Hydroamination of alkynes catalyzed by NHC-Gold(I) complexes: the non-monotonic effect of substituted arylamines on the catalyst activity

Imines are valuable key compounds for synthesizing several nitrogen-containing molecules used in biological and industrial fields. They have been obtained, as highly regioselective Markovnikov products, by reacting several alkynes with arylamines in the presence of three new N-Heterocyclic carbene gold(I) complexes (3b, 4b, and 6b) together with the known 1-2b and 7b gold complexes as well as silver complexes 1-2a. Gold(I) complexes were investigated by means of NMR, mass spectroscopy, elemental analysis, and X-ray crystallographic studies. Accurate screening of co-catalysts and solvents led to identifying the best reaction conditions and the most active catalyst (2b) in the model hydroamination of phenylacetylene with aniline. Complex 2b was then tested in the hydroamination of alkynes with a wide variety of arylamines yielding a lower percentage of product when arylamines with both electron-withdrawing and electron-donating substituents were involved. Computational studies on the rate-determining step of hydroamination were conducted to shed light on the significantly different yields observed when reacting arylamines with different substituents.


Introduction
Nowadays, considerable chemical research is aimed at developing greener strategies for synthesizing value-added compounds from low-cost reagents and using environmentally sustainable processes.The hydroamination reaction is an excellent example of this focus (Müller et al., 2008).This reaction, able to build C-N bonds by adding amines to multiple carbon bonds, can be eulogized as a model of a modern sustainable catalytically promoted chemical process with a 100% atom economy.The production of N-containing compounds (amines, imines, enamines, etc.) represents an important branch of the pharmaceutical and chemical industries, due to the importance of these molecules as scaffolds in the synthesis of biologically active compounds, drugs, N-heterocycles, polymers, bulk, and fine chemicals (Pohlki and Doye, 2003;Severin and Doye, 2007;Hartwig, 2008;Müller et al., 2008;Huang et al., 2015;Patel et al., 2017;Huo et al., 2019).
The amine addition to double and triple carbon bonds requires very high activation barriers for the repulsion between electron-rich species (Müller et al., 2008).Nevertheless, metal complexes can decrease these barriers by coordinating one or more nucleophilic species (Scheme 1).
The metal plays the important role of activating the double (or triple) C-C bond or the amine.As for alkaline and alkaline-earth metals, rare earth metals, and early transition metals, activation of the amine has been hypothesized.The catalytic cycle would involve the insertion of multiple C-C bonds into an M-N bond followed by fast protonolysis by other amino substrates (Michael et al., 2003;Reznichenko et al., 2010b;2010a;Wixey and Ward, 2011).
On the other hand, two possible mechanisms have been proposed in the presence of late transition metals (E.Müller et al., 1999;Shanbhag and Halligudi, 2004;Katari et al., 2012): 1) the activation of the olefin (alkene or alkyne) would occur through its coordination to the metal, followed by the nucleophilic attack by the amine (Zhang et al., 2006); and 2) activation of the amine through oxidative addition to the metal center would be followed by the insertion of an unsaturated C-C bond into the M-N bond, where reductive elimination of the obtained intermediate would generate the hydroamination product and restore the catalyst (Zhao et al., 2005;Tsipis and Kefalidis, 2006).
In the last 30 years, since the first isolation of free carbene by Arduengo (Arduengo et al., 1991), N-heterocyclic carbenes (NHCs) have frequently replaced phosphines for their ability to coordinate and stabilize transition metals as strong σ and π-donors and πacceptors and their easily tunable electronic and steric properties (Jacobsen et al., 2009;Hopkinson et al., 2014;Nolan, 2014).NHC gold complexes have been extensively used to promote the hydroamination of alkynes (Mariconda et al., 2022).Recently, Bertrand et al. compared gold complexes bearing a variety of phosphine and carbene ligands, highlighting the superior performances of the latter (Yazdani et al., 2020).Herein we report a comparison among the activities of complexes 1a-b, 2ab, and 3-8b (Figure 1) with the addition of aniline to alkynes.Complexes 3b, 4b, and 6b are described here for the first time, while all other complexes have already been reported in the literature (Napoli et al., 2013;Saturnino et al., 2016;Mariconda et al., 2020;Sirignano et al., 2021).Complexes 1, 2, 3b, and 4b differ in the substituents on the backbone of the NHC, while for complexes 5b-6b and 7b-8b, the authors have decided to study two effects: substituents on the backbone and modification of a substituent on a nitrogen atom.The choice of different substituents influences the electronic properties of the NHC, as reflected in the catalytic activity.In addition, the presence of the pendant hydroxyl group could be used as an advantageous linker functionality for immobilizing catalysts onto solid supports.Complex 2b, which was found to be the best performing, was tested in the hydroamination of phenylacetylene, diphenylacetylene, and 4-octyne with a large variety of arylamines.Density Functional Theory (DFT) studies were conducted to understand the dramatical yield differences observed when reacting variously substituted arylamines.

Synthesis and characterizations
The synthesis of NHC metal complexes were conducted following the procedure reported in the literature: 1a (Napoli et al., 2013), 1b and 5b (Saturnino et al., 2016), 2a and 2b (Mariconda et al., 2020), and 7b and 8b (Sirignano et al., 2021).The synthetic routes used for the preparation of imidazolium salts and their relative silver(I) and gold(I) complexes are illustrated in Scheme 2. The NHC proligands were obtained following the procedure reported by Tacke (Patil et al., 2010) and modified for our purposes (Napoli et al., 2013;Saturnino et al., 2016;Mariconda et al., 2020;Sirignano et al., 2021).The sp 3 hybridized nitrogen atom of imidazole-derivative was deprotonated by potassium carbonate to produce the nucleophilic species.Next, it was reacted with styrene oxide or cyclohexene oxide to give the monoalkylated product, to which an excess of iodomethane was added, to lead to the alkylation of the sp 2 -hybridized nitrogen atom and the formation of imidazolium salts .
All the new-synthesized proligands and their relative silver(I) and gold(I) complexes were characterized by nuclear magnetic resonance ( 1 H-and 13 C-NMR), mass spectrometry (ESI or MALDI), and elemental analysis (see Materials and Methods).Moreover, crystals of 4b suitable for X-ray diffractometry were also grown.In 1 H-NMR spectra, the acid protons of imidazolium salts PL-3, PL-4, and PL-6 show signals at 9.50, 9.77, and 9.72 ppm,
respectively, while in 13 C-NMR spectra, signals at 138.88, 144.00,  and 135.67 ppm are due to the carbocationic carbons (NCHN).The attribution of signals in the 13 C-NMR spectra was supported by DEPT 135 experiments (see Supplementary Material).
MALDI-MS analyses present the signal attributable to the cationic portion of imidazolium salts.
The NHC silver(I) complexes were obtained by reacting the corresponding proligand with silver nitrate, in the presence of K 2 CO 3 , following the procedure published by Nolan and Gimeno (Collado et al., 2013;Visbal et al., 2013).The absence of the singlet signal of the acid proton in 1 H-NMR spectra demonstrates the deprotonation and the consequent formation of carbene species, while the formation of the silver complexes is confirmed by 13 C-NMR spectroscopy.In fact, the signals at 181.3 8 , 190.9 1 , and 182.9 0 ppm of carbene carbons of 3a, 4a, and 6a, respectively, were observed.MS analyses of three silver complexes indicate several signals of a bis-carbene structure [Ag(NHC) 2 ] + .The presence of double signals for 3a and 4a is due to the silver isotopes 107 Ag and 109 Ag, almost equally abundant.Due to isotopes of chlorine ( 35Cl 75%, 37 Cl 25%), the spectrum of 6a is more intricate.
The presence bis-carbenic structures of Ag-complexes is well established in the literature, as also observed by solid state analysis (Mariconda et al., 2014).On the other hand, it is also well accepted that bis-carbenic species are in fast equilibrium with NHC-Ag(I)X complexes (Scheme 3).
This equilibrium is mainly influenced by the nature of the counterion (Lin and Vasam, 2007;Hintermair et al., 2011) as well as by the steric and donating properties of the N-heterocyclic carbene (Garrison and Youngs, 2005).
NHC-Au(I) complexes were synthesized by reaction among NHC-Ag(I) (3a, 4a, and 6a) complexes and chloro-gold(I) dimethyl-sulfide [Au(SMe 2 )Cl].The gold complexes were obtained as yellow powder in good yield: 70% for 3b, 75% for 4b, and 78% for 6b, respectively. 1H-NMR spectra of gold(I) complexes exhibited all the expected signals, corresponding to NHC-silver complexes.However, some differences were observed in the 13 C-NMR spectra (see Supporting Information).As for 13 C-NMR, carbene carbons of 3b, 4b, and 6b were related to signals at 169.4 6 , 177.4 1 , and 171.2 0 ppm, respectively.The upfield shift of the carbene carbon signals is due to the different nature of the metal center as well as the different electronic properties of counterion bound to the metal center (iodide for silver vs. chloride for gold) (Frenking et al., 1997;2005;Baker et al., 2006).The mass spectra of gold complexes show peaks at 905.31858 for 3b, 701.22194 for 4b, and 693.06319 for 6b m/z, confirming the presence of bis-carbene structures.All the complexes are stable in moisture and light.In fact, the spectra of all complexes in DMSO/D 2 O (90/10) stay unchanged after 24 h also when exposed to light.

X-ray crystallography
The X-ray single crystal molecular structure of complex 4b, with the atomic numbering scheme, is shown in Figure 2. Selected bond distances and angles are shown in Table 1.
The 3D packing of 4b is characterized by the presence of dimers of discrete molecules, built up by aurophilic interactions with Au . . .Au contacts of 3.449 ( 5) Å (Figure 3).
Intermolecular hydrogen bonds between the-OH group and the chlorine atom of each molecule cooperate with the aurophilic interaction to the assembling of monomers (O . . .Cl (1) i distance of 3.276 (1) Å and O-H . . .Cl (1) angle of 166.33 °, i = -x+1, -y+1, -z).Each dimer is connected to the others mainly through C-H . . .Cl weak hydrogen bond interactions, involving both aromatic and a methylene hydrogen atom.Finally, C-H . . .O weak hydrogen bonds involving a methyl hydrogen atom are a further structural feature in the 3D crystal packing of 4b.

Catalytic activity in hydroamination reactions
NHC-Au(I) complexes, as shown in Figure 1, have been tested for the intermolecular hydroamination of phenylacetylene with SCHEME 3 Possible dynamic equilibrium between bis and mono NHC-Ag(I) complex.

FIGURE 2
ORTEP diagram (thermal ellipsoids drawn at 50% probability) of complex 4b with atomic numbering scheme (labels of hydrogen atoms omitted for clarity).
The reaction is co-catalyzed by two equivalents of silver salt in order to precipitate the chloride anion coordinated to the metal center and generate in situ the catalytic species a (Scheme 5).To select the best cocatalyst, different silver salts (hexafluoroantimonate, hexafluorophosphate, nitrate, and acetate) were tested using gold complex 7b as catalytic precursor in the reaction between phenylacetylene and aniline.Screening of silver salts is reported in Table 2.The performances of the gold(I) complex were strongly influenced by the silver co-catalyst, and the best catalytic activities were found with non-coordinating anions such as hexafluoroantimonate (best performing) and hexafluorophosphate (Entries 1 and 2, Table 2).Low yields were obtained for reactions carried out in the presence of oxyanions (acetate and nitrate).Baron et al. (Baron et al., 2018) have reported similar results with different oxyanions (TsO − , TfO − ).They asserted that the differences in catalytic activities could be the output of different reaction mechanisms or diverse rate-determining steps.
An additional study conducted on the solvent identified acetonitrile as the most effective solvent in the hydroamination reaction using complex 2b.Results are listed in Table 3 and agree with those reported in the literature (Dash et al., 2010;Nuevo et al., 2018;Kumar et al., 2020).The best catalytic performance in CH 3 CN (Entry 1, Table 3) is possibly caused by the coordination and stabilization of the catalytic species a (Scheme 5), after the abstraction of chloride anion.Indeed, Nolan and co-workers suggested that the use of a coordinating solvent can avoid the decomposition of gold(I) complexes to give colloidal gold (0) (de Frémont et al., 2009).
Consequently, AgSbF 6 co-catalyst and acetonitrile were chosen to compare the activity of gold complexes (1-8b), chloro-gold(I)dimethyl-sulfide, and silver complexes 1a and 2a in the hydroamination reaction of phenylacetylene with aniline.As shown in Table 4, all complexes were able to promote hydroamination.Gold complexes (1b and 2b) showed a higher catalytic activity than the silver analogues (compare entries 1 and 2 with entries 10 and 11, Table 4), highlighting the role of gold(I) complexes in this kind of reaction.The low catalytic activity of the chloro-gold(I)dimethyl-sulfide (Entry 11, Table 4) suggests the relevance of the NHC ligand on the stabilization and activation of the catalytic species.NHC-gold(I) complexes with chlorine atoms on the backbone of the ligand (2b, 6b and 8b) were more active than other gold(I) complexes.The better catalytic activity of these complexes could be caused by the ability of the chlorine atoms to reduce the σ-donor ability of the carbene, making the metal center more electrophilic.This would possibly allow faster coordination of the olefin to the metal at the early stages of the catalytic cycle (Mariconda et al., 2020;Sirignano et al., 2021) (see Scheme 5).An additional comment on the role of chlorine atoms can be found in the "Molecular modeling studies" section.
Once 2b was identified as the most efficient complex, the catalyst/co-catalyst ratio was screened, identifying a 1:1 ratio as the optimal proportion.Lowering the co-catalyst to 1% mol caused an increase of the yield from 70% to 99% (compare Entry 13 with Entry 2, Table 4).Once the optimal conditions were identified, the hydroamination reaction scope was extended to a large variety of primary arylamines, keeping AgSbF 6 as co-catalyst and acetonitrile as solvent.
As depicted in Table 5, all substrates generated the expected imines.Quantitative yields are obtained with aniline and methyl substituted anilines (entries 1-4, Table 5).Yields decrease when isopropyl substituted anilines and 2-naphthylamine are used (Entries 5-8, Table 5), as well as with 4-methoxyaniline (51%).Deactivating amines with electron-withdrawing groups on the aryl ring (entries 10, 11, 12 in Table 5) showed yields of 51 and 64% when substituted with halogens and only 20% yield when bearing the nitro group.Finally, the reaction between an internal alkyne (diphenylacetylene or 4-octyne) and aniline leads to a drastic reduction of the yield of the corresponding imine (15% and 5%, respectively).

SCHEME 5
Proposed mechanism for the hydroamination reaction of phenylacetylene with aniline.

Molecular modeling studies
According to experimental studies, when phenylacetylene reacts in the presence of catalyst 2b, quantitative yield percentage was observed only with aniline and orto-methyl aniline (Table 5).All other substituted anilines gave lower percentage yield independently from the nature and position of the substitution.This means that electrondonating activating aryl substituents on aniline influence the kinetics of the reaction in the same direction as the electron-withdrawing activating substituents and the electron-withdrawing deactivating substituents.To investigate this intriguing outcome, DFT (Density Functional Theory) studies at the PBE0/6-311-G (d,p) level were conducted.
The hydroamination reaction mechanism in the presence of NHC-Au complexes was extensively studied by Ghosh et al. (Katari et al., 2012).In detail, Ghosh and co-workers investigated the hydroamination reaction between MeC≡CH and PhNH 2 , as representative substrates, in the presence of [1,3-dimethylimidazol-2-ylidene] gold chloride.In this study, the hydrogen transfer (reaction d→e of Scheme 5) from nitrogen to carbon enabling the formation of the enamine [(NHC) Au(PhNHMeC = CH 2 )] + (e) from the intermediate [(NHC)AuCH = CMeNH 2 Ph] + (d) was revealed to be the rate-determining step.
In detail, this proton transfer can be assisted by a water molecule or a PhNH 2 substrate (Katari et al., 2012).As shown by the authors,   Frontiers in Chemistry frontiersin.org07 Sirignano et al. 10.3389/fchem.2023.1260726 TABLE 5 Substrate Screening in the hydroamination reaction with 2b.
b Yields are averaged of two runs and determined by 1 H-NMR, analysis through internal standard.
Frontiers in Chemistry frontiersin.org08 Sirignano et al. 10.3389/fchem.2023.1260726 the proton transfer assisted by a water molecule presents a slightly lower energy with respect to that assisted by PhNH 2 substrate, occurs in only one step, and would possibly occur even in presence of only traces of water.
In the hydroamination reactions conducted in this work, we can assume the presence of traces of water since substrates employed were not dried before the reaction.
As a consequence, we investigated the proton transfer assisted by water from [(NHC)AuCH = CPhNH Geometries and free energies calculated in acetonitrile have been reported in Figure 4.
According to molecular modeling results, intermediate d-H and TS [d-e-H] ≠ , involving aniline, present higher energies with respect to those calculated by Ghosh and co-workers (Katari et al., 2012), possibly due to the higher steric hindrance of phenylacetylene with respect to propyne and to the higher electron-withdrawing NHC bearing chlorines on the backbone.
Shifting to a comparison among intermediates d, we can observe an increase of free energy for substituted phenylamines.As for d-ipr, the electro-donating ability of the isopropyl group does not compensate its steric hindrance, which introduces internal repulsions as reported in Figure 4. On the other hand, electronwithdrawing groups in para position, such as chlorine or -NO 2 , lead to intermediates with higher energy, possibly due to electron depletion of the metal.
The same energy trend was seen for hydrogen transfer TS ([d-e] ≠ ), although energy differences were reduced.This is possibly due to an increase of acidity of the hydrogen bound to the nitrogen, especially in the presence of electron-withdrawing groups.
To gain details on the electronic effects of the various substrates on the percentage yields, we calculated the Au charge for all intermediates and TS by carrying out a natural bond orbital (NBO) analysis.In Table 6, experimental percentage yield, intermediate and free energy barriers in gas phase and acetonitrile, and Au charges were collected.Electron depletion of the Au can be observed for amine with electronwithdrawing groups and could be responsible for the increase of energy barriers for these substrates.
On the other hand we can speculate that, besides the steric effects, the presence of electron-donating substituents increases the energy barrier due to a decrease of the amine acidity since electronwithdrawing substituents actually give lower energy barriers.
According to computational studies, the non-monotonic trend observed for the reactivity of substituted aniline, where a drop in the percentage yield has been observed with both electron-donating or withdrawing substituents, would be the balance of two contrasting effects: the stabilization of the intermediate preceding the ratedetermining step barrier (favored for electron-donating substituted anilines) and the decrease of the barrier itself (favored for electronwithdrawing substituted anilines due to their acidity).The global effect leads to the highest percentage yield for non-substituted aniline where these two factors find the best balance.
In this framework, the higher performances of catalysts with chlorine on the backbone could be rationalized supposing that electron-withdrawing substituents on NHC would increase the acidity of the ammonium intermediate d decreasing the overall [d-e] ≠ barrier and favoring the hydrogen transfer.
This study confirms, as previously reported by Ghosh (Katari et al., 2012), that the hydrogen transfer represents a key step in the alkyne hydroamination, and variables able to decrease the energy of this step can be responsible for the increase of percentage yields.It is important to underline that the hypothesis that the proton transfer from the amine to the carbon bonded to the metal is mediated by water is also supported by the fact that when conducting the reaction between aniline and phenylacetylene as in Entry 1, but in the presence of molecular sieves to eliminate traces of H 2 O, no product is obtained.

SCHEME 6
Proposed mechanism for the hydroamination reaction of phenylacetylene with aniline.
NHC-Au(I) complexes (1-8b) have been tested as catalysts in the hydroamination reaction of alkynes to give imines.New complexes 3b, 4b, and 6b were characterized by NMR, mass spectroscopy, elemental analysis, and, as for 4b, by X-ray diffraction analysis.All complexes were shown to be active in the hydroamination reaction of phenylacetylene.During the optimization of the reaction conditions, AgSbF 6 was selected as the best co-catalyst, and acetonitrile as the best solvent.Complex 2b   7 Materials and methods

General methods
All the reactions were carried out using Schlenk and glove-box techniques, under a dry nitrogen atmosphere.Solvents were dehydrated by heating at reflux temperature over suitable drying agents.Reagents were purchased from Merck KGaA (Darmstadt, Germany) and TCI Chemicals (Tokyo, Japan), and they were used as received.NMR spectra were recorded on Brucker AM 300 spectrometers (300 MHz for 1 H; 75 MHz for 13 C) and Brucker AVANCE 400 spectrometer (400 MHz for 1 H; 100 MHz for 13 C) using DMSO-d 6 and CDCl 3 as solvents.The chemical shifts are referenced to tetramethylsilane (SiMe 4 , δ = 0) by using residual protons impurities of deuterated solvents as internal standards.The multiplicities of spectra are abbreviated in the following manner: singlet (s), doublet (d), triplet (t), multiplet (m), broad (br), and overlapped (o).Elemental analyses for C, H, and N were recorded with Thermo-Finnigan Flash EA 1112 following microanalytical procedures.Chloride and iodide were determined by the reaction of AgNO 3 with halogen, precipitation of AgX (X = Cl, I), which was dissolved in Na 2 S 2 O 3 .The content of silver was determined by flame atomic absorption spectroscopy (FAAS), and halogen content was calculated by using the content of silver.
ESI-MS measurements of organic compounds were acquired on a Waters Quattro Micro triple quadrupole mass spectrometer equipped with an electrospray ion source.MALDI-MS was performed using a Brucker SolariX XR Fourier transform ion cyclotron resonance mass spectrometer (Brucker DaltonikGmBH, Bremen, Germany) equipped with a 7T refrigerated actively shielded superconducting magnet (Brucker Biospin, Wissembourg, France).The mass range is set to m/z 200-3000.To improve the mass accuracy, the sample spectra were calibrated internally by matrix ionization (2,5-dihydroxybenzoic acid).Single crystal X ray diffraction data of complex 4b were collected at room temperature with a Bruker-Nonius X8APEXII CCD area detector system equipped with a graphite monochromator with radiation Mo Kα (λ = 0.71073 Å).Data were processed through the SAINT (SAINT, 2023) reduction and SADABS (Sheldrick, 2003) absorption software.The structure was solved by direct methods and refined by full matrix least-squares based on F 2 through the SHELX and SHELXTL-2018 structure determination package (Sheldrick, 2008;Sheldrick, 2015).All non-hydrogen atoms were refined anisotropically, and hydrogen atoms were included as idealized riding atoms.All graphical representations were obtained by using Olex2 (Dolomanov et al., 2009) and CCDC Mercury 4.0 (Macrae et al., 2020).Details of data and structure refinements are reported in Table 1.The supplementary crystallographic data were deposited as CCDC 2260506.

FIGURE 1 N
FIGURE 1 N-Heterocyclic carbene silver(I) and gold(I) complexes tested in the hydroamination reaction of phenylacetylene.
FIGURE 3Crystal packing view of 4b showing the main intermolecular interactions.
2 Ph] + (d) to [(NHC) Au(PhNHPhC = CH 2 )] + (e) for selected substrates in the presence of 2b.Substrates were chosen taking into account results of Table 5, in order to compare entries 1, 5, 10 and 12, involving phenylamines with different electron-withdrawing and donating groups and steric hindrance.Minimum energy intermediates (d in Scheme 6) and transition states (TS) of proton transfer ([d-e] ≠ of Scheme 6) were calculated and compared with the energy of the solvent coordinated initiating species [(NHC)AuCH 3 CN] + (a in Scheme 5).

a
among percentage yield of hydroamination and calculated free energies and Au charges for intermediate d (d-H, d-iPr, d-Cl, d-NO 2 ) and TS [d-e] ≠ ([d-e-H] ≠ , [d-e-ipr] ≠ , [d-e-Cl] ≠ , [d-e-NO 2 ] ≠ ) relative to water-assisted proton transfer according to Scheme 6. Free energies in kcal/mol are calculated with respect to intermediate active species a, according to Scheme 4. b Au charges were obtained from NBO, analysis.

FIGURE 4
FIGURE 4 Minimum energy intermediates (d-H, d-ipr, d-Cl, d-NO 2 ) and transition states relative to proton transfer ([d-e-H] ≠ , [d-e-ipr] ≠ , [d-e-Cl] ≠ , [d-e-NO 2 ] ≠ ) located according to Scheme 6, starting from minimum energy active species a of Scheme 5. Free energies calculated at PBE0/6-311-G (d,p) in CH 3 CN are in kcal/mol.Distances are in Å.Some hydrogens of the NHC ligand skeleton were omitted for clarity.

TABLE 1
Details of data collection and structure refinements for complex 4b.

TABLE 3
Screening of the solvent in the reaction of hydroamination promoted by 2b.

TABLE 2
Screening, promoted by 7b, of the silver salt co-catalyst for the hydroamination reaction of phenylacetylene with aniline.