexes are believed to interact with S and Se-containing proteins.6 Among several Au-complexes synthesized and tested recently, the medicinal use of N-heterocyclic carbene (NHC) complexes has been considered quite promising.7 It is known that NHCs belong to the most strongly binding ligands8,9 for a wide range of transition metals,10,11 such as ruthenium and palladium. Furthermore, the fact that NHCs are highly stable,12 easily synthesized and chemically modified, increases their interest as ligands for new metal-based drugs. Several gold(I)-NHC complexes have been synthesized by anchoring different alkyl groups at the secondary nitrogen atom to facilitate cellular uptake and, therefore it has been of interest to researchers obtaining important information about lipophilicity, charge, reactivity, cytotoxicity and inhibition of the thioredoxin reductase (TrxR) enzyme.13



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Since the past decade gold complexes have attracted more interest for potential anticancer agents due to their considerable cytotoxic properties7 and solubility. Cationic complexes14 showed more effectiveness compared to neutral complexes causing apoptosis in cancer cells lines. Studies have demonstrating that the effect of Au-bis(NHC) against breast and colon cancer cells is independent of the metal oxidation state and the anionic counter ion. These compounds follow a different cancer cells elimination path with strong gold-protein interactions, suggesting that the programmed cell death (apoptosis) should be the result of DNA-independent processes.6,15 As it is well known,16 mitochondria plays an important role in apoptosis by controlling cell oxidative stress, and therefore, the metal drugs, notably gold(I) complexes, might target mitochondria proteins instead of DNA replication inhibition. TrxR enzyme is a selenoenzyme of the disulfide reductase family present in the cytoplasm (TrxR-1), mitochondria (TrxR-2) and testicles (TrxR-3).17–19 In the TrxR cycle, the enzyme acts by reducing the oxidized thioredoxin (Trx), therefore maintaining the oxidation state of the cell and avoiding oxidative stress. The inhibition of TrxR unbalances one of the main oxidative stress control processes and triggers apoptosis by mitochondria pathway, which can be by activation of several caspase cascades. Gold(I)-NHC complexes have considerable selectivity13,20,21 for TrxR inhibition. In the present paper, the reactivity of six Au(I) R-N-heterocyclic carbene complexes with alkyl side chains is investigated (Scheme 1),16,22 using cysteine (Cys) as nucleophile. Their cytotoxic properties were tested by Hickey et al.22 and the perspective of our group is to study the reaction mechanism of these compounds, providing structure-property relationships useful to design new compounds. For all complexes shown in Scheme 1 the X-ray structures are


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available16 and for complexes 1/Me2 and 3/i-Pr2, experimental rate constants for reaction with Cys (k1 and k2 in Scheme 1) are provided.22

METHODOLOGY

The crystal structures for the complexes shown in Scheme 1 were reported in ref.16 and are used here as initial guess to assess the computation scheme used. The geometries of the complexes were firstly optimized at DFT-B3LYP23 level using the well-balanced basis-set 6-31+G(2df) and the LanL2TZ(f)24–26 for non-metal and metal atoms, respectively. In order to assess the role of long-range correction on the structure of the complexes, mainly those with bulky alkyl substituents, geometry optimization was also accomplished using the LC-BLYP,27 CAMB3LYP28 and wB97XD29 long-range corrected (LC) hybrid functionals. The solvent effect was accounted for within the continuum aqueous solution approach using the IEFPCM30 method with dielectric constant set to 78.35 (water) and UFF atomic radii. Similar level of theory was used for Au(III)31,32 and Au(I)33,34 complexes previously. The transition states (TS) for the two steps indicated in Scheme 1 (TS-1 and TS-2) were proposed as distorted trigonal-planar geometry, with the entering amino acid in the zwitterion form as found in the physiological medium (Scheme 2). The side chain protonation state was also considered based on the pKa values (8.5 for Cys) and the pH of 7.2 of the experiments. Therefore, the Cys was protonated in the SH form before coordination. It is noted in Schemes 1 and 2 that the coordinated Cys is deprotonated in TS-2 as consequence of the decreasing of pKa



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of the SH group, which is directly bound to Au center. The TS structures were optimized at B3LYP level only and characterized as first-order saddle point on the potential energy surface (PES) through harmonic frequency analysis. True TS must have only one imaginary frequency representing the bond breaking and bond formation vibrational mode. Furthermore, single-point energies for minimum and TS structures were obtained with the LC functionals (CAM-B3LYP, LC-BLYP and wB97XD) and the activation barriers estimated. All calculations were carried out with the Gaussian 09 program release D.01.35

RESULTS AND DISCUSSION

Structures of Au-NHC complexes

The structures of the Au-NHC complexes are discussed firstly. The B3LYP results are shown in Table 1 where it can be noted that the Au-C bond length is slightly overestimated (14%, maximum deviation of 0.08 Å) relative to the solid state experimental data. This is within the error margin for any DFT method, and is also due to the solvent effect that tends to enlarge the bond lengths in solution. When LC functionals are addressed, the Au-C bond length is closer to the solid state value with maximum deviation found 0.07 Å at wB97XD and 0.06 Å at LCBLYP level. The predicted and actual Au-C bond lengths are compared in Figure 1a. In general, the Au-C bond length is overestimated in solution as expected by 1-4% regardless the DFT method used, with the largest deviation found for complexes 2/Me,Et and 6/Cy2 (3-4%). The angular parameters are more sensitive to the DFT method than the bond length. The B3LYP values in Table 1 are in satisfactory agreement with experiment, except for complex


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6/Cy2, which the N-C-C’-N’ interplanar dihedral angle (ϕ) calculated in aqueous solution were much larger (72.8°) than observed in the solid state (16.7°). One possible reason is that in the solid state, the packing arrangement favors intermolecular contacts. For the complex 6/Cy2, weak intermolecular interactions of type C-H…Au (2.774 Å) are observed in the solid state and contribute to stabilize the more planar form (lower ϕ in Table 1). In addition, the intramolecular hydrophobic contacts between the parallels N-alkyl groups may also contribute to the more planar form. These weak interactions are mostly due to dispersion forces and are partially recovered when empirical LC corrections are included in DFT as shown in Figure 1b. The interring angle ϕ calculated at wB97XD level was 16.5°, in accordance with experimental geometry obtained in the solid state, 16.7°. The LC-BLYP and CAM-B3LYP methods also lead to the conformation of the complex 6/Cy2 in good agreement with experimental data, predicting a more interring planar structure. In summary, based on the profile of Figure 1 comparing standard hybrid DFT method (B3LYP) with LC functionals (LC-BLYP, CAM-B3LYP and wB97XD), it can be said that the solid state experimental geometries are better reproduced by DFT functionals with empirical LC correction. The dispersion forces are not much relevant for Au-C bond length, but play an important role on the conformation of complex 6/Cy2 which has the bulkiest alkyl substituent. Nonetheless, it should bear in mind that the calculations were performed for single molecule in PCM aqueous solution; therefore, some differences between theory and experiment must be expected. Unfortunately, experimental data in solution are not available for direct comparison. As noted in Figure 1a, the predicted trends over the series of molecules for Au-C bond length are similar for all methods used. Therefore, the B3LYP values given in Table 1 were used to stablish some structure-properties relationships. The Au-C bond length is somehow correlated



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with the σ-HOMO orbital eigenvalue (εσ) of the free NHC, which represents mostly the lone pair of the Ccarbene atom (Figure 2, R2=0.97). It means that longer Au-C bonds are predicted for NHC with higher εσ (less negative eigenvalue). In a recent paper by Bernhammer et al.,36 a deep analysis of electronic structure trends in free NHC was performed and one important conclusion was that εσ is correlated to the donor strength of NHC. Thus, weaker donors present lower (more negative) εσ value and stronger donors present higher (less negative) εσ value. From Figure 2, the weakest NHC donor is the ligand 1/Me2 (short Au-C bond, 2.04 Å) and the strongest donor is the derivative 5/t-Bu2 (long Au-C bond, 2.07 Å). In ref.36 the interaction energy for binding of a NHC with Au-NHC fragment was calculated and revealed that stronger Au-C bonds are found for more strongly donating NHC, which present higher εσ. For the set of molecule studied here the following Au-C bond strength order is expected based on εσ value (Figure 2) and the conclusions from ref.:36 1/Me2 < 2/Me,Et < 4/n-Bu2 < 3/i-Pr2 < 6/Cy2 < 5/t-Bu2.

Ligand exchange reactions of Au-NHC with Cys

The ligand exchange process is a key step towards the biological action of metal-based drugs. In some cases, the rate of ligand exchange might play a primary role on the observed biological response.37 For the complexes 1-6 the reaction with Cys was studied. This process was investigated experimentally in aqueous media at pH 7.2 and the rate constants for the first and second steps, represented in Scheme 1, provided for complexes 1/Me2 and 3/i-Pr2. For Cys the pKa=8.5, therefore at experimental condition of pH 7.2, only ~5% of the cysteine residues are found in the deprotonate state. Thereby, the reaction with Cys was studied considering the 8 ACS Paragon Plus Environment

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protonate state of the side chain (SH) with the amino acid group in the zwitterion form. Only the attack through sulphur atom was analyzed based on the softness of the Au(I) center. An associative-type mechanism was assumed, which passes through a transition state (TS) where the entering and leaving atoms are in the vertices of a triangle as represented in Scheme 2. Several attempts were made to optimize TS structures with LC functionals, but neither of them could be fully converged. The most successful attempt was for complex 2/Me,Et at wB97XD level, which lead to a structure with three imaginary normal modes; therefore only B3LYP TS geometries are discussed here. The main structural parameters for the TS geometries calculated at B3LYP level are shown in Tables 2 (TS-1) and 3 (TS-2) for the first and second reaction steps, respectively. From Table 2 (TS-1 structures) it is clear the role of steric hindrance of alkyl substituents on the Cys approaching. The Au-S distance ranges from 2.376 (1/Me2 – Figure 3a) to 2.516 Å (5/t-Bu2 – Figure 3b). Conversely, the Au-CL (CL stands for the coordinated carbon of the leaving carbene) decreases for bulky alkyl groups, found the shortest value for the 5/t-Bu2 derivative (2.772 Å). The overall trend for Au-S distance among the NHC studied is represented in Figure 3c. The angular arrangement around the metal is also affected. The θ2 is the angle between the entering and the leaving groups, and is close to 70°, except for compound 5/t-Bu2, which was larger, 83.5°. As consequence, θ1 [∠(S-Au-CB)] decreases and is found ~150° for 5/t-Bu2. The parameter θ1 (Figure 3d) is particularly important, because Au(I) complexes tend to assume a linear geometry on the first coordination shell, thereby the deviation of θ1 from the ideal angle of 180° will cause an increase in the strain energy and, consequently, increase the activation barrier (this will be seen later in the analysis of the energy barriers). It is worth noting in Figures 3c-d that the r(Au-S) bond increasing is correlated with the θ1 decreasing. These trends follow the 9 ACS Paragon Plus Environment


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nature of the carbon attached to the heterocyclic nitrogen, namely from CH3 (1/Me2) to tertiary carbon (5/t-Bu2). The change on the interring dihedral angle (ϕ) in the TS-1 structure relative the Au(I) complex can be evaluated from the values in Tables 1 (free complexes) and 2 (TS-1). For the bulkier derivatives (5/t-Bu2 and 6/Cy2) the heterocyclic rings are forced to the plane upon the nucleophile approach, decreasing the interring torsion angle from 70-90° to 30-40°. This is clearly illustrated in Figure 4 for the complex 6/Cy2. It is opportune to remind that the interring conformation of the complex 6/Cy2 was more planar when LC functionals are used (ϕ~20° Figure 1b). Analyzing the values in Table 3 for TS-2 it is noted that the trends represented in Figure 3 for r(Au-S) and θ1 for TS-1 are followed in some extent for the second step (TS-2), though, both parameters are less sensitive to the NHC alkyl wings (see Figure 5). The r(Au-S) distance (S is the sulfur from the entering Cys) ranged from 2.45 to 2.50 Å (Figure 5b) and θ1 from 149 to 141° (Figure 5d) for complexes 1/Me2 and 5/t-Bu2, respectively. Moreover, the Au-S distance is longer in TS-2 than TS-1, except for complex 5/t-Bu2. This trend is mainly due to the fact that the nucleophile and the complex are neutral species, reducing the electrostatic forces. Interestingly, the θ1 angle differs significantly from the ideal value of 180°. Nonetheless, the gain in strain energy is compensating by a moderate hydrogen bond between the NH3+ group and the carbon in the leaving carbene (see Figure 5a). The NH…CL hydrogen bond distance was ~2 Å, found slightly longer for the bulky derivative 5/t-Bu2 (~2.2 Å) (see Figure 5c). The overall mechanism can be assigned through the descriptor ∆Σ, which measures the role of bond breaking and bond formation upon the ligand exchange process.31 It means that if ∆Σ=0, the mechanism is perfectly “concerted”. For ∆Σ0 the bond breaking dominates and the mechanism is named “dissociative interchange”. Herein the ∆Σ was calculated as {d(AuCL)TS-d(Au-C)R}-{d(Au-S)TS-d(Au-S)P} where TS, R and P represent the structures of the transition state, reagent and product, respectively (see Tables 2 and 3). The first term measures the magnitude of the role of the bond breaking and the second one the magnitude of the effect of the bond formation (both terms are defined to be positive). According to the values in Tables 2 and 3, all compounds react through a “dissociative interchange” mechanism (∆Σ>0), with the bond breaking playing a more pronounced role, mainly for the first step (∆Σ>0.5). For the second step, the bond breaking still dominates, but ∆Σ values are smaller (∆Σ 1/Me2, as predicted theoretically by B3LYP



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and CAM-B3LYP// methods. Nevertheless, the 2nd step is observed to be slightly slower than the 1st step, contrary to the theoretical results. Indeed, theoretically, the 1st ligand substitution was much slower than the 2nd step, with energy barrier found ~6-12 kcal mol-1 higher. This is probably due the N-H…C hydrogen bond formed in the TS-2 (see Figure 5a) that leads to an over stabilization of transition state. In a real system this could not play a role due solute-solvent specific interactions which can stabilize the zwitterion form of cysteine. Regardless, this is an interesting finding which could be part of enzyme catalysis were the amino acid residue is found in a more hydrophobic region and available to interact with the substrate. This was not verified here but certainly is a point to be investigated in depth later. Lastly, we discuss a final structure-property relationship for the series of Au(I) complexes analyzed based on electronic descriptors (B3LYP data only). It has been previously shown35 that the 1st proton affinity of free carbenes is linearly correlated with σ-HOMO energy and, therefore, it suggests that this parameter might be useful to rank the carbenes’ reactivity based on their electronic properties. It was verified for the series of molecules studied here. The Figure 7 clearly shows the correlation of activation enthalpy for Cys/carbene exchange process with the σ-HOMO energy of free carbenes for the activation steps. The interpretation of the trend in Figure 7 is that weakly donating NHC reacts faster with Cys, which means that the transition state is less stabilized by σ-donation of the leaving carbene, which Au-C bond has being breaking. Moreover, the reactivity rank predicted at B3LYP level is (from most reactive – weakest donor to less reactive – strongest donor): 1/Me2, 2/Me,Et, 4/n-Bu2, 3/i-Pr2, 6/Cy2, 5/tBu2. The most straightforward factor influencing the donor strength of the NHC series studied here is the nature of carbon-containing functional groups. For the most weakly donating NHC (1/Me2) the N atoms are both substituted by CH3 and for the strongest donor NHC (5/t-Bu2), both


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N atoms are substituted for tertiary carbon groups. For the 2nd step, the extremes of the trend are respected however the correlation is not perfectly linearly. The reason is again the small range which activation barrier varies.

CONCLUSIONS

The ligand exchange reactions between Au(I)-NHC complexes and Cys were theoretically investigated by means of DFT calculations in aqueous solution. Six compounds containing distinct alkyl-substituted NHC ligands were considered, which provided some structurereactivity relationships important for tuning the chemical properties of such complexes. The first and second steps for the ligand exchange processes were calculated and the structures and energies along the reaction paths obtained. For the free cationic Au(I)-NHC complexes the strength of Au-C bond was linearly correlated (r2=0.97) with the eigenvalue of the σ-HOMO orbital of the free carbene, with the following order stablished for the Au-C bond strength: 1/Me2 < 2/Me,Et < 4/n-Bu2 < 3/i-Pr2 < 6/Cy2 < 5/t-Bu2. The previous stability trend was the same as found for the activation enthalpy for the first reaction step (r2=0.99), which is the rate-limiting step of the whole substitution reaction. This finding suggests that weakly donating NHC (with more negative εσ) reacts quickly with nucleophiles, which means that the transition state is less stabilized by σ-donation of the leaving carbene. For the series of complexes studied, the structural feature responsible for the σ-donation ability is the nature of the carbon linked to the nitrogen of the NHC, namely from primary (1/Me2 - weaker donor) to tertiary carbon (5/t-Bu2 stronger donor). Steric properties also play a role on the complexes reactivity and we proposed two structural parameters from the TS structure as steric descriptors: The distance r(Au-S) and 17 ACS Paragon Plus Environment


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the angle ∠(S-Au-CB) where S is the sulphur ligand from the entering nucleophile and CB e the coordinated carbon. The activation barrier increases with r(Au-S) due the more efficient shielding of metal center by bulkier alkyl-substituent. Conversely, the energy barrier decreases as ∠(S-Au-CB) approaches to 180°, the ideal angle for Au(I) linear complexes. The relationships stablished using steric descriptors are not perfectly linear, but converges asymptotically to a maximum value for complex 5/t-Bu2, with the very same reactivity order observed for the electronic properties maintained. Concerning the biological action of Au(I)-NHC complexes, they are expected to bind to enzymes and both electronic and steric effects will act differently from the reaction with free amino acids. Nonetheless, according the results discussed here small alkyl-substituents would speed up the first ligand exchange reaction with both electronic and steric features favoring the process. Surely, the magnitude of such effects will depend on the binding site.

ACKNOWLEDGMENTS

The authors would like to thank CNPq (485779/2013-7) for providing support for this project.

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TOC


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Page 25 of 33

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


R1

R1

N

R1

+

L N

HCys

L

Au

Au

H2 C

S

-H CH

k1

R2

CPX_n

C R2

R1(0)_n

k2 TS-2

O

O

NH3+ H2 C

CH

S

Au

S

NH3+

H2 C

C

+H+ CH

CH

HCys

NH3+

H H2 C

S

Au

S

H2 C

CH

-H+ C

O

O-

P2(-1)_n

-L

O-

-

C

O

O-

R1(1)_n

O-

CH C

R2

O-

TS-1

H2 C

N

O

CPX_n n=1: R1=R2=Me n=2: R1=Me, R2=Et n=3: R1=R2=i-Pr n=4: R1=R2=n-Bu n=5: R1=R2=t-Bu n=6: R1=R2=Cy

S

Au

+H+

N

NH3+

N +

-L

N R2

NH3

H

N

N

R1

+ +

NH3+

C

P2(0)_n

Scheme 1. Au(I) R-N-heterocyclic carbene complexes and the ligand-exchange paths for reaction with Cys. The 1st and 2nd steps are indicated by the red arrows. Note that after coordination, the pKa of Cys decreases and the proton from SH side chain is released to the medium.


O-

O


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+

+

H3N CH

COO-

O-

CH

H r(Au-S)

θ1

Au N

r(Au-CB)

COO-

H

R N

H3N

CH2

S

O

C r(Au-S)

θ2 r(Au-CL)

θ3

R

+

R

CH

H2 C

θ1

S

Au

r(Au-SB)

N NH3+

CH2

S θ2

r(Au-CL)

θ3

N

R N

N

R

R

TS-2

TS-1

Scheme 2. Schematic representation of the TS structures for the first (TS-1) and second (TS-2) steps of ligand-exchange reaction with Cys. The important structural parameters calculated for the TS structures are indicated. Note that in the TS-2 structure the coordinated Cys has its side chain deprotonated.

Figure 1. Structural parameters calculated for the Au(I)-NHC complexes with standard hybrid DFT (B3LYP) and long-range corrected DFT methods (CAM-B3LYP, LC-BLYP, wB97XD). The geometries were optimized in aqueous solution. The r(Au-C) bond length is shown in (a) and the interring angle ϕ(N-C-C’-N’) in (b). 26 ACS Paragon Plus Environment

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Figure 2. Correlation plot of r(Au-C) bond length and the eigenvalue of σ-HOMO orbital calculated for the free carbene (εσ). The image inset was obtained for the ligand NHC-Me2 (B3LYP results).



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Figure 3. B3LYP optimized geometries for the TS-1 for complexes 1/Me2 (a) and 5/t-Bu2 (b). The figures (c) and (d) show the variation of some parameters for the TS-1 geometries, namely the Au-S(Cys) distance (c) and S(Cys)-Au-CB (θ1) angle (d) where CB is the carbon of the NHC bound to the metal.

Figure 4. B3LYP Optimized structure for the complex 6/Cy2 and the corresponding TS-1. The figure shows the change in the interring angle (ϕ) upon reaction with Cys. The angle ϕ change from 72.8° (6/Cy2) to 29.5° (TS-1).

Figure 5. Structural trends predicted for TS-2 (B3LYP results). (a) Optimized geometry for TS-2 involved in the reaction of the complex 1/Me2. (b) Distance between the entering sulphur ligand and gold center, r(Au-S). (c) Hydrogen bond distance between the amino group and leaving carbene, r(NH-CL). (d) S(Cys)-Au-CB (θ1) angle where CB is the carbon of the NHC bound to the metal.


Page 29 of 33

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Figure 6. Activation enthalpy (∆Ha) calculated for reaction of Cys with the series of complexes considered in the present work. The values for the 1st (a) and 2nd (b) steps are plotted following the reactivity order obtained for the first ligand-exchange process at B3LYP level.

Figure 7. Activation enthalpy (∆Ha – B3LYP) as function of the eigenvalue of σ-HOMO orbital of the free carbene. The black balls show the trend for the 1st step and the red squares for the 2nd step.



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Table 1. Selected geometric parameters calculated at B3LYP/6-31+G(2df)/LanL2TZ(f) in continuous aqueous solution for the cationic, linear Au(I)-NHC complexes. The X-ray values are provided in brackets* Distances/Å Angles/degrees Au-C

∠C-Au-C

ϕa/N-C-C’-N’

δb/N-N-Au-C

1/Me2

2.043 [2.018(8)]

180 [180]

0.88 [1.2]

0.47 [0.65]

2/Me,Et

2.042 [1.96(3)]

179.3 [178.5(8)]

23.1 [8.1]

0.68 [2.7]

3/i-Pr2

2.046 [2.027(2)]

180 [180]

0.33 [2.5]

0.17 [1.3]

4/n-Bu2

2.042 [2.03(1)]

180 [180]

0.34 [0.12]

0.18 [0.06]

5/t-Bu2

2.070 [2.038(3)]

179.9 [176.1(1)]

93.8 [86.9]

0.00 [0.35]

6/Cy2

2.045 [1.97(1)]

180 [180]

72.8 [16.7]

0.00 [0.00]

*

Experimental values from Ref..16 a ϕ is the interring dihedral angle. b δ is the deviation of the gold atom from the ring plane.


Page 31 of 33

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Table 2. Selected geometric parameters calculated for the TS-1 structures at B3LYP/631+G(2df)/LanL2TZ(f) in continuous aqueous solution. Distances/Å Angles/degreese

1/Me2

Au-Sa

Au-CBb

Au-CLc

∆Σd

θ1

θ2

θ3

ϕf/N-C-C’-N’

2.376

2.019

3.012

0.9

174.6

73.6

111.5

1.81

0.9

174.1

74.5

110.9

0.85

0.9

172.8

73.2

113.8

23.9

0.9

173.4

75.2

110.8

37.8

0.5

149.9

83.5

126.2

39.9

0.9

169.1

73.9

116.8

29.5

[2.356]

2/Me,Et

2.379

{2.043} 2.019

[2.356]

3/i-Pr2

2.382

{2.042} 2.023

[2.356]

4/n-Bu2

2.379

2.516

2.020

2.387 [2.356]

2.958 {2.042}

2.058

[2.355]

6/Cy2

3.010 {2.046}

[2.357]

5/t-Bu2

2.956

2.772 {2.070}

2.023

3.000 {2.045}

a

The values in [] are for the product where Cys was completely transferred to the metal coordination sphere (R1(1)_n in Scheme 1). b CB stands by the carbon atom bound to the Au. c The values in {} are for the reagent where both carbenes are coordinate to the metal (CPX_n in Scheme 1). The CL represents the carbon atom of the leaving carbene. d ∆Σ={d(Au-CL)TS-d(Au-C)R}-{d(Au-S)TS-d(Au-S)P}. e The angles are defined in Scheme 2. f ϕ is the interring dihedral angle.



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Table 3. Selected geometric parameters calculated for the TS-2 structures at B3LYP/631+G(2df)/LanL2TZ(f) in continuous aqueous solution. Distances/Å Angles/degreese

1/Me2

Au-Sa

Au-SBb

Au-CLc

∆Σd

θ1

θ2

θ3

2.450

2.331

2.583

0.4

148.9

84.5

126.5

0.4

149.0

83.3

127.6

0.5

149.5

83.9

126.5

0.4

147.5

85.3

127.1

0.3

140.9

87.8

131.2

0.4

148.5

84.9

126.4

[2.345]

2/Me,Et

2.452

{2.030} 2.328

[2.345]

3/i-Pr2

2.441

{2.031} 2.327

[2.345]

4/n-Bu2

2.461

2.506

2.333

2.443 [2.345]

2.565 {2.029}

2.338

[2.345]

6/Cy2

2.653 {2.034}

[2.345]

5/t-Bu2

2.587

2.561 {2.049}

2.330

2.623 {2.034}

a

The values in [] are for the product where Cys was completely transferred to the metal coordination sphere (P2(0)_n in Scheme 1). b SB stands by the sulphur atom bound to Au. c The values in {} are for the reagent where the carbene is coordinate to the metal (R1(1)_n in Scheme 1). The CL represents the carbon atom of the leaving carbene. d ∆Σ={d(Au-CL)TS-d(Au-C)R}-{d(Au-S)TS-d(Au-S)P}. e The angles are defined in Scheme 2.


Page 33 of 33

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Table 4. Activation enthalpy (∆Ha) and free energy (∆Ga) calculated in continuous aqueous solution at 298.15K (values in kcal mol-1). 1st reaction step 2nd reaction step ∆Ha ∆Ga ∆Ha ∆Ga 1/Me2 1/Me2 B3LYP 28.7 39.6 B3LYP 22.7 35.9 CAM-B3LYP// 28.3 39.2 CAM-B3LYP// 21.3 34.5 LC-BLYP// 27.8 38.7 LC-BLYP// 19.4 32.6 wB97XD// 22.4 33.3 wB97XD// 13.0 26.2 Expt.a [20.44] Expt.a [21.46]

2/Me,Et B3LYP CAM-B3LYP// LC-BLYP// wB97XD//

3/i-Pr2

B3LYP CAM-B3LYP// LC-BLYP// wB97XD// Expt.a

4/n-Bu2

B3LYP CAM-B3LYP// LC-BLYP// wB97XD//

5/t-Bu2


2/Me,Et 29.1 28.6 28.0 23.1

39.8 39.3 38.7 33.8

29.9 29.0 27.8 21.9

40.1 39.1 37.9 32.1 [20.95]

29.7 28.9 27.7 21.8

39.7 38.8 37.7 31.8

35.2 33.4 31.1 23.6

49.6 47.8 45.4 38.0


3/i-Pr2

B3LYP CAM-B3LYP// LC-BLYP// wB97XD// Expt.a

4/n-Bu2


5/t-Bu2


6/Cy2

6/Cy2

22.6 21.2 19.2 13.0

35.9 34.4 32.5 26.2

23.3 21.6 19.3 12.3

37.8 36.1 33.8 26.8 [21.89]

24.0 22.2 20.0 13.9

37.8 36.1 33.8 27.8

23.7 21.7 19.2 10.7

37.9 35.9 33.4 24.9

B3LYP 30.5 41.7 B3LYP 23.2 37.0 CAM-B3LYP// 28.9 40.1 CAM-B3LYP// 21.3 35.2 LC-BLYP// 26.9 38.0 LC-BLYP// 18.8 32.7 wB97XD// 19.2 30.4 wB97XD// 11.1 24.9 The double slashes followed the DFT methods means the calculation was carried out within the single-point approach where the B3LYP geometry and thermal corrections for energy were assumed. a Experimental values from Ref.22 are given in brackets.


Ligand Exchange Reaction of Au(I) R-N-Heterocyclic Carbene

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