Hyperconjugative aromaticity and protodeauration reactivity of polyaurated indoliums

Aromaticity generally describes a cyclic structure composed of sp2-hybridized carbon or hetero atoms with remarkable stability and unique reactivity. The doping of even one sp3-hybridized atom often damages the aromaticity due to the interrupted electron conjugation. Here we demonstrate the occurrence of an extended hyperconjugative aromaticity (EHA) in a metalated indole ring which contains two gem-diaurated tetrahedral carbon atoms. The EHA-involved penta-aurated indolium shows extended electron conjugation because of dual hyperconjugation. Furthermore, the EHA-induced low electron density on the indolyl nitrogen atom enables a facile protodeauration reaction for the labile Au-N bond. In contrast, the degraded tetra-aurated indolium with a single gem-dimetalated carbon atom exhibits poor bond averaging and inertness in the protodeauration reaction. The aromaticity difference in such two polyaurated indoliums is discussed in the geometrical and electronic perspectives. This work highlights the significant effect of metalation on the aromaticity of polymetalated species.

A romaticity is a ubiquitous and exhaustively studied concept in chemistry, which generally describes cyclic structures with significant resonance stabilization energy [1][2][3] . Generally, the aromatic ring is composed of sp 2 -hybridized carbon or hetero atoms due to the requirement of a fully conjugated π system (such as Hückel-and Möbius-π aromaticity [4][5][6][7]. The presence of a sp 3 -hybridized atom in the cyclic ring would severely damage the aromaticity due to an interrupted electron conjugation. Schleyer and Nyulászi demonstrated that the aromaticity of substituted cyclopentadienes 5,5-C 5 H 4 (MH 3 ) 2 (M = Si, Ge, Sn) is comparable to that of the common five-membered heteroaromatics like furan based on theoretical studies, whereas the substituted cyclopentadiene becomes antiaromatic when the substituents are changed to electron-withdrawing group (e.g. F), which act as an vacant p orbital 8,9 . Therein, the methylene group substituted by two electron-donating atoms could contribute pseudo 2π electrons by hyperconjugation to the four olefinic π electrons, thus leading to hyperconjugative aromaticity (HA) in cyclopentadiene with 6π electrons (Fig. 1). This finding nicely rationalizes the experimental fact that the germinal (gem) 5,5-isomer is the most stable one among disubstituted isomers of C 5 H 4 (MMe 3 ) 2 (M = Si and Ge) 10 . Recently, Zhu group reported that combining the negative hyperconjugation of the electronwithdrawing group (e.g. F) and push and pull effect leads to the strongest antiaromatic pyrrolium 11 . More importantly, HA helps people understand and explains some typical reactivity. For example, O'Ferrall and co-workers once correlated the HA in arenium intermediates with the enhancement of dehydration reaction rates of diols 12,13 . Recently, Houk and co-workers revealed that the reactivity and stereoselectivity of 5-substituted cyclopentadienes in Diels-Alder reactions are also related to HA [14][15][16] . On the other hand, Mauksch and Tsogoeva reported an alternative explanation to HA in charged sigma complexes that the topology of highest occupied molecular orbital (HOMO) of the complexes containing charged sp 3 carbon is a key factor to determine the aromaticity 6 .
Thereafter, we found that transition metal substituents give better performance on HA over the traditional main-group ones [17][18][19] . For example, the five-membered ring (5MR) of the metalated indolium (B) containing a gem-dimetalated carbon moiety exhibits aromaticity while its parent indolium (A) is nonaromatic (Fig. 1). Such HA is reminiscent of the frequent appearance of gem-dimetalated structural units in many reported metalated aromatic intermediates [20][21][22][23] . Following this line of thinking, it is intriguing for chemists to know if the cyclic ring containing two gem-dimetalated sp 3 -hybridized atoms is still aromatic or not. This fundamental question is not only conducive to expanding our knowledge boundaries in aromaticity, but also sheds light on the mechanistic studies of related transition metalcatalyzed reactions, wherein polymetalated aromatics often act as key intermediates.
In this work, we report an extended hyperconjugative aromaticity (EHA) in a penta-aurated indolium compound and disclose its effect on the reactivity of polymetalated aromatics. In contrast to the transformation from indolium A to dihydroindole C that would lead to interrupted electron conjugation in the 5MR due to the presence of two sp 3 carbon atoms (Fig. 1), we find that the introduction of two vicinal gem-dimetalated motifs in the polymetalated analog D does not impair the aromaticity. Although the penta-aurated prototype (complex 1) of D arises from the addition of a gold(I) species onto the tetra-aurated indolium 2 of type B, structural analysis reveals that the bond averaging scenario in the 5MR of 1 is more remarkable than that of 2. Theoretical studies show that the more extensive electron conjugation in 1 should be ascribed to dual hyperconjugation of two vicinal gem-diaurated motifs. Furthermore, the EHA in 1 leads to better electron conjugation in the indolyl 5MR and relatively low electron density on the indolyl nitrogen atom, enabling a facile protodeauration reaction for the labile Au-N bond. In contrast, no reaction occurs between the HA-involved 2 and the same substrate. Our finding in this work not only demonstrates the existence of aromaticity in a permetalated dihydroindole analog containing two gem-disubstituted sites, but also reveals the close relationship of HA with the reactivity of polymetalated aromatics.

Results and discussion
Synthesis and characterization of polyaurated indoliums 1 and 2. The well-established gold(I) catalysis chemistry in the past decades has shown that the gold(I) ion often acts as a π-acidic center to activate the unsaturated hydrocarbon substrates by π-activation [24][25][26] . However, in our previous synthesis of tetraand octa-aurated heteroaromatics by 2-ethynylaniline derivatives, the σ-activation of the ethynyl group by a gold(I) species is more essential 17 . Therein, the σ-aurated carbon-carbon triple bond is subject to the nucleophilic attack by an aurated imido group, which is formed by the reaction of a NH 2 group with a μ 3 -oxo trinuclear gold(I) compound [(PPh 3 Au) 3 27 , to yield the cyclized polyaurated heteroaromatics. In order to probe the possible role of the σ, π dual activation in such transformation, we purposefully added one equivalent [PPh 3 Au] (BF 4 ) to the 1:1 mixture of the σ-aurated compound 3 and [Au 3 O] (Fig. 2). The mixture was originally supposed to generate the tetra-aurated indolium complex 2. However, the 1 H-NMR monitoring showed the quantitative formation of complex 1 ( Supplementary Fig. 1). X-ray crystallographic analysis (vide infra) revealed that 1 has a penta-aurated indolyl structure with two vicinal carbon atoms on the indolyl 5MR being gem-aurated. Remarkably, as an alternative synthetic pathway, complex 1 can also be directly synthesized by mixing 2 with one equivalent [PPh 3 Au](BF 4 ) by aurophilic interaction, suggesting the precursor role of 2. Complexes 1 and 2 both show good stability upon exposure to ambient air and moisture or heating up to 70°C ( Fig. 3b and Supplementary Fig. 2). Noticeably, upon elevating the temperature of the solution of 1 until decomposition, no 1-to-2 dissociation was detected in NMR monitoring (Fig. 3b). In addition, the calculated ΔG is −36.4 kcal mol −1 in the 2-to-1 transformation ( Supplementary Fig. 3). The results jointly suggest that the complexation of 2 with a gold species may bring about extra stabilizing effect in 1.
We further made structural comparison between 1 and 2. Due to the poor precision of bond lengths in the previously reported crystal structure of 2 (space group P2 1 /c), we modified the purification method and re-collected the crystal data of 2 (space group Pbca). X-ray crystallographic analysis shows that compound 1 has a coplanar indolyl trianion skeleton, which is coordinated by five AuPPh 3 units via a μ 5 -C1,C2,N1-η 2 ,η 2 ,η 1 mode (Fig. 3a). The two carbon centers C1 and C2 in 1 each is bonded by a gem-digold unit with the Au-C bond lengths in the range of 2.086(7)-2.154(6) Å, which is comparable with the bond distances of the CAu 2 unit in 2 (2.096(12) and 2.135(11) Å). In addition, the Au···Au distances and ∠Au-C-Au angles of the gem-digold units in 1 (2.805(1) Å and 82.6(2)°for Au2-Au3, and 2.855(1) Å and 85.0(3)°for Au4-Au5) are also similar with those of 2 (2.874(1) Å and 85.5(4)°for Au3-Au4). The Au-N bond length in 1 (2.062(6) Å) is slightly longer than that of 2 (2.052(11) Å). Despite the high similarity in the aspect of interaction between the inner indolyl skeleton and the outer gold substituents in 1 and 2, the dimensions of the indolyl ring in these two complexes show remarkable difference. The bond length alternations (ΔBLs) of three C-C and two C-N bonds of the 5MR in 1 are 0.019(1) and 0.010(0) Å, respectively, smaller than the ΔBLs of 2 (0.031(1) Å for ΔBL C-C and 0.052(2) Å for ΔBL C-N ). The more equalized bond lengths in the 5MR of 1 indicate better electron delocalization than 2.
The molecular composition and excellent stability of 1 in solution were confirmed by electron-spray ionization mass spectroscopy (ESI-MS) and nuclear magnetic resonance (NMR). ESI-MS exhibits two isotopically well-resolved peaks at m/z = 2497.3281 and 1205.1597 corresponding to the [1-BF 4 ] + and [1-2(BF 4 )] 2+ species, respectively. 1 H NMR spectrum of 1 reveals two doublets at 8.15 and 8.04 ppm, which can be assigned to two protons on C4 and C7 of the indolyl six-membered ring (6MR) (Fig. 3b), respectively. In contrast, the signals of the indolyl 6MR protons in 2 appear as a merged multiplet at the upfield position of 7.79 ppm. Such NMR difference should be ascribed to more remarkable electron-withdrawing effect of total five gold(I) species in 1 relative to four ones in 2. In addition, due to the steric effect of four gathering PPh 3 units around two vicinal carbon atoms in 1 that causes a rich variety of hardly interchangable conformations, the corresponding resonance signals of PPh 3 in 1 are much broader than those of 2. Upon heating from 293 to 343 K, these peaks in 1 turned into sharp due to the interconversion of different conformations (Fig. 3b).
Theoretical investigations on the aromaticity of 1 and 2. In view of the remarkable structural difference of the indolyl 5MR between 1 and 2 arising from the decoration of different numbers of AuPPh 3 units, we further carried out density functional theory (DFT) calculations to study the aromaticity of the indole rings in 1 and 2. Model complexes 1-PMe 3 and 2-PMe 3 were simplified by replacing the PPh 3 ligands in 1 and 2 with PMe 3 . Among many calculated descriptors applied to quantify aromaticity by criteria like energetic, structural, and electronic characteristics, the nucleus independent chemical shift (NICS) 28 and anisotropy of the current-induced density plot (ACID) 29,30 have gained wide recognition. In general, negative NICS values indicate aromaticity while positive ones show anti-aromaticity. As shown in Fig. 4a, b, the calculated NICS(1) zz values of the indolyl 6MR/5MR in 1-PMe 3 and 2-PMe 3 are −24.5/−20.9 and −26.4/−18.2 ppm, respectively. This result supports the aromatic nature of the 5MR in 1-PMe 3 and 2-PMe 3 . In general, introduction of a sp 3 -hybridized carbon atom into a ring will impair its aromaticity to some extent. When two carbon atoms in a ring become sp 3 -hybridized, its aromaticity might disappear. In contrast to the HA in 2-PMe 3 that has a gem-disubstituted moiety at the sp 3 -hybridized carbon atom, the unexpected aromaticity in 1-PMe 3 containing two gemdiaurated sp 3 -hybridized carbon atoms, as will be shown later, is enhanced rather than reduced by hyperconjugation of polyaurated substituents. The aromaticity in 1-PMe 3 was further confirmed by the diatropic ring current in the ACID plots (high resolution ACID graphs of 1-PMe 3 and 2-PMe 3 were shown in Supplementary Figs. 4 and 5). ACID plots are used to visualize electron delocalization in the ring, in which aromatic rings exhibit diatropic circulation whereas anti-aromatic ones show a paratropic ring current. According to the key occupied π-orbitals of 1-PMe 3 and 2-PMe 3 ( Supplementary Figs. 6 and 7), both of them have five π-orbitals, leading to a 10π system. Nevertheless, accurate electron counting in metallaaromatic compounds is still puzzling and difficult 31 . Moreover, Solà and Szczepanik once pointed out that it was very challenging to unambiguously associate the aromaticity of metallaaromatics with the 4n + 2 (Hückel) and 4n (Möbius) rules because both Hückel and Mobius topology may contribute to the HOMO of some metallacycles together 32 . As shown in Fig. 4 or Mobius for the key occupied π-orbitals in 1-PMe 3 and 2-PMe 3 is indeed difficult due to the low symmetry of their geometries. In order to probe the difference of aromaticity between 1-PMe 3 and 2-PMe 3 , multiple theoretical methods were applied to investigate the dissimilarity from the geometrical and electronic perspectives (Supplementary Table 1). As illustrated in the structures of 1-PMe 3 and 2-PMe 3 , the ΔBL C-C (0.023 Å) for the indolyl 5MR in 1-PMe 3 is smaller than that of 2-PMe 3 (0.043 Å), which is in agreement with the trend shown in the crystal structures and suggests a better electron delocalization of the EHA-involved indolyl 5MR in 1-PMe 3 than that of the common hyperconjugative aromatic 2-PMe 3 . To confirm the higher electron delocalization in 1-PMe 3 , we further examined the aromaticity in 1-PMe 3 and 2-PMe 3 via the methods of the electron localization function separated by the π molecular orbitals (ELF π ) 33-35 and the electron density of delocalized bonds (EDDB) analysis 36 . ELF π maps the extent of spatial localization of π electrons in a multiple electronic system. If the difference of the bifurcation values (ΔBV(ELF π )) is small, the π electrons should be highly delocalized. EDDB provides an explicit degree of electronic delocalization in the π-system of the aromatic ring. Our calculations reveal that 1-PMe 3 has a smaller ΔBV(ELF π ) (0.222) and a larger EDDB by fragment analysis (EDDB_F(r) = 2.663 e) in comparison with the corresponding calculated values of 2-PMe 3 (ΔBV(ELF π ) = 0.544 and EDDB_F(r) = 2.085 e), demonstrating more delocalized π-electrons in the indolyl 5MR   Supplementary Fig. 8), the aromaticity of 1-PMe 3 is close to furan and indole. And the aromaticity of 2-PMe 3 is relatively weaker. But according to the EDDB and ELF analyses, both of them are more aromatic than the 2Au-indolium reported in 2016 (ref. 17 ). Moreover, the aromatics induced by HA could be regulated by changing types and numbers of substituents, especially the transition metal substituents based on our previous works 11,17,18 .
Protodeauration reactivity of 1 and 2. To gain further insight into the effect of aromaticity difference on reactivity, we then conducted the protodeauration studies of 1 and 2. Previous investigations on gold catalysis have shown that the protodeauration reaction of organogold intermediates is the key step for catalyst regeneration and often acts as the rate-limiting step for the whole catalytic cycle 39 . Accordingly, we embarked on the protodeauration study of 1 and 2 with the 2-ethynylaniline analogs in order to reproduce the regeneration step of active gold species. Compound 4 was selected as the substrate due to its strong luminescence (quantum yield 76%) (Supplementary Table 3), which is good for reaction monitoring. As shown in Fig. 5a, we observed rapid luminescence decay upon mixing 1 with 4 while no obvious color change in the [2 + 4] mixture. UV-vis spectroscopic monitoring reveals the appearance of a absorption band from 400 to 520 nm upon mixing 1 and 4 (Fig. 5b). This band experienced a dramatic increase within the beginning 5 min and then a slight decrease during the next 30 min. We hypothesize that this variation arises from the formation of sequentially transformed reaction intermediates. ESI mass spectrum of the [1 + 4] (Fig. 5b). The nitrogen atom on the benzo[cd]indole ring in 5 is σ-bonded to a AuPPh 3 unit, substantiating the occurrence of deprotonation for the amino group of 4 in the reaction process. Notably, the characteristic absorption band of 5 spans the range of 400-520 nm, which is similar with that of the [1 + 4] reaction mixture (Fig. 5c)  gives two sets of NMR signals (highlighted in blue and red) corresponding to the products derived from 1 and 4, respectively ( Fig. 5d and Supplementary Fig. 14). The blue NMR signals in the range of 7.7-8.5 ppm are consistent with the doublets and triplets of 5 due to six protons on the naphthalene ring. Above spectroscopic similarity with 5 suggests that the [1 + 4] mixture possibly undergoes a similar deprotonation and cyclization pathway to generate a mixture of benzo[cd]indole-based polyaurated complexes (Fig. 5e), which is supported by the ESI-MS spectrum ( Supplementary Fig. 13). In order to make sure that the amino group in 4 indeed undergoes a deprotonated process under the treatment of 1, we studied the reaction of 1 with a simplified model substrate aniline. The NMR monitoring showed the gradual vanishment of the characteristic doublets at 8.04 and 8.15 ppm corresponding to 1, and the synchronous appearance of a NH singlet of indole at 9.69 ppm ( Supplementary Fig. 15). Such observation is in agreement with the variation of NMR signals in the [1 + 4] mixture (Fig. 5d). The above experimental facts together with previous theoretical studies that reported the higher energy barriers of the gem-digold moieties for a protodeauration process than the unidentate ones 40,41 suggest that the N-Au bond of 1 is the true reactive site for protodeauration.
To further clarify the reaction details between 1 and 4, kinetic studies based on stop-flow methods were conducted. In view of the fact that 1 and the resulting products of [1 + 4] like complex 5 show weak emission above 500 nm while the substrate 4 is highly luminescent at the same region ( Fig. 6a and Supplementary Fig. 16), we thus monitored the decline of the luminescence above 495 nm in the stop-flow measurement. As shown in Fig. 6b, the reaction of excessive 1 with 4 is quickly finished within 30 s. The reaction acceleration upon heating from 273 to 293 K gives a good fit with a pseudo-first-order equation (Fig. 6c). According to the Arrhenius equation, the activation energy of protodeauration between 1 and 4 is estimated as 3.75 ± 0.14 kcal mol −1 (Fig. 6d). This activation energy is among the range of 3.1-25.8 kcal mol −1 for the protodeauration of organogold compounds based on previous theoretical studies 42 . We then carried out the reaction of 1 with the deuterated 4 to confirm the rate determining step of protodeauration. Hydrogen atoms of 4 were partially deuterated by mixing 4 with deuteroxide in d 4 -methanol ( Supplementary  Fig. 17b). Upon replacing 4 with the partially deuterated one, we observed an approximate three-fold elongation of reaction time at 273 K ( Supplementary Fig. 17a). The slowdown of reaction rate due to the isotopic effect demonstrates the proton donor role of the amino group of 4 in the protodeauration step.
In sharp contrast to the remarkable reaction phenomena of 1 and 4, no protodeauration reaction occurs between complex 2 with 4 or aniline (Supplementary Figs. 15b, 18). We subsequently probed the reasons for such distinct reactivity by computational methods. The condensed Fukui functions (f k − ) (using Hirshfeld charge) 43,44 were utilized to study different susceptibility of the N atom in 1-PMe 3 and 2-PMe 3 subject to electrophilic attack (Table 1). Generally, the atom with the largest f k − value is the most nucleophilic site. The calculations show that the N atom in 1-PMe 3 (f k − = 0.048) is more preferentially attacked by electrophilic reagents than 2-PMe 3 (f k − = 0.038). In addition, the calculated BDE of the N-Au bond in 1-PMe 3 (56.5 kcal mol −1 ) in dichloromethane is weaker than This biased charge distribution should be ascribed to the dual hyperconjugative effect at both C1 and C2 of the 5MR in 1-PMe 3 , which causes more electron density on C1 and the reduction of charge distribution on the N atom. Thus, the N-Au bond is elongated (2.046 Å in 1-PMe 3 relative to 2.036 Å in 2-PMe 3 ) and weakened, enabling a facile protodeauration reaction. In a word, the higher protodeauration reactivity of 1-PMe 3 over 2-PMe 3 should be ascribed to the weaker N-Au bond in 1-PMe 3 due to the EHA-caused high electron delocalization.
In conclusion, the present work shows that the 5MR in the penta-aurated indolium 1 with two gem-digold groups exhibits better electron delocalization and HA than that of the tetraaurated indolium 2 containing one gem-digold group. As a result, the NPA charge density of the nitrogen atom and the BDE value of the N-Au1 in 1 are smaller than 2. Such difference in aromaticity accounts for the easy occurrence of protodeauration for 1. These findings not only promote better understanding on the concept of HA, but also open bright prospects in the future development of polymetallic reactions depending on HA.  31  X-ray crystallographic analysis. Single-crystal X-ray data for complexes 1, 2 and 5 were collected respectively at 100 K, 173 K and 107 K with Cu-Kα radiation (λ = 1.54178 Å) on a Rigaku Saturn 724/724 + CCD diffractometer with frames of oscillation range 0.5°. The selected crystal was mounted onto a nylon loop in polyisobutene and immersed in a low-temperature stream of dry nitrogen gas during data collection. All structures were solved by direct methods, and non-hydrogen atoms were located from difference Fourier maps. Non-hydrogen atoms were subjected to anisotropic refinement by full-matrix least-squares on F 2 using the SHELXTL program and Olex 2 program 47 . All Figures were processed by using X-seed program. The details of X-ray crystallographic measurements are summarized in the Supplementary Methods.

Methods
Computational details. The calculated models (1-PMe 3 and 2-PMe 3 ) were optimized at the TPSS 48 level of DFT with the dispersion corrections described by EmpiricalDispersion = GD3(BJ) 49 in the gas phase with 298.15 K and 1.00 Atm. The cartesian coordinates are shown in Supplementary Data 1. The suitability of the method mentioned above was already tested in previous works 17 . The structures without imaginary frequency indicates they have arrived the minima of all stationary points. The Au atom was described by ECP60MDF basis set 50 and other atoms (C, H, N and P) were described by the standard 6-31 G(d) basis set 51 at all calculations which were carried out in Gaussian 09 package 52 . The BDE energy of N-Au bonds in solvent was the single-point energy with SMD model 53

Data availability
The X-ray crystallographic coordinates for structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition number CCDC-1922291(1), 1922290(2) and 1936578 (5). These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/ data_request/cif. For full characterization data including NMR and ESI-MS spectra and experimental details, see the Supplemental Information. Any further relevant data are available from the authors upon reasonable request.  Calculated condensed Fukui function (fk − ), NPA analysis on N, Au1 and C1 atoms, bond length (Å), Mayer bond order and bond dissociation energy (BDE, kcal mol −1 ) of the N-Au bond.