Toward Thermodynamically Stable Triplet Yumiao Ma* BSJ Institute, Haidian, Beijing, 100084 [email protected]

Abstract In sharp contrast to the widely studied and applied stable singlet carbenes, only several kinetically persistent triplet carbenes have been studied, and thermodynamically stable triplet carbenes are much less developed. With the Gibbs free energy of C-H bond insertion into methane as a probe, DFT calculations were employed to examine a variety of candidate molecules for stable triplet carbenes. Guided by these calculations, some molecules with significant stability against C-H insertion were designed by fine tuning of geometry and electronic structures. These compounds might be potential candidates for experimental development of stable triplet carbenes.

Introduction Pioneered by , Armin Arduengo and others, stable singlet carbenes have been well developed since 1980s1-3, and have exhibited great importance as , reagents, etc. On the other hand, stable, or even kinetically persistent triplet carbenes are still scarce. A persistent triplet , 2, 2', 4, 4', 6, 6'-hexabromodiphenylcarbene, was reported by Hideo Tomioka et al in 19954, with a half-life at ~1 s. In 2001, persistent triplet carbene with half-life of 19 min at room temperature was reported5, which was a great breakthrough. Several other kinetically persistent triplet carbenes were also studied, and the half-life ranges from microseconds to a week6, 7. However, thermodynamically stable triplet carbenes are still unknown hitherto, to the best of our knowledge. In this work, a variety of potential candidates for stable triplet carbenes were designed and examined by quantum chemical calculations. Guided by calculations and rational design, some competitive candidates were obtained, which may be helpful for the development of stable triplet carbenes, and for the understanding of the chemical properties related to open shell organic compounds.

Figure 1. Summary of this work

Results and discussions

Figure 2. (a)The probe for stability (G(ins)), the first generation structures and its G(ins) value (in kcal/mol). Values inside brackets were obtained at DLPNO-CCSD(T)-F12/cc-pVDZ-F12//M06- 2X/def2-SVP level, whereas others were obtained at M06-2X/def2-SVP level. Spin density isosurface of 31 with isovalue at 0.02 is shown in the inner picture.

It is known that triplet carbenes are usually prior to undergo insertion into C-H (or other) bonds, or abstraction from other compounds, or reaction with dioxygen. In this work, the thermodynamics of insertion into methane, G(ins), was used as a probe for the thermodynamical stability. A stable triplet carbene should exhibit a near-zero or positive insertion free energy. There are two methods to achieve this: to stabilize the carbene itself by enhancing electron delocalization, or to destabilize the insertion product. The design of first generation of candidates originates from the stable Blatter’s . A series of carbon analogues of Blatter’s radical were examined (1 – 5 in Figure 2) at M06-2X/def2-SVP level. High accuracy calculations at DLPNO-CCSD(T)-F12/cc-pVDZ-F12 were also performed for 1 and 2, showing that the DFT calculations have been perfectly accurate, despite the fact that the def2-SVP basis set seems moderate. Except 1, all compounds exhibited triplet ground state. It can be seen that 1 shows similar thermodynamics stability with a (di(2,4,6- trichlorophenyl)carbene), whereas further enlarging conjugation system provides extra stabilization. It was originally expected that conjugating (-Ph) or polarizable group (-SMe) at C2 or C6 sites might provide stabilization toward the unpaired electron at C1 by weak interactions. Unfortunately, the effect of this substitution pattern is negligible.

Figure 3. The G(ins) values for several “second-generation” candidates (in kcal/mol). The ground states for insertion products were shown in brackets, if not close-shell singlet (CSS). OSS means open-shell singlet. The DLPNO-CCSD(T)-F12/cc-pVDZ-F12//M06-2X/def2-SVP value for 6 was shown in bracket.

In order to provide further stabilization toward the triplet carbenes, the second generation of structures was designed (Figure 3). The basic idea is to introduce an aromatic ring that would be lost upon insertion into C-H bond. Following this idea, the Gibbs free energy of insertion for compound 6 has been tuned to -35.3 kcal/mol. A fused quinone ring significantly stabilized the triplet carbene 7. It can be seen that 7 and its insertion product 7HMe adopt significantly different geometries (Figure 4). The ring A bearing two-coordinated carbon atom deviates from the plane consisted of ring B and C in 7, whereas in 7HMe (with closed shell singlet (CSS) as ground state) the coplanarity between A and B is largely kept, although serious distortion is introduced into both ring B and C. Thus it is natural to propose that an extra rigid fused ring may destabilized the inserted structure. Indeed, the Gibbs free energy change for insertion was further tuned into -20.9 kcal/mol for 8. Since the spin density of 7 shows that unpaired electron mostly distributes at the O1 site (Figure 4), it is safe to introduce further modification to O2. Due to the fact that the ring A and B tends to be more coplanar in the inserted structure, the O2 atom was replaced with two to achieve more geometry constraint (Figure 3d). The resulted structure 11 exhibits an insertion Gibbs free energy of only -15.3 kcal/mol. On the basis of the observations above, some modification was added to 11 in order to obtain more sterically rigid and constraining and thus less negative G(ins). Unfortunately, the bottleneck was soon met when the ground state of insertion product changed from close shell singlet (CSS) to open shell singlet (OSS) upon large distortion. Obviously a new backbone is in need to overcome the last 10 kcal/mol gap between current G(ins) and ideal 0 kcal/mol.

Figure 4. The geometries for 7 and its insertion product 7HMe are shown in (a) and (b) respectively. (c) The spin density isosurface of 7 with isovalue at 0.02. (d) A schematic representation for the design of 11 and related structures.

Figure 5. (a) G(ins) for the “third generation” candidates (in kcal/mol). The ground states for insertion products were shown in brackets, if not CSS. (b) The geometry and spin density isosurface (at 0.02) of 18. (c) The geometry for 18HMe (CSS state).

The third generation of backbone directly comes from the second generation molecules. There are two core designs. The first, the introduction of N-N bond will provide an extra aromatic pyridine ring for triplet carbenes, which is expected to be lost upon insertion (into CSS product). The second, a distant quinone motif promotes intramolecular charge transfer, which is proposed to be beneficial for radical delocalization. The so-designed structure 18 exhibits insertion free energy of only -13.0 kcal/mol, much more positive than its second generation analog 7, proving this strategy effective. The spin density of 19 is very located at the quinone ring C. In contrast to the case of 7, in which spin density strongly tends to distribute at O1 but not O2, both two atoms bear similar spin density, indicating that the electronic structure of 19 should be better considered as a single electron reduced quinone ring and close-shelled aromatic ring A and D. The of ring A and D can be clearly seen in , and is significantly lost after insertion. With 19 as a starting point, several structures were tested in combination with all design strategies mentioned above. Although introduction of electron-withdrawing groups might lead to more favorable electron transfer at the first glance, it actually leads to an open shell singlet state insertion product, and a more negative insertion G(ins). This can be understood considering the fact that too much intramolecular electron transfer will lead to small spatial overlap of the two single electrons, and thus stabilize the triplet state (and the related OSS state) of insertion product. Also too large R2 and R3 lead to insertion products with triplet state as its ground state, in consistent with the fact that ring A and D comes perpendicular for 20 and 21, for which the insertion free energies are much more negative than that expected for an CSS state product. Then came a contradictory. While spin delocalization stabilizes unpaired electron and large R2 and R3 destabilize the CSS state of insertion products, they also stabilize its OSS and triplet state. Another bottleneck appears now.

Figure 6. G(ins) for the “modified third generation” candidates (in kcal/mol).

Huge efforts were paid to overcome this bottleneck (Figure 6). A seven-member ring was introduced to fix the dihedral angle between A and D (compound 25). Although it could be seen that the conformation of this seven-member ring changed after insertion (see Supporting Information), further conformational constraints failed to improve the G(ins) (27-30). It is proposed that the conformation has very complex and significant influence, although our efforts to understand it was in vain. Electron-withdrawing cyano groups at Ring C again failed to improve the G(ins). Modifications at Ring B also failed, which was proposed to originate from the fact that any substitution at Ring B will change the relative conformation between Ring B and D. The Hirshfeld atom charge8 showed that for the triplet and OSS insertion products, charges on most atoms remains unchanged in comparison with the carbene, except the C2 and C6 (inner page of Figure 6), of which charges get more positive upon insertion. However, the attempts to introduce electron-withdrawing groups at these positions also failed (compound 44 and 46). The only conclusion that could be drawn at this stage is that the structure-property relationship is rather complex.

Figure 7. (a). The schematic representation of two proposed strategies to further improve G(ins). Molecular orbital levels are in Hartree. (b). The plot of G(ins) versus substitution constants at four positions.

It was noticed that the largest change after insertion appears on the Ring A: a benzene ring is replaced with a cyclopentadiene radical in conjugation with a pyridine ring. It was proposed that by tuning the lowest unoccupied molecular orbital (LUMO) level of substituted pyridine motif or the partial molecular orbital (PMO) of the ethylene motif in cyclopentadiene radical, the conjugation stabilization of insertion product could be lowered (Figure 7a). However, using four aryl substituted 25 as model, the relationship between substitution electronic effects and G(ins) is rather irregular. It is only shown that compound 25_RingD3Ar (RD3=H) is prior to any other candidate. It has to be noticed that any polar substitution group may lead to changes at PMO level, geometry and conformation, atomic charge, or even weak interactions, simultaneously. Thus it might be hard to tune the G(ins) by simple qualitative guidelines.

Table 1. The relative isomerization energies (RIEs) and relative stable energies (RSEs) for several phenyl radicals.

R RIE (kcal/mol) Ph 0.9

4-NMe2C6H4 0.9

4-MeC6H4 -0.4 2,6-(CCl3)2C6H3 -0.5

CH2SMe 0.9

CH2SOMe 2.2

CMe2Cl -3.0

CMe2Ph -5.0 t-Bu -6.4

R RSE (kcal/mol) t-Bu -4.5

CMe2Ph -3.1

CMe2NMe2 -1.7

CMe2PMe2 -5.5

t-C4F9 -5.6

CMe2SMe -4.0

It was noticed that the sp2-carbon centered radical motif had never been taken into account till now. With relative isomerization energy (RIE) and relative stable energy (RSE) as probes, the effects of several substitution groups at C2 and C6 were explored (Table 1). Only substitution groups with weak conjugation effects were considered, since those strongly interacting with pi systems will obviously stabilize a cyclopentadiene radical. Both RIE and RSE showed that bulky groups (t-Bu and its analogs) provides significant stabilization effect toward a phenyl radical. The and containing groups were also examined, in hope that the weak interaction between polarizable elements and radical center could help. Indeed -CMe2SMe and -CMe2PMe2 are good candidates for phenyl radical stabilizer.

Figure 8. (a) The G(ins) and G(HAT) values (in kcal/mol) of several “final” structure. Ground state of insertion products are shown in brackets. (b) The definition of G(HAT) and the corresponding values for some well-known carbenes. (c) A proposed retrosynthesis of our potential stable carbenes. (d) The geometries and spin density isosurfaces at 0.02 for 54 and 54HMe.

Based on the information from Table 1 and Figure 7, several C2 and C6-substituted analogs to 25_RingD3Ar were designed (Figure 8). Surprisingly many of them exhibit positive G(ins), as shown in red. Next the structural expandability was examined and it was found that N-Ac instead of synthetically difficult N-CHO is acceptable (compound 58), and several other bulky groups at C2 and C6 are tolerated, although the tendency in G(ins) is not perfectly consistent with RSE in Table 1. Impressively the CMe2PMe2 group is tolerated, which provides further possibility to develop the structure as a general . The G(ins) values shown in Figure 8 have been comparable or even more positive than the NHC shown in Figure 2. However, there are still some limitations. The free energies for hydrogen abstraction from methane (G(HAT)) were examined for selected structures, and all of them exhibited near-zero G(HAT). This means that the carbenes in this work is not sufficiently stable toward hydrogen abstraction. Although this might be overcome by kinetically blocking, these molecules are still not truly “stable triplet carbenes”. Also they are sensitive toward dioxygen. The calculated dioxygen combining free energy is as negative as -24.4 kcal/mol for compound 54. Another limitation is for all t-Bu substituted structures: they are prior to undergo intramolecular hydrogen abstraction from t-Bu. Thus the compound 55, 60 and 62 are potentially better candidates than their t-Bu analogues. The last but not the least important limitation is that these compounds might be challenging for synthesis. Next the possibility of using our structures as ligand was explored. The complex of 55 with Cu(I) ion was compared to its NHC analog (Figure 9). The ground state of both complexes are CSS state, and in the 55CuCO+ complex the bond lengths of pyridine ring D remain average. The oxidation state of Cu was determined by the localized orbital bonding analysis (LOBA) method9 to be +1 for both complexes. Thus it was concluded that the electronic structure of 55CuCO+ should be best shown in the Lewis structure in Figure 8, i.e. the ligand acts as a two-electron donor by firstly transferring one electron from ring C to copper, and then forming a C-Cu bond (Mayer bond order is 0.817, very similar to 0.811 in its NHC analog). Both the C-O stretching frequency and the Hirshfeld charge show that 55 is a stronger donor than NHC.

Figure 9. The structures and related properties of copper(I) complex with NHC and 55. Frequencies are in cm-1.

In conclusion, a class of potential stable triplet carbene candidates, as well as the chemical properties of related spin polarized molecules, was explored. By computationally optimization of molecular skeleton and substitution group, several compounds with positive insertion free energy toward C-H bond in methane were obtained. Although these compounds still suffer from the limitations due to thermo-neutral hydrogen abstraction and sensitivity toward oxygen, this work might provide some insights into both theoretical and experimental development of truly stable triplet carbenes.

Acknowledgement Thank all students in the Department of Chemistry, Tsinghua University for their great love and encouragement toward the author. Especially thank all the 2019-year students, for it was after a visit to them that the author occurred to the idea of the third generation of structures.

Methods Quantum chemical calculations were carried out using the ORCA 4.2.0 program10, 11. Geometry optimization and frequency calculations were performed at M06-2X/def2-SVP level12-14 based on stable wavefunctions. DLPNO-CCSD(T)-F12/cc-pVDZ-F12 and wB97MV-D3BJ/def2-TZVP calculation15-17 was performed to validate the accuracy of M06-2X/def2-SVP level. Wavefunction analysis was carried out with the Multiwfn program18. The VMD program19 was used to generate pictures for configurations and spin densities.

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