Functional

Article Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX

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Co(III) Complexes with N2S3‑Type Ligands as Structural/Functional Models for the Isocyanide Hydrolysis Reaction Catalyzed by Nitrile Hydratase Takuma Yano,† Yuko Wasada-Tsutsui,† Tomohiro Ikeda,† Tomonori Shibayama,† Yuji Kajita,‡ Tomohiko Inomata,† Yasuhiro Funahashi,§ Tomohiro Ozawa,† and Hideki Masuda*,† †

Department of Frontier Materials, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso-cho, Showa-ku, Nagoya 466-8555, Japan ‡ Department of Applied Chemistry, Graduate School of Engineering, Aichi Institute of Technology, Yakusa, Toyota 470-0392, Japan § Department of Chemistry, Graduate School of Science, Osaka University, Machikaneyama, Toyonaka, Osaka 560-0043, Japan S Supporting Information *

ABSTRACT: It has been before reported that, in addition to hydration of nitriles, the Fe-type nitrile hydratase (NHase) also catalyzes the hydrolysis of tert-butylisocyanide (tBuNC). In order to investigate the unique isocyanide hydrolysis by NHase, we prepared three related Co(III) model complexes, PPh4[Co(L)] (1), PPh4[Co(L-O3)] (2), and PPh4[Co(L-O4)] (3), where L is bis(N-(2-mercapto-2-methylpropionyl)aminopropyl)sulfide. The suffixes L-O3 and L-O4 indicate ligands with a sulfenate and a sulfinate and with two sulfinates, respectively, instead of the two thiolates of L. The X-ray analyses of 1 and 3 reveal trigonal bipyramidal and square pyramidal structures, respectively. Complex 2, however, has five-coordinate trigonal-bipyramidal geometry with η2-type S−O coordination by a sulfenyl group. Addition of tBuNC to 1, 2, and 3 induces an absorption spectral change as a result of formation of an octahedral Co(III) complex. This interpretation is also supported by the crystal structures of PPh4[Co(L-O4)(tBuNC)] (4) and (PPh4)2[Co(L-O4)(CN)] (5). A water molecule interacts with 3 but cannot be activated as reported previously, as demonstrated by the lack of absorption spectral change in the pH range of 5.5−10.2. Interestingly, the coordinated tBuNC is hydrolyzed by 2 and 3 at pH 10.2 to produce tBuNH2 and CO molecule, but 1 does not react. These findings provide strong evidence that hydrolysis of tBuNC by NHase proceeds not by activation of the coordinated water molecule but by coordination of the substrate. The mechanism of the hydrolysis reaction of tBuNC is explained with support provided by DFT calculations; a positively polarized C atom of tBuNC on the Co(III) center is nucleophilically attacked by a hydroxide anion activated through an interaction of the sulfenyl/sulfinyl oxygen with the nucleophile.

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INTRODUCTION Enzymes of the nitrile hydratase (NHase) family, which have a Co(III) or an Fe(III) ion in the active site, convert nitriles to the corresponding amides.1 Both types of NHases are isostructural with each other and consist of a heterodimer composed of α and β subunits.2,3 Crystal structure analyses of both types have revealed that the metal ion has octahedral geometry with two deprotonated amide nitrogen atoms and three cysteine thiolates, in which the two sulfur atoms in the equatorial plane are oxidized to sulfenate (SO) and sulfinate (SO2) in the N2S3 coordination environment with a water molecule (Co-type)3 or an NO molecule (Fe-type)4,5 at the sixth coordination site. The coordination of an amidate nitrogen atom is unique in metalloenzymes, and the oxidation of cysteine residues can be unpredictable. A genetic recombination treatment has been performed on the enzyme in order to investigate its reaction mechanism. Reconstituted © XXXX American Chemical Society

Fe-type NHase, whose sulfur atoms are unoxidized thiolates, does not promote nitrile hydrolysis, indicating that the hetrogeneously oxygenated sulfur atoms are one of the essential factors for enzymatic activity.6 In a study of the βY68F mutant of the Co(III) type NHase, it was discovered that the mutation causes a decrease in activity, although the site of the mutation is far from the active site. Furthermore, the hydroxyl group of Tyr68 is linked to the amidate carbonyl oxygen through a series of water molecules and Arg56 in the crystal structure.7 These observations suggest that not only the unique coordination of three thiolate sulfurs with different oxidized forms and two amidate nitrogens but also the hydrogen bonding networks linked to Tyr68 in the vicinity of the unique active site coordination environment are important for NHase function. Received: November 18, 2017

A

DOI: 10.1021/acs.inorgchem.6b02324 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry

Inc. and were used without further purification. Reagent grade solvents were obtained from Wako Pure Chemical Industry Inc. and Kanto Kagaku Inc. and were doubly distilled before use. Synthesis of Ligand L. An N2S3-type ligand, L, was prepared according to a previous report27a and isolated as a white solid. 1H NMR data (δ ppm from TMS in CDCl3); 1.60 (s, 12H), 1.83 (m, 4H), 2.21 (s, 2H), 2.57 (t, 4H), 3.37 (q, 4H), 7.18 (t, 2H). Selected IR bands (cm−1); 3364 (s, ν(NH)), 2568 (w, ν(SH)), 1641 (s, ν(CO)), 1521 (s, δ(NH)). Synthesis of PPh4[Co(L)] (1). Sodium hydride, NaH (77.8 mg, 3.24 mmol), was added to a DMF solution (20 mL) containing ligand H4L (200 mg, 0.567 mmol). The resulting bright yellow solution was stirred for ca. 15 min. Then, [CoCl(NH3)5]Cl2 (142 mg, 0.567 mmol) was added to the solution. The resultant slurry was heated to 70 °C overnight until a deep purple color developed. Tetraphenylphosphonium chloride, PPh4Cl (269.4 mg, 0.72 mmol), was added to the solution. After the solution was stirred for 30 min, the DMF was removed under vacuum, and the purple residue was again dissolved in 50 mL of dry EtOH. The solution was filtered, and the solvent was evaporated. Recrystallization of the compound from an acetone/ diethyl ether mixed solution with the residue afforded a single crystal under an Ar atmosphere (yield 42.5%). Elemental analysis (%); Found: C; 60.83, H; 5.99, N; 3.74. Calcd for C38H44CoN2O2PS3 (PPh4[Co(L)]): C; 61.11, H; 5.94, N; 3.75. Selected IR bands (KBr pellet, cm−1): 1560 (ν(CO)). Electronic absorption spectrum in MeOH: (λmax, nm (ε M−1cm−1)); 369 (5000), 527 (2500). ESI-MS (negative mode): m/z 407.1 ([Co(L)]−). Synthesis of PPh4[Co(L−O3)] (2). Complex 1 (200 mg, 2.74 mmol) was dissolved in a methanol solution (20 mL), and urea hydrogen peroxide was added (580 mg, 6.4 mmol). After the mixture was stirred for 3 h, and the solution was evaporated, a red crude compound was obtained. The solid was recrystallized from an acetone/ethyl acetate mixed solution to afford a red powder. A red plate crystal was obtained after the filtrate was allowed to stand for a few days (yield 76.6%). Elemental analysis of the red powder (%); Found: C; 55.95, H; 5.90, N; 3.65. Calcd for C38H46CoN2O6PS3 (PPh4[Co(L−O3)]·H2O): C; 56.15, H; 5.70, N; 3.45. Selected IR bands (KBr pellet, cm−1): 1568 (ν(CO)), 1176, 1049, 1017, and 893 (ν(SO)). Electronic absorption spectrum in MeOH: (λmax, nm (ε M−1cm−1)); 329 (5930), 342 (3510), 500 (∼550). Synthesis of PPh4[Co(L−O4)] (3). Complex 3 was prepared according to a previous report.27a Elemental analysis (%); Found: C; 56.38, H; 5.38, N; 3.37. Calcd for C38H44CoN2O6PS3 (PPh4[Co(L− O4)]): C; 56.29, H; 5.47, N; 3.45. Selected IR bands (KBr pellet, cm−1): 1569 (ν(CO)), 1224 and 1070 (ν(SO)). Electronic absorption spectrum in MeOH: (λmax, nm (ε M−1 cm−1)); 335 (8200), 400 (sh), 561 (590). ESI-MS: m/z 471.1 ([Co(L−O4)]−). Synthesis of PPh4[Co(L−O4)(tBuNC)] (4). The monodentate ligand tBuNC, (200 μL, 1.76 mmol) was added to an acetone solution (150 μL) containing PPh4[Co(L−O4)] (2) (5 mg, 6.17 × 10−3 mmol) and H2O (5 μL). A red crystal was isolated as a result of slow diffusion of diethyl ether into the solution under air (yield 78.1%). Elemental analysis (%); Found: C; 51.02, H; 6.59, N; 4.07. Calcd for C 43 H 66 N 3 O 12.5 CoPS 3 (PPh 4 [Co(L−O 4 )(tBuNC)]·6.5H 2 O): C; 51.08, H; 6.58, N; 4.16. Selected IR bands (KBr pellet, cm−1): 2197 (ν(NC)), 1541 (ν(CO)), 1198 and 1049 (ν(SO)). Electronic absorption spectral data in H2O (λmax, nm (ε M−1cm−1)): 340 (13800), 450 (sh). Synthesis of (PPh4)2[Co(L−O4)(CN)] (5). Complex 3 (5 mg, 6.17 × 10−3 mmol) was dissolved in 5 mL of acetonitrile. Addition of PPh4CN (5 mg, 0.027 mmol) to the solution caused a color change from green to red. A small volume of diethyl ether was poured onto the acetonitrile solution. A red plate crystal was afforded after the solution was allowed to stand at −20 °C for a few days (yield 58.9%). Elemental analysis (%); Found: C; 60.71, H; 5.79, N; 4.35. Calcd for C65H75CoN4O10P2S3 ((PPh4)2[Co(L−O4)(CN)]·4H2O·CH3CN): C; 60.55, H; 5.86, N; 4.35. Selected IR bands (KBr pellet, cm−1): 2113 (ν(CN)), 1545 (ν(CO)), 1190 and 1037 (ν(SO)). Electronic absorption spectral data in MeOH (λmax, nm (ε M−1cm−1)): 328 (14300), 420 (sh).

Various research results for Fe-type NHase enzymes have recently indicated that the catalytic reaction proceeds through direct ligation of the nitrile to the central metal ion.8−10 Furthermore, Odaka and co-workers also discovered that Fetype NHase has the potential to hydrolyze tert-butylisocyanide (tBuNC) to produce the corresponding amine and carbon monoxide (CO) in a single reaction step, although the reaction rate is quite slow.8 The isocyanide, which is a structural isomer of the corresponding nitrile compound, has been investigated for antimalarial activity because of the toxicity of its CN group.11 In nature, isocyanides are hydrated and converted to corresponding N-substituted formamide compounds by isonitrile hydratase (IsoNHase).12 Further hydrolysis by Nsubstituted formamide deformylase (NfdA) converts them to N-substituted amine compounds and formic acid.13 The structure−function relationships of these enzymes are not yet well-defined. Many Co(III) and Fe(III) structural/functional model complexes have been synthesized and studied14−39 in efforts to understand the structure−function relationships of the active sites of Co- and Fe-type NHases. However, there have been no reports on hydrolysis of an isocyanide molecule using an NHase model complex, although we previously studied the effect of the oxidation of a thiolate sulfur atom on the Lewis acidity of a metal center as well as the interactions of SO and SO 2 groups with solvent molecules using (PPh 4 )[CoIII(LCO:N2S2)(tBuNC)2],24 Na[CoIII(LCO:N2(SO)2)(tBuNC)2],26 and (PPh4)[CoIII(LCO:N2(SO2)2)(tBuNC)2].24 Furthermore, we have also reported that strong interaction of solvent molecules to amido O atoms accelerates the coordination of the tBuNC molecule.24,27b It suggests that the interaction such as a hydrogen bonding to the outersphere is also one of the important factors to hydrolyze. In the present work, in order to investigate the influence of the unique structure at the NHase active center with respect to coordination of a sixth ligand and the isocyanide hydrolysis mechanism, we synthesized two new N2S3-type five- and sixcoordinated Co(III) complexes (PPh4[Co(L)] (1) and PPh4[Co(L-O3)] (2), where L = bis(N-(2-mercapto-2methylpropionyl)aminopropyl)sulfide ligand) which have coordination environments similar to that of the NHase active center structure. We also prepared PPh4[Co(L-O4)] (3) for a comparison.27 The notation L-O3 indicates that two of three sulfurs of L are oxidized to a sulfenate and a sulfinate. Likewise, the notation L-O4 indicates that two of the three sulfurs of L are oxidized to two sulfinates. Each of the complexes 1, 2, and 3 is suitable as the structural models of the active site of NHase than those reported previously, particularly with respect to the similarity of the coordinating atoms.14−39 tBuNC and CN− adducts of 3 generate octahedral Co(III) complexes with tBuNC and CN− at the sixth vacant site as revealed in their Xray structures. The coordination behavior of monodentate ligands H2O, tBuNC, and CN− to complexes 1, 2, and 3 and hydrolysis of the tBuNC are discussed. The hydrolysis reaction of the tBuNC molecule is also studied on the basis of the crystal structure of PPh4[Co(L-O4)(tBuNC)] (complex 4) by fulloptimization using DFT calculations.

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EXPERIMENTAL SECTION

Reagents and Methods. All manipulations were performed using Schlenk techniques under argon or in a glovebox under an argon atmosphere. Reagents used in this study were purchased as reagent grade from Wako Pure Chemical Industry Inc. or Tokyo Kasei Kogyo B

DOI: 10.1021/acs.inorgchem.6b02324 Inorg. Chem. XXXX, XXX, XXX−XXX

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N1−Co1−N2 S1−Co1−S2 S1−Co1−N1 S1−Co1−N2 S2−Co1−N1 N1−Co1−N2 S1−Co1−S2 S1−Co1−N1 S1−Co1−N2 S2−Co1−N1 S2−Co1−N2 S3−Co1−N1 S3−Co1−N2 87.99(9) 82.6(2) 119.66(5) 87.40(9) 93.45(9) 94.0(1) 86.6(1) bond angles 178.6(1) 116.78(4) 152.2(2) 123.52(5) 87.7(2) 90.59(9) 96.2(2) N1−Co1−N2 S1−Co1−S2 S1*−Co1−S2 S1−Co1−S3 S1*−Co1−S3 S1−Co1−N1 S1*−Co1−N1

a

[deg] S1−Co1−N2 S1*−Co1−N2 S2−Co1−S3 S2−Co1−N1 S2−Co1−N2 S3−Co1−N1 S3−Co1−N2

2.177(1) 2.173(1) 2.316(6) Co1−N1 Co1−N2 Co1−S1

The atom with the * is in relation of disorder with the atom without the * to each other.

143.23(3) 99.09(5) 115.55(3) 159.61(5) 44.18(5) 94.35(7) 89.00(7)

2.044(2) 1.471(4) 1.472(2) 1.573(2)

Co1−N1 Co1−N2 Co1−S1 Co1−S2 Co1−S3

3

Co1−N1 Co1−N2 Co1−S1 Co1−S2 Co1−S3

bond lengths [Å] 1.942(2) Co1−O3 1.928(2) S2−O1 2.2565(6) S2−O2 2.1329(6) S3−O3 2.1332(7) bond angles [deg] 175.57(8) S1−Co1−S3 101.22(3) S1−Co1−O3 90.66(6) S2−Co1−S3 91.67(6) S2−Co1−O3 83.64(6) S3−Co1−O3 92.20(6) N1−Co1−O3 91.69(6) N2−Co1−O3 86.86(6)

2·2H2O 1

bond lengths [Å] 1.909(3) Co1−S2 1.921(3) Co1−S3 2.344(1) Co1−S1*

Table 1. Selected Bond Lengths [Å] and Angles [deg] for PPh4[Co(L)] (1), PPh4[Co(L−O3)]·2H2O (2·2H2O), and PPh4[Co(L−O4)] (3)a C

bond lengths [Å] 1.905(3) S2−O2 1.930(3) S2−O3 2.323(1) S3−O5 2.102(1) S3−O6 2.107(1) bond angles [deg] 176.9(1) S2−Co1−N2 154.85(5) S3−Co1−N1 96.0(1) S3−Co1−N2 83.6(1) S1−Co1−S3 85.9(1) S2−Co1−S3

1.449(3) 1.473(3) 1.499(3) 1.452(3)

X-ray Structure Analysis. A single crystal suitable for X-ray diffraction measurements was mounted on a glass fiber using grease oil. The diffraction data were collected with a Rigaku Mercury diffractometer using graphite-monochromated Mo−Kα radiation at −100 °C with the oscillation technique. Crystal data and experimental details are listed in Table 1. All structures were solved by a combination of direct methods and Fourier techniques. Non-hydrogen atoms were anisotropically refined by full-matrix least-squares calculations. Hydrogen atoms were included but not refined. Refinements were continued until all shifts were smaller than onetenth of the standard deviations of the parameters involved. Atomic scattering factors and anomalous dispersion terms were taken from the International Tables for X-ray Crystallography.40 All calculations were performed using the Crystal Structure crystallographic software package (Rigaku Crystal Structure 4.0) except for refinement, which was performed using SHELXL-97. Determination of Equilibrium Constants for Coordination of tBuNC. Equilibrium constants were estimated by means of electronic absorption spectral changes of the complex solution with consecutive addition of tBuNC. The intensity change at ca. 350 nm was used and calculated according to eq 2.24 The total concentration was kept constant at 5.00 × 10−5 M for the complexes 1 and 2. Acceptor numbers of solvents were obtained from the literature.41−43 Product Analysis of the Hydrolysis of tBuNC. Product analyses of the hydration of tBuNC by the NHase model complexes were performed on a SHIMADZU GC-2014 gas chromatograph equipped with a flame-ionization detector (FID) and 30 m Stabilwax-DB capillary column (RESTEK). The model complex was dissolved ([complex] = 2 μM) in a mixture of 1.9 mL aqueous buffer solution and 0.1 mL tBuNC (1.0 mmol) in a Teflon sealed screw-cap vial, and the mixture was kept for 24 h in a constant-temperature bath at 20 °C. The buffer solutions used were 0.1 M CH3COOH/CH3COONa, 0.1 M Tris/HCl, and 0.1 M NaHCO3/NaOH for pH values of 4.8, 7.5, and 10.2, respectively. Dimethylsulfone was used as the internal standard, and the products were identified and estimated by comparison with authentic samples. The retention times of the reaction products, N-tert-butylamine and N-tert-butylformamide, were 3.10 and 14.9 min, respectively. The products were also identified by GC-2010 gas chromatography mass spectrometry (GC−MS). GC− MS analyses were performed on a SHIMADZU GC-2010 equipped with a 30 m Stabilwax-DB capillary column (RESTEK). In the hydrolysis reaction of isocyanide, the product analyses of carbon monoxide were performed on a SHIMADZU GC-8A gas chromatograph equipped with a thermal conductivity detector (TCD) and a 4 m SHINCARBON ST packed column. The retention time of carbon monoxide in this system was 5.3 min. Other Physical Measurements. Elemental analysis was performed using a using PerkinElmer 2400II CHNS/O fully automatic analyzer. All mass spectra were acquired using a LCT mass spectrometer equipped with an electrospray interface (Micromass Limited, Manchester, UK). Samples were introduced using a single syringe pump (KD scientific Inc., USA) fitted with Hamilton syringes (Hamilton Co, Reno, NE). The samples used for all spectral measurements were prepared in MeCN or MeOH. 1H NMR spectra were recorded on a Varian Gemini-300 FT-NMR instrument. Electronic absorption spectra were measured on a JASCO V-570 spectrophotometer in the wavelength range of 900−250 nm. A matchpaired quartz cell was used with a 10 mm length. Infrared spectral measurements were carried out using a JASCO FT/IR 410 spectrophotometer. Solid samples were prepared from KBr powder under pressure over 5 tons. Solution spectra were measured using a double-piled CaF2 cell with a path length of 0.1 mm. Differential spectra between the sample and the corresponding solvent were adopted to make sure the spectral feature. DFT Calculation Details. All the electronic structure calculations by the DFT method were carried out at the OPBE level.44 The following basis sets were used for the respective atoms: 6-311G(d) for Co,45a,b 6-31+G(d) for S,45c−e N, and O,45c,e,f and 6-31G(d)45c,e,f for C and H atoms, respectively. For drawing electron density maps, 6-311G

93.3(1) 96.3(1) 86.8(1) 99.17(4) 105.57(5)

Inorganic Chemistry

DOI: 10.1021/acs.inorgchem.6b02324 Inorg. Chem. XXXX, XXX, XXX−XXX

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Inorganic Chemistry

Figure 1. ORTEP views of the [Co(L)]− anion in 1 and the [Co(L−O3)]− anion in 2, showing 50% probability ellipsoids and the structure of the [Co(L−O4)]− anion in the previously reported complex 3. was employed for the Co atom. Two diffuse p functions were added to the basis set of the Co atom, which were multiplied by 1.5.45a We performed all the geometry optimization under a condition of an aqueous solution where the solvent waters would reduce an electrostatic repulsion between negative charges of the reactants of the basic hydrolysis of isocyanide. We estimated the solvent effect on structure along the reaction pathway by using polarizable continuum model with the integral equation formalism variant (IEFPCM).46 We attempted to search for reaction paths of the basic and neutral hydrolysis of isocyanide by geometry optimizations using DFT calculations for the following states; an initial adduct of complex 4 with OH− or H2O, a possible final state structure that is expected from the reaction products, tert-butylamine and CO, and the transition state on the path connecting the initial and the final states. The calculation of natural atomic charges and atom−atom overlap-weighted NAO (Natural Atomic Orbital) bond order at the stationary points along the reaction pathway were carried out in order to investigate reactivity of the coordinated isocyanide.47 All the electronic structure calculations were performed using the Gaussian 09 Rev. D.01,48 and the isosurfaces of the molecular orbitals were drawn using MOPLOT and MOVIEW programs49 on the Fujitsu CX400 system at the Nagoya University Information Technology Center.

octahedral Co(III) complexes with thiolates reported previously (2.21−2.32 Å).18−20,34−37 The average ligand-to-metal bond lengths of complex 1, Co−S(1)av (2.330 Å) is longer than those of a previously reported Co-thioether (2.25−2.27 Å)52 and Co−Nav (1.915 Å), are within the range of Co−Namide bonds (1.89−1.96 Å).18−25 On the other hand, oxidation of coordinated thiolates to sulfinates, as seen in the differences between complex 1 and complex 3, drastically changes the coordination structure from trigonal bipyramidal to square-pyramidal geometry. This coordination behavior is very much similar to the coordination behavior of [Co(III)(SMe2(SO2)N3(Pr,Pr))]+,33 although only one of the two coordinated sulfur atoms was oxidized to a sulfinate. The τ value (0.37)27a of complex 3 indicates that it has a distorted square pyramidal structure with a sulfinate, a thioether, and two nitrogen atoms in the equatorial plane and a sulfur atom of the sulfinyl group at the axial position. The τ value of 3 is smaller than that of 1. This may suggest that the trans influence of the sulfinyl group of complex 3 is larger than that provided by the unoxidized sulfur of complex 1, and therefore, it is likely that the two sulfinates of complex 3 adopt the cis-geometry with respect to each other in order to avoid the strong trans influence. The conformational change results in formation of a vacant site that can be occupied by a small molecule at a trans-position of one of the sulfinyl sulfur atoms. The formation of the vacant site was also observed for [Co(III)(SMe2(SO2)N3(Pr,Pr))]+.33 Treatment of 1 with urea hydrogen peroxide forms complex 2. Recrystallization of crude compound 2 from an ethyl acetate/acetone mixed solution afforded a single crystal suitable for an X-ray structural analysis. 2 was crystallized as the complex linked with two hydrated water molecules through the amidato oxygen atoms in the unit cell (2·2H2O). It is shown in Figure 1 that the geometry of complex 2 is a trigonal bipyramid, in which the trigonal plane is coordinated to a thioether sulfur (Co−S(1) = 2.2565(6) Å), a sulfinyl sulfur (Co−S(2) = 2.1329(6) Å), and sulfenyl S−O π-orbital in η2-fashion (Co− S(3) = 2.1332(7), Co−O(3) = 2.044(2) Å). The axial positions are occupied by two deprotonated amide nitrogen atoms (Co− N(1) = 1.942(2), Co−N(2) = 1.928(2) Å). The Co−S(2) bond (2.1329(6) Å) of 2 is somewhat shorter than Co−S bonds of other six-coordinate complexes with sulfinyl Scoordination (2.164−2.232 Å)18,35,38,52−54 as well as the Co− S(O2) bond length (2.118(1) Å) in [Co(III)((η2-SO)(SO2)-

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RESULTS AND DISCUSSION Crystal Structures of PPh4[Co(L)] (1), PPh4[Co(L−O3)]· 2H2O (2·2H2O), and PPh4[Co(L−O4)] (3). The Co(III) complexes with an N(amide)2S3-type ligand, PPh4[Co(L)] (1), PPh4[Co(L-O3)] (2), and PPh4[Co(L-O4)] (3),27 which have sulfur atoms in different oxidation states, were isolated as single crystals. The crystal data are listed in Table S1. The crystal structures of the anion moieties and selected bond lengths and angles for complexes 1 and 2·2H2O are shown in Figure 1 and Table 1, respectively, together with those of complex 3 previously reported. The crystal structure of complex 3 and its coordination behavior of water molecules were previously described and discussed.27a Complex 1 has five-coordinate trigonal-bipyramidal geometry with two thiolate S(2) and S(3) atoms and a disordered thioether S(1) atom in the trigonal plane and with two amide N(1) and N(2) atoms at the axial sites, with a τ value50 of 0.92. The Co−S(2) and Co−S(3) bond lengths are 2.177(1) and 2.173(1) Å, respectively, which are similar to those of a previously reported,33 structurally similar Co(III) complex with two thiolate sulfurs, two imine nitrogens, and one amine nitrogen, [Co(III)(S2Me2N3(Pr,Pr))]+ (2.162(2) and 2.158(2) Å), and are shorter than those of structurally saturated D

DOI: 10.1021/acs.inorgchem.6b02324 Inorg. Chem. XXXX, XXX, XXX−XXX

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Inorganic Chemistry N3(Pr,Pr))]+.33 The inclined coordination of the sulfenyl oxygen (Co−O(3) = 2.044(2) Å) by η2-coordination may have the effect of shortening the Co−S(O2) bond. The structure is very similar to that of [Co(III)((η2-SO)(SO2)N3(Pr,Pr))]+, which has two azomethine nitrogen atoms and an aliphatic nitrogen atom instead of the two amide nitrogen atoms and the thioether of 2. The bond lengths and angles are similar to those of [Co(III)((η 2-SO)(SO2)N 3(Pr,Pr))]+, although some of the coordinated atoms are different. Coordination of the sulfenyl oxygen at the axial site indicates that this oxygen atom is nucleophilic. This observation is consistent with the results of our previous work which indicated that the stretching vibration frequency of an SO group linearly depends on the acceptor numbers of solvents which provide an indication of electrophilicity.26 Complex 2·2H2O is stable with respect to further oxidation by atmospheric molecular oxygen. Structural Estimations of PPh4[Co(L)] (1), PPh4[Co(L− O3)]·2H2O (2·2H2O), and PPh4[Co(L−O4)] (3) in Solution. Electronic absorption spectra of complexes 1, 2, and 3 were measured in solution. Complex 1 has two maximum absorption bands at 527 nm (ε 2480 M−1 cm−1) and 369 nm (ε 5000 M−1 cm−1) and two broad bands at 480 nm (ε ∼ 1980 M−1 cm−1) and around 750−800 nm (ε ∼ 200 M−1 cm−1) in MeOH (Figure 2). These spectral features are also observed for

Complex 2 has an absorption spectrum with two clear bands at 372 nm (ε 3510 M−1 cm−1) and 329 nm (ε 5930 M−1 cm−1) and a broad band at about 500 nm (ε 550 M−1 cm−1) in MeOH, as shown in Figure 2. Furthermore, we also measured IR spectra of complex 2 both in solution and in the solid state. The vibration band assignable to the SO stretching frequency was detected at 895 and 896 cm−1 in MeCN and acetone solutions, respectively. In the solid state, the vibration band was detected at 893 cm−1. These results indicate that the structure of 2 in the solid state is maintained in solution. These spectral features were observed not only in the noncoordinating solvent, CHCl3, but also in the coordinating organic solvents, EtOH, MeCN, DMF, and acetone, indicating that these solvent molecules do not coordinate to the metal ion. Complex 3, which was reported to have pyramidal geometry in the crystalline state,27a has two maximum absorption bands at 561 nm (ε 590 M−1 cm−1) and 355 nm (ε 8170 M−1 cm−1) and a shoulder peak at around 400 nm (ε 5180 M−1 cm−1) in MeOH (Figure 2). These spectral features were also observed for complex 3 dissolved in coordinating organic solvents such as EtOH, MeCN, DMF, and acetone. Interestingly, pyramidal geometry is also retained in CHCl3 as reported previously.25 This indicates that solvent molecules do not coordinate to the Co(III) center, in contrast to the arrangement observed in the crystal structure. As described previously,27a a water molecule coordinates only to complex 3 and not to 1 and 2. This will be discussed in more detail below. As discussed above, 1 and 2 have trigonal-bipyramidal structure and 3 is a square-pyramidal structure both in the solid state and in organic solvents, such as CHCl3, acetone, MeOH, EtOH, MeCN, and DMF. However, it has been found that strong coordinating ligands such as tetraphenylphosphonium cyanide (PPh4CN) and tBuNC can bind to complexes 1, 2, and 3 in solution, although complex 2 does not have a small molecule-accessible vacant site. The coordination of these molecules to complex 2 suggests that the metal-bound sulfenyl oxygen is exchanged for CN− and tBuNC. This is confirmed by IR spectroscopic observations as follows. The vibration band assignable to the SO stretching frequency at 895 cm−1 in MeCN shifts to a higher wavenumber region at 944 cm−1 when CN− is added to 2 in MeCN solution. This vibration band is similar to those of the S-coordinated sulfenato-Co(III) complexes reported hitherto (950−1000 cm−1).33,57 The lower energy shift of ν(SO) of the sulfenato group is explained in terms of the decrease in electron density on the SO group which occurs upon coordination to the metal. The coordination behavior of CN− to complex 2 will be discussed below. In order to understand the coordination behavior at the sixth sites of 1 and 3, anions or small molecules were added to MeOH or EtOH solutions of these complexes. Also, no spectral changes were observed in the visible region for both cases, even though large excess amounts of tert-butylammonium hydroxide (OH−), 4-phenylpyridine, or sodium phenolate were introduced. However, complexes 1 and 3 interact with CN− and tBuNC at ambient temperature. A quantitative treatment of the coordination behavior will be described below. Coordination Behavior of the tBuNC Molecule to 1, 2, and 3. It has recently been found that tert-butylisocyanide, which is a structural isomer of tert-butylnitrile, acts as a substrate for NHase.8 The coordination behavior of tBuNC was investigated for complexes, 1, 2, and 3, and the N2S2-type Co(III) complex [Co(L:N2S2)]− in various solvents.24

Figure 2. Electronic absorption spectra of 1 (a), 2 (b), and 3 (c) in MeOH. [complex] = 50 mmol.

complex 1 in acetone, CHCl3, and EtOH. This suggests that complex 1 is not coordinated by any of these solvent molecules. The 1H NMR spectrum of complex 1 has broadened and unidentified signals in the paramagnetic field range between −50 and 60 ppm in CDCl3 (Figure S1). This clearly suggests that the structure of Co(III) complex 1 is a trigonal-bipyramid with high spin state or a square-pyramid with an intermediate one.55 It is consistent with the crystal structure of 1 with trigonal-bipyramidal geometry as mentioned before. These findings suggest that complex 1 has a four-coordinate squareplanar,38,39 five-coordinate square-pyramidal, or five-coordinate trigonal-bipyramidal structure in solution.33,34,55,56 The previously reported Co(III) complex with an N3S2 donor set, [Co(III)S2Me2N3(Pr,Pr))](PF6),34 has a trigonal-bipyramidal structure with absorption maxima at 358, 445, and 525 nm in MeOH solution in the absorption spectrum. The spectral feature is very similar to that of 1, indicating that complex 1 has a trigonal-bipyramidal geometry similar to that of [Co(III)S2Me2N3(Pr,Pr)]](PF6).34 E

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index of its electrophilicity.41−43 A similar linear relationship of solvent acceptor number was observed in the previously described [CoIII(L:N2S2)] system.24 Plots of the log K values against AN also showed a linear relationship as shown in Figure 4. Likewise, equilibrium constants calculated for 2 and 3 are as

For complex 1 in MeOH, the two clear absorption maxima at 369 and 527 nm decrease with addition of tBuNC, and a new absorbance band appears at 317 nm with an isosbestic point at 347 nm. Complexes 2 and 3 in MeOH also exhibit absorption changes with addition of tBuNC. For complex 2, the absorption bands at 329 and 372 nm increase in intensity and shift to higher and lower energy regions, respectively, with isosbestic points at 295 and 556 nm. A new band appears at about 500 nm, and the band at 600 nm decreases in intensity. For complex 3, the band at 355 nm increases in intensity and undergoes a shift to 340 nm. The bands at 400 and 561 nm both decrease in intensity. The spectral change includes an isosbestic point at 372 nm. Figure 3 shows the representative

Figure 4. Plots of log K of 1 (▲), 2 (●), and 3 (■) vs acceptor numbers of solvents. (a) acetone; (b) DMF; (c) MeCN; (d) CHCl3; (e) EtOH; (f) MeOH; (g) MeOH: H2O = 9:1 (v/v); (h) H2O.

follows: for complex 2; 1.92 for EtOH (AN = 37.1), 2.03 for MeOH (AN = 41.3), 2.45 for MeOH/H2O (9:1 v/v) (AN = 45.2), 4.22 for H2O (AN = 54.8); and for complex 3; 1.04 for acetone (AN = 12.5), 2.04 for DMF (16.0), 2.43 for MeCN (18.9), 2.75 for CHCl3 (23.1), 4.57 for EtOH (37.1), and 5.26 for MeOH (41.3), and 5.76 for H2O (54.8). As in the case of the [CoIII(L:N2S2)] system,24 the equilibrium constants also exhibit a linear relationship with ANs of solvents as shown in Figure 4 for complexes 2 and 3, respectively. However, such linearity was not identified with respect to physiological parameters such as donor number and dielectric constant. Such solvent dependency for isocyanide coordination was also observed in the CO stretching vibration of the coordinated amidato ligand. Representative IR spectra of C O stretching region in selected solvents are shown in Figure S3. The stretching frequency corresponding to the CO bond appeared at around 1500−1600 cm−1 for complexes 1/2/3 as follows: 1567/1581/1590 cm−1 in acetone (AN = 12.5), 1565/ 1580/1587 cm−1 in DMF (AN = 16.0), 1562/1574/1586 cm−1 in MeCN (AN = 18.9), 1547/1564/1571 cm−1 in CHCl3 (AN = 23.1), 1541/1556/1564 cm−1 in EtOH (AN = 37.1), and 1540/1558/1562 cm−1 in MeOH (AN = 41.3). Interestingly, a linear relationship has been observed between the frequencies and ANs for all the Co(III) complexes, as shown in Figure 5. These linear relationships indicate that the coordination of the substrates to the vacant site is controlled through an electrostatic interaction between the carbonyl oxygens and the solvent molecules: electron density on the amidate nitrogen atom is reduced by the electrostatic interaction, which provides a higher Lewis acidity on the metal ion. Such solventdependent coordination behavior of the monodentate tBuNC ligand and the increase in the Lewis acidity by the oxidation of the coordinated sulfur atoms in N2S2-type Co(III) complexes have been evaluated as described previously.24,26 Here, the slopes of the linear relationships for log K vs AN and for the CO stretching frequency vs AN did not show any significant difference between 1 and 3. This indicates that the interaction

Figure 3. Electronic absorption spectral changes of 3 occurring with consecutive addition of tBuNC in MeOH (0 eq.: dashed line, 8 eq.: bold solid line). [complex] = 50 mM.

coordination behavior of tBuNC to 3. The final absorption spectrum of complex 3 completely resembles the absorption spectrum of PPh4[Co(L−O4)(tBuNC)] crystal (4) in water. The structure of 4 determined by an X-ray crystal structural analysis indicates that one tBuNC molecule is coordinated to 3. This finding was confirmed by elemental analysis. The absorption spectral changes of complexes 1 and 2 are shown in Figure S2. The coordination equilibrium for the reactions of 1, 2, and 3 with tBuNC is expressed as shown in eq 1. K

[Co(L−OX )]− + t BuNC ⇌ [Co(L−OX )(t BuNC)]− x = 0, 3, or 4

(1)

An equilibrium constant, K, can be evaluated in different solvents using the intensity changes according to eq 2.24 log{(A 0 − A)/(A max − A)} = log[C Bu − {(A 0 − A)/A max − A} × CCo(L−Ox)] + log K

(2)

Here, Amax = the completely coordinated tBuNC species; A0 = the uncoordinated species and A = a mixture of coordinated tBuNC species and uncoordinated species, each with respect to the absorption intensities at 350 nm. CBu = the concentration of tBuNC and CCo(L‑Ox) = the Co species. Interestingly, the equilibrium is solvent-dependent. To form an octahedral complex, significantly greater amounts of tBuNC were required in DMF than in MeOH. The log K values for complex 1 in different solvents are as follows: 0.84 for DMF (AN = 16.0), 1.71 for CHCl3 (AN = 23.1), 2.70 for EtOH (AN = 37.1), and 4.71 for MeOH (AN = 41.3), where the values in parentheses represent the solvent acceptor number (AN) which provides an F

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Addition of PPh4CN to a MeOH solution of 2 also induces absorption spectral changes similar to the spectral changes for complex 3. For complex 2, two intense bands at 322 and 384 nm and a broad band at 500 nm decrease in intensity, and a new intense absorption band at 331 nm with a shoulder band around 450 nm appears with isosbestic points at 291 and 381 nm. The coordination of cyanide anion to complex 2 was also identified from ESI-MS measurements. The ESI-MS spectrum provides an isotope feature assignable to [Co(L-O3)(CN)]2− at m/z 240.5, which is clearly identified in the isotopic simulation result. These results indicate that formation of [Co(LO3)(CN)]2− occurs by replacing the oxygen atom of the SO group in 2 with CN− ion, and the S coordination of the sulfenyl group is maintained without further oxidation. Previously, we proposed that the nucleophilicity of the sulfenyl oxygen may be a factor in NHase activity.26 The S−O s t r e tc h in g f r e q u e n c y of t h e s u lf e ny l g r o u p fo r [CoIII(LCO:N2(SO)2)(tBuNC)2]− is linearly dependent on the AN of the solvent used; the SO stretching frequency decreases when a solvent with a larger AN is used.26 In contrast, sulfinate in [Co{L:N2(SO2)2}(tBuNC)2]− did not show such a dependency on the AN of the solvent. Similar relationships were also observed for SO and SO2 stretching frequencies of [Co(L-O3)(CN)]2−. The plots of ANs of solvents are shown in Figure 6.

Figure 5. Plots of CO stretching vibration values of 1 (▲), 2 (●), and 3 (■) vs acceptor numbers of organic solvents. (a) THF; (b) acetone; (c) DMF; (d) MeCN; (e) EtOH; (f) MeOH.

of the solvent molecules with the carbonyl moiety has an equal influence on the coordination equilibrium for the two complexes. However, the intercepts of the relationship for the equilibria are significantly different. This difference may be caused not only by the structurally sufficient coordination space in 3 as compared with 1 but also by the difference in Lewis acidity (1 < 3), as estimated in our previous report.24 In the case of 2, the sulfenyl oxygen atom was not replaced by tBuNC in the solvents with low AN values, as judged from the lack of absorption spectral changes. In solvents with greater AN values, the sulfenyl oxygen atom was replaced by tBuNC. Coordination of the sulfenyl oxygen atom, which is favorable in entropy as a result of the chelation effect, is preferred over the interaction with the tBuNC molecule because the Lewis acidity of the metal center is low in solvents where the electron-withdrawing interaction with the amidate carbonyl is weak. Thus, both the oxygenation of sulfur atoms and the electrostatic interaction between the carbonyl oxygens and water molecules in the second coordination sphere may provide an advantage in the process of coordination of substrates at the vacant position of the NHase active site. Coordination of the CN− Ion to 2 and 3 and SolventDependence of the S−O Stretching Frequency. In addition to the interaction with tBuNC, complex 3 interacts with the CN− ion at the sixth site of the metal center to afford an octahedral compound. This octahedral compound was evaluated by monitoring the electronic absorption spectral change induced by addition of PPh4CN to complex 3 in MeOH. The spectral change includes decreases in intensity of the intense band at 355 nm, the shoulder band around 400 nm, and the broad band at about 561 nm of complex 3. These changes are accompanied by the appearance of a new absorption band at 328 nm with an isosbestic point at 358 nm. These spectral changes are quite similar to the absorption spectral changes which occur when tBuNC is added to complex 3. The presence of the isosbestic point indicates a transition from a first species to a second species in a one-step reaction. Support for this interpretation is provided by the crystal structure of (PPh4)2[Co(L-O4)(CN)] (5) obtained from a mixed solution of acetonitrile and diethyl ether, in which complex 3 is coordinated by a cyanide anion at the apical position (Figure S4).

Figure 6. Plots of SOsulfinyl (■) and SOsulfenyl (○) stretching vibration values for [Co(L−O3)(CN)]2− (6) on acceptor numbers of organic solvents. (a) acetone; (b) DMF; (c) MeCN; (d) CHCl3; (e) EtOH; (f) MeOH.

Crystal Structures of PPh4[Co(L−O4)(tBuNC)]·7H2O (4· 7H2O) and (PPh4)2[Co(L−O4)(CN)]·3H2O (5·3H2O). Addition of tBuNC or PPh4CN to an acetone or acetonitrile solution of 3 and successive slow diffusion by diethyl ether in both cases afforded red crystals of PPh4[Co(L-O4)(tBuNC)]· 7H2O (4·7H2O) or (PPh4)2[Co(L-O4)(CN)]·3H2O (5· 3H2O), respectively. Unfortunately, we failed to obtain good crystal structure analysis of complex 5·3H2O although that of 4· 7H2O was obtained, because the former was not a fine crystal; so the description of crystal structure of 5·3H2O has been given in the Supporting Information. The crystal data of 4·7H2O is listed in Table S2. ORTEP views of the anion moieties of 4 and 5 are shown in Figure 7 and Figure S4, respectively, and selected bond lengths and angles for 4 are listed in Table 2. The Co(III) ions of 4 and 5 both have octahedral geometry, and the G

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For complex 4, Co−SSO2 (Co(1)−S(2) 2.1926(7) and Co(1)−S(3) 2.1805(7) Å) and Co−Namide bond lengths (Co(1)−N(1) 1.931(2) and Co(1)−N(2) 1.939(2) Å) are within the range of those in octahedral Co(III) complexes with sulfinyl groups (Co−S 2.16−2.23 Å)18,19,22,24,28,35 and/or amide groups (Co−N 1.90−2.00 Å).18−22,24,26,28,35 These bond lengths are longer than those of 3 (cf. Table 1), which may be due to the increased coordination number from five (3) to six (4). The Co(1)−C(15) and N(3)−C(15) bond lengths of the coordinated tBuNC ligand are 1.920(3) Å and 1.151(3) Å. The N(3)−C(15) is within the range of NC bond lengths for octahedral Co(III) complexes reported previously (1.14− 1.16 Å).22,24,26,28 The Co−C(tBuNC) bond is slightly longer than bond lengths for octahedral Co(III) complexes reported previously (1.84−1.89 Å).22,24,26,28 This difference may be caused by the trans influence of the sulfinyl sulfur atom.18 Interestingly, the amidate carbonyl oxygens in the ligand L−O4 are significantly linked to a water molecule cluster through a hydrogen bond (O(carboxyl) ··· O(water) = 2.81−2.88 Å). Coordination Behavior of a Water Molecule to 1, 2, and 3. The unique active site structure of the NHase has hindered the determination of its reaction mechanism. Two types of active intermediate species have been proposed as being included in the mechanism: One proposed species has a hydroxide ion coordinated at the vacant site, and the other has a coordinated substrate molecule (Scheme 1).14 Focusing on coordination and activation of a water molecule, we describe the coordination behavior of a water molecule to the complexes 1, 2, and 3 in this section. Complex 3 has an absorption spectrum with peak maxima at approximately 456 nm (ε = 940 M−1·cm−1) and 360 nm (ε = 10200 M−1·cm−1) in aqueous solution. This spectrum is quite different from the spectrum of complex 3 measured in CHCl3 solution, which has maxima at 590 nm (ε 700 M−1 cm−1) and 355 nm (ε 8000 M−1 cm−1).27a The different spectral features indicate that 3 captures a water molecule at the sixth vacant site to form an octahedral complex only in an aqueous solution. The corresponding parent species was also detected in aqueous solution at 35 °C from an ESI-MS spectral measurement.27a The coordination of water molecules has also been reported in other NHase model complexes by Mascharak et al.18 The protonation/deprotonation behavior

Figure 7. ORTEP view of the [Co(L−O4)(tBuNC)]− anion in 4, showing 50% probability ellipsoids.

respective isocyanide molecule and cyanide ion occupy a larger vacant site of 3. Table 2. Selected Bond Lengths [Å] and Angles [deg] for PPh4[Co(L−O4)(tBuNC)]·7H2O (4·7H2O) 4·7H2O Co1−N1 Co1−N2 Co1−S1 Co1−S2 Co1−S3 N1−Co1−N2 S1−Co1−S2 S1−Co1−N1 S1−Co1−N2 S2−Co1−N1 S2−Co1−N2

bond lengths [Å] 1.931(2) Co1−C15 1.939(2) S2−O1 2.3173(7) S2−O2 2.1926(7) S3−O3 2.1805(7) S3−O4 bond angles [deg] 174.68(8) S3−Co1−N1 88.82(3) S3−Co1−N2 81.30(6) S1−Co1−S3 99.97(6) S2−Co1−S3 89.03(7) Co1−C15−N3 93.3(1)

1.920(3) 1.469(2) 1.467(2) 1.470(2) 1.462(2) 91.69(6) 87.53(6) 170.91(3) 96.48(3) 173.8(2)

Scheme 1. Previously Proposed Mechanisms of Nitrile Hydration by NHase

H

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tBuNH2. Similar reaction behavior was also identified for natural Fe-type NHase.8 We now propose a reaction scheme for catalysis of isocyanide hydrolysis by our model cobalt complexes. As described above, the hydrolysis reactions are promoted by complexes 2 and 3, although the rates are slow as for NHase itself.8 Complex 1 does not catalyze isocyanide hydrolysis. The hydrolysis reaction promoted by complexes 2 and 3 is the first example of the reaction being catalyzed by a model complex, to the best of our knowledge. Interestingly, as indicated above, the water molecule at the sixth site of complex 3 can be replaced by a tBuNC molecule, although a Co(III) complex, in general, is substitutionally inert. Previously, Grapperhaus et al. have proposed that the oxidation of S is closely related to the activation of ligand exchange at its trans position, using the Ru(III) complex with N2S3-type supporting ligand that both the thiolate S atoms were oxidized to sulfinate.58 Such a replacement acceleration at the trans position of the oxygenated S atom has been reported for Co(III) complexes.51 Actually, the NHase model Co(III) complex with a sulfinate S coordinate, which was previously reported by Mascharak and co-workers, showed an easy replacement of the CN− ligand to the water molecule under aqueous conditions in spite of the octahedral structure.18 Therefore, replacement of the water molecule to tBuNC in complex 4 may be explained as follows: the sulfinyl S atom at the trans position of the water molecule at the sixth site promotes the replacement to tBuNC even at room temperature. Under these reaction conditions, complexes 1, 2, and 3 are in the Co(III) state with a bound tBuNC molecule, because the reaction is carried out in water solvent in the presence of a large excess amount of tBuNC. The oxygenation of sulfur atoms raises the Lewis acidity of the metal ion to induce strong binding and activation of the tBuNC molecule. The isocyanide molecule is hydrolyzed under basic conditions. This is quite different from the observations of Chottard et al.,22 although their hydration reaction used MeCN as a substrate instead of isocyanide. The hydration reaction of solvent MeCN was carried out under acidic conditions, which promotes a nucleophilic attack on the MeCN molecule by the sulfenyl group.22 On the other hand, in our case, it appears that the OH− group attacks the isocyanide substrate instead of the sulfenyl group, because the reaction is carried out under basic conditions. When we compare the reactivity of complexes 2 and 3, complex 2 is slightly active under basic conditions. This means that the reactivity is attributed not only to the higher Lewis acidity of the metal ion induced by oxygenation of sulfur atoms but also to the nucleophilicity of the sulfenyl group. Previously, Grapperhaus et al. have proposed in relation to this as follows, by using a Ru(III) complex with an N2S3-type supporting ligand that both the thiolate S atoms were oxidized to sulfinate: the oxidation of S is closely concerned with the activation of a water molecule through the formation of a hydrogen bonding.59 In our complex 2, however, it has been demonstrated that the sulfenate oxygen may activate the water molecule more effectively than the sulfinate one because of its stronger basicity (vide supra). Energy Full Optimization of the Reaction of Complex 4 with OH− Put near the Complex. In order to understand the reaction mechanism of the hydrolysis reaction of tBuNC as achieved with complexes 2 and 3 under basic conditions, we followed up the reaction pathway by using DFT calculations. We focused on complex 4 directly attacked by OH− and H2O,

has been identified in model complexes and found to depend on the pH of the solution. The electronic absorption spectral changes occur with an isosbestic point. For example, in [Co(PyPS)(H2O)]−, which has two amidate nitrogen atoms, one pyridyl nitrogen atom and two thiolate sulfur atoms (N3S2) as donor atoms, the water molecule is deprotonated to form the hydroxide species with a pKa value of 8.3.18 Therefore, we also investigated the pH dependence of the electronic absorption spectrum of an aqueous solution of complex 3. However, no spectral changes were observed in the pH range of 5.5−10.5 as shown in Figure S5, indicating that a hydroxide species does not form. This finding suggests that the coordinated water molecule is not activated by a Co(III) complex with an N2S3 coordination environment and may suggest that a hydroxidecoordinated species, as shown in mechanism (i) of Scheme 1, is unlikely included in the hydration mechanism. On the other hand, complex 1 does not interact with water molecules. The Co(III) complex with thiolate sulfur atoms (S−) does not capture a water molecule at the sixth site. This is because the Lewis acidity of the Co(III) ion decreases relative to that of complex 3 as a result of the strong electron-donating character of the sulfur atom without an electron-withdrawing oxygen atom. 18,26 In addition, complex 1 is expected to be accompanied by a larger conformational change than that of complex 3 to form an octahedral complex. For complex 2, the coordination of water molecules was also not identified in aqueous solution. This suggests that the sulfenyl oxygen is strongly coordinated, indicating that the oxygen atom can interact with a nucleophile if available. Thus, oxidation of sulfur is important for coordination of a small molecule at the vacant site, but the coordinated water molecule in complex 3 cannot be activated even though it has two sulfinates which provide the most effective coordination group and the highest Lewis acidity among the three oxidation states of S, SO, and SO2.26 Hydrolysis of tBuNC Using 1, 2, and 3. tBuNC has been used by Odaka and co-workers as a surrogate for a substrate nitrile to understand the reaction mechanism of the Fe-type NHase, because its rate of hydrolysis is relatively slow, making it useful for time-resolved X-ray structural analysis.8 NHase hydrolyzes tBuNC to tBuNH2 and carbon monoxide (CO). In order to investigate the reaction mechanism for NHase, we performed hydrolysis of tBuNC using complexes 1, 2, and 3 at pH 4.7, 7.5, and 10.2. In the reaction system, tBuNH2 was detected by GC for complexes 2 and 3 only at pH 10.2 but not for complex 1. With the conditions of the ratio of complex: tBuNC:H2O = 2.0 μmol (2: 1.63 and 3: 1.62 mg, respectively): 880 μmol (0.1 mL): 0.106 mol (1.9 mL) at pH 10.2, the catalytic reaction was effectively promoted. At 20 °C, complexes 2 and 3 provided 7.2 and 2.4 μmol of tBuNH2, respectively, with TONs estimated to be 3.6 and 1.2, respectively, after 24 h. The TONs increased to 10.6 and 9.7, for complexes 2 and 3, respectively, by increasing the reaction temperature to 40 °C, and a small amount of N-tertbutylformamide (tBuNHCHO) was also detected (TON for 1, 2, and 3: 0.2, 0.4, and 0.3, respectively) at the retention time of 14.9 min by GC−MS. The tBuNHCHO obtained here does not appear to be an intermediate in the hydration process because, as was judged from the lack of an absorption spectral change, it is believed that tBuNHCHO does not interact with the Co(III) center in the reaction solutions. In addition, the reactions of tBuNHCHO with the cobalt complexes do not produce I

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Figure 8. Fully optimized structures of complex 4 with OH− anion in the vicinity of the coordinated isocyanide according to DFT calculations on the basic hydrolysis reaction pathway. The initial OH− adduct (left), the transition state (middle), and the iminol intermediate (right).

accompanied by the hydrogen bond of the hydroxide H atom with an oxygen atom of the cis SO2 group (Figure 8). In the transition state, the estimated energy barrier was higher by 27.1 kcal/mol as compared with the total energy in the complete dissociation state. At the stage, the O atom of OH− was apart from the C atom of tBuNC by 2.329 Å. Through this barrier, the reaction proceeded to generation of an iminol intermediate to form a cyclic intermediate, which is lower in energy by 3.8 kcal/mol than the complete dissociation state as follows. Such a formation of the cyclic intermediate has also been described in the hydration of nitrile compounds by Kovacs et al. previously.17 The calculated energy barrier of the OH− attack, as described above, is too high (27.1 kcal/mol) for the reaction to occur at room temperature. Previous DFT works suggested that isonitrile hydrolysis occurring in mimic complexes of nitrile hydratase is promoted by hydrogen bonding of protic solvents to the complex.26 To investigate hydrogen bonds to O atoms on the ligands in hydration, we considered a water molecule bound to the O atom of the equatorial amido group where a molecule is easily accessible. The hydrogen bonding reduces the barrier to 26.8 kcal/mol due to lowering the π* orbitals of the isocyanide group which is an acceptor of a lone pair of the nucleophile. The hydrogen bond to the amide O atom withdraws electron density and decreases negative charge on the amido N atom from −0.56 to −0.55 at the reactant complex. This decrease in electron density lowers the energies of the two dπ orbitals, dxz and dyz orbitals, on the Co center by 0.08 and 0.16 eV and leads to reduction of π-back bonding to the π* orbitals on the isocyanide ligand. This accompanies reducing the corresponding antibonding orbital energy level and lowers the π* orbitals on the isocyanide ligand by 0.03 and 0.04 eV, respectively. Hydration to plural O atoms of the ligands seems to be one of the reasons to reduce the barrier and to facilitate the OH− attack.

in which the structure of complex 4 has been the same as the structure that the sixth site of complex 3 has been occupied by tBuNC. The energy barrier of the H2O attack to the anionic complex is 35.6 kcal/mol versus the completely dissociated reactants and is higher than the OH− attack due to lower nucleophilicity of H2O (Figure S6) as mentioned below. Then, we consider the OH− attack pathway only. Figure S7 shows the fully optimized geometry of complex 4, and Figure 8 exhibits those of the initial OH− adduct (left), the transition state (middle), and the iminol intermediate (right) on the basic hydrolysis reaction pathway. Unfortunately, the calculation, however, failed to model the subsequent pathway of tautomerization to amido under the conditions. The optimized structure of complex 4 is in good agreement with the crystallographic structure; e.g. the lengths of coordination bonds in the optimized structure and the crystal structure of 4 agree within 0.05 Å (Table S3). In the initial adduct, the OH− ion was put at the C···(HO) distance of 6.823 Å remote from the carbon atom of tBuNC turning the H atom to the carbon (Figure 8). The energy of the initial adduct is almost equal to that which they have completely dissociated, because they are unstable due to the electrostatic repulsion between negative charges on the OH− ion and complex 4. The interaction between these ions is so weak that the initial adduct calculated has kept almost the same structure as complex 4. The tBuNC molecule bound to Co(III) ion is almost linear; ∠Co−C−N is 174.7°. Interestingly, the LUMO+2 and LUMO+3 in the initial adduct (Figure S8) spread over the π* orbitals of the coordinated isocyanide carbon. It suggests that the lone pair orbitals of the OH− ion are accessible to the large orbital on the carbon atom. Next, the transition state of the reaction was found when the OH− approached the isocyanide carbon. The coordinated tBuNC molecule was bent with the ∠Co−C−N angle of 142.5° and the ∠C−N−C(tBu) angle of 152.5°, which was J

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complex 4. At the first stage, the coordinated tBuNC molecule was bent when the OH− approached the isocyanide carbon, and the reaction gave the iminol intermediate through the C··· O(H) bonding interaction as the transition state under the basic hydrolysis conditions, which was accompanied by the hydrogen bond of the hydroxide H atom with an oxygen atom of the cis SO2 group. We therefore propose the following mechanism for NHase: the hydrolysis of tBuNC proceeds not by coordination of a water molecule but by nucleophilic attack of the water molecule activated through an interaction of the sulfenyl/sulfinyl oxygen with the coordinated substrate (Scheme 2).

In the formation of the iminol intermediate, the CN bond of the isocyanide molecule was reduced to a double bond character, accompanied by bending at the C and N atoms with ∠Co−C−N and ∠C−N−C(tBu) angles of 118.4° and 121.7°, respectively. The lone pairs on the N and C atoms having an sp2 character were found on HOMO-4 and HOMO-2 (Figure S9). The natural atomic charges and overlap-weighted NAO bond orders at the stationary points along the reaction pathway are listed in Table 3. The negative charge localized on the Table 3. Atomic Charge and Bond Order of the Coordinated tert-Butylisocyanide of the Stationary Points along the Basic Hydrolysis Reaction Pathway initial adduct

transition state

natural atomic charge Co −0.30 −0.20 N (isocyanide) −0.39 −0.45 C (isocyanide) +0.38 +0.36 O (OH−) −1.43 −1.15 atom−atom overlap-weighted NAO bond order Co−C 0.77 0.71 N−C 1.62 1.59 C−O 0.00 0.17

Scheme 2. Proposed Mechanism of Nitrile Hydration by NHase As Estimated on the Basis of Results in This Study

iminol intermediate −0.13 −0.63 +0.41 −0.76 0.60 1.36 0.87

attacking OH− moves onto the N atom of the tBuNC through the π* orbital (LUMO+3) of the initial adduct when the reaction proceeds. The electron donation accompanied by the C−O bond formation and polarization of the CN bond lead to a large increase in the negative atomic charge on the N atom of tBuNC from −0.39 to −0.63 and to a decrease in the C−N bond order of the isocyanide from 1.62 to 1.36. On the other hand, the bond order of the newly formed C−O bond is 0.87, indicating that the isocyanide C and hydroxide O atoms formed a single bond. The localization of the negative charge on the N atom of the iminol intermediate suggests that the imine is a good proton acceptor from water, although the proton transfer from water to the imine nitrogen has not been estimated from the DFT calculations.

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Thus, in this study, it has been suggested that a coordinating tBuNC molecule has been hydrolyzed via OH− attacking. Furthermore, complex 2 with a sulfenate group showed slightly higher activity for the hydrolysis of the coordinating tBuCN molecule than complex 3 without sulfenates. This finding suggests that the sulfenate group may further induce the formation of OH− by interacting with the water molecule even though the reaction was performed under alkali conditions, because sulfenate oxygen in complex 2 may further activate the water molecule substantially to increase the concentration of the nucleophile through a hydrogen bonding interaction. In addition, the coordination of substrate is also a key factor to promote the reaction, so we speculate that a nitrile molecule coordinates to the metal center by replacing the water molecule in Co-type NHase and is attacked by a water molecule largely polarized by interacting with the sulfate group in NHase.

SUMMARY In order to understand the reaction mechanism of the isocyanide hydrolysis function in NHase discovered by Odaka et al., three Co(III) complexes 1, 2, and 3 with different N2S3 donor sets composed of two deprotonated amide nitrogens and thiolate, sulfenate, sulfinate, and/or a thioether were prepared. We examined the coordination behavior of H2O and tBuNC molecules to complexes 1, 2, and 3. The oxygenation of sulfur atoms was found to promote the coordination of the substrate ligands, as a result of an increase in Lewis acidity on the metal center. However, the water molecule coordinated to complex 3 does not undergo protonation/deprotonation. This indicates that complex 3 cannot activate the coordinated water molecule, although the donor set (two amidato nitrogens, two sulfinates, and a thioether) is expected to provide a weaker ligand field than the native Co-type NHase (two amidato nitrogens, one sulfinate, one sulfenate, and one thiolate). On the other hand, the coordinated tBuNC molecule is hydrolyzed at pH 10.2 in aqueous solution when catalysts 2 and 3 are used. These findings suggest that the oxygenation of the sulfur atom from S to SO and to SO2 promotes the coordination and activation of the isocyanide substrate molecule. The DFT calculation of the hydrolysis reaction of the tBuNC molecule was studied using

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.6b02324. 1 H NMR spectrum of complex 1 in CDCl3 (Figure S1), electronic absorption spectral changes of 1 and 2 by K

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Odaka, M. Time-Resolved Crystallography of the Reaction Intermediate of Nitrile Hydratase: Revealing a Role for the Cysteinesulfenic Acid Ligand as a Catalytic Nucleophile. Angew. Chem., Int. Ed. 2015, 54, 10763−10767. (b) Light, K. M.; Yamanaka, Y.; Odaka, M. Spectroscopic and computational studies of nitrile hydratase: insights into geometric and electronic structure and the mechanism of amide synthesis. Solomon, E. I. Chem. Sci. 2015, 6, 6280−6294. (10) (a) Gumataotao, N.; Kuhn, M. L.; Hajnas, N.; Holz, R. C. Identification of an active site-bound nitrile hydratase intermediate through single turnover stopped-flow spectroscopy. J. Biol. Chem. 2013, 288, 15532−15536. (b) Stein, N.; Gumataotao, N.; Hajnas, N.; Wu, R.; Lankathilaka, K. P. W.; Bornscheuer, U. T.; Liu, D.; Fiedler, A. T.; Holz, R. C.; Bennett, B. Multiple States of Nitrile Hydratase from Rhodococcus equi TG328−2: Structural and Mechanistic Insights from Electron Paramagnetic Resonance and Density Functional Theory Studies. Biochemistry 2017, 56, 3068−3077. (11) König, G. M.; Wright, A. D.; Angerhofer, C. K. Novel Potent Antimalarial Diterpene Isocyanates, Isothiocyanates, and Isonitriles from the Tropical Marine Sponge Cymbastela Hooperi. J. Org. Chem. 1996, 61, 3259−3267. (12) Goda, M.; Hashimoto, Y.; Takase, M.; Herai, S.; Iwahara, Y.; Higashihara, H.; Kobayashi, M. Isonitrile hydratase from Pseudomonas putida N19−2. Cloning, sequencing, gene expression, and identification of its active amino acid residue. J. Biol. Chem. 2002, 277, 45860−45865. (13) Goda, M.; Hashimoto, Y.; Shimizu, S.; Kobayashi, M. Discovery of a novel enzyme, isonitrile hydratase, involved in nitrogen-carbon triple bond cleavage. J. Biol. Chem. 2001, 276, 23480−23485. (14) Kovacs, J. A. Synthetic Analogues of Cysteinate-Ligated NonHeme Iron and Non-Corrinoid Cobalt Enzymes. Chem. Rev. 2004, 104, 825−848. (15) (a) Ellison, J. J.; Neinstedt, A.; Shoner, S. C.; Barnhart, D.; Cowen, J. A.; Kovacs, J. A. Reactivity of Five-Coordinate Models for the Thiolate-Ligated Fe Site of Nitrile Hydratase. J. Am. Chem. Soc. 1998, 120, 5691. (b) Schweitzer, D.; Ellison, J. J.; Shoner, S. C.; Barnhart, D.; Cowen, J. A.; Kovacs, J. A. A Synthetic Model for the NO-Inactivated Form of Nitrile Hydratase. J. Am. Chem. Soc. 1998, 120, 10996−10997. (16) Shearer, J.; Jackson, H. L.; Schweitzer, D.; Rittenberg, D. K.; Leavy, T. M.; Kaminsky, W.; Scarrow, R. C.; Kovacs, J. A. The First Example of a Nitrile Hydratase Model Complex That Reversibly Binds Nitriles. J. Am. Chem. Soc. 2002, 124, 11417−11428. (17) Swartz, R. D.; Coggins, M. K.; Kaminsky, W.; Kovacs, J. A. Nitrile hydration by thiolate- and alkoxide-ligated Co-NHase analogues. Isolation of Co(III)-amidate and Co(III)-iminol Intermediates. J. Am. Chem. Soc. 2011, 133, 3954−3963. (18) Tyler, L. A.; Noveron, J. C.; Olmstead, M. M.; Mascharak, P. K. Modulation of the pKa of Metal-Bound Water via Oxidation of Thiolato Sulfur in Model Complexes of Co(III) Containing Nitrile Hydratase: Insight into Possible Effect of Cysteine Oxidation in CoNitrile Hydratase. Inorg. Chem. 2003, 42, 5751−5761. (19) Tyler, L. A.; Olmstead, M. M.; Mascharak, P. K. Conversion of Azomethine Moiety to Carboxamido Group at Cobalt(III) Center in Model Complexes of Co-Containing Nitrile Hydratase. Inorg. Chem. 2001, 40, 5408−5414. (20) Noveron, J. C.; Olmstead, M. M.; Mascharak, P. K. Co(III) Complexes with Carboxamido N and Thiolato S Donor Centers: Models for the Active Site of Co-Containing Nitrile Hydratases. J. Am. Chem. Soc. 1999, 121, 3553−3554. (21) Rat, M.; de Sousa, R. A.; Tomas, A.; Frapart, Y.; Tuchagues, J.P.; Artaud, I. Synthesis, X-ray structure and properties of a trinuclear mixed-valence CoIII-CoII-CoIII complex with carboxamido N and sulfinato S donors. Eur. J. Inorg. Chem. 2003, 2003, 759−765. (22) (a) Heinrich, L.; Mary-Verla, A.; Li, Y.; Vaissermann, J.; Chottard, J.-C. Cobalt(III) complexes with carboxamido-N and sulfenato-S or sulfinato-S ligands suggest that a coordinated sulfenate-S is essential for the catalytic activity of nitrile hydratases. Eur. J. Inorg. Chem. 2001, 2001, 2203−2206. (b) Heinrich, L.; Li, Y.; Vaissermann, J.; Chottard, J.-C. A bis(carboxamido-N)diisocyanidobis-

addition of tBuNC (Figure S2), IR spectra of CO stretching region in selected solvents (Figure S3), ORTEP view of the anion moiety of 5 (Figure S4), pH dependence of electronic absorption spectrum of 3 (Figure S5), X-ray crystallographic data of 1, 2 and 3 and 4 (Tables S1 and S2, respectively), DFT calculation results (Figures S6−S9) (PDF) Accession Codes

CCDC 1588609−1588613 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*Phone: +81-52-735-5228. Fax: +81-52-735-5209. E-mail: [email protected]. ORCID

Yuji Kajita: 0000-0002-5066-4038 Hideki Masuda: 0000-0002-1235-1129 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge support for this work by the Japan Society for the Promotion of Science (JSPS) for a Grant-in-Aid for Scientific Research (B)(C) (No. 16H04117, 15K05606) and by the Japan Society for the Promotion of Science “Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation”.

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DOI: 10.1021/acs.inorgchem.6b02324 Inorg. Chem. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.inorgchem.6b02324 Inorg. Chem. XXXX, XXX, XXX−XXX