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Synlett 2024; 35(03): 319-324
DOI: 10.1055/a-2153-6819
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Organic Chemistry Under Visible Light: Photolytic and Photocatalytic Organic Transformations

A Combination of Computational and Experimental Studies to Correlate Electronic Structure and Reactivity of Donor–Acceptor Singlet Carbenes

Shweta Singh
a   Dept. of Chemistry, School of Natural Sciences, Shiv Nadar Institution of Eminence Deemed to be University, Tehsil Dadri, Gautam Buddha Nagar, U.P. 201314, India
,
Ludovic Gremaud
b   University of Applied Sciences Western Switzerland, Faculty of Engineering and Architecture, Department of Chemistry, Pérolles 80, Fribourg 1700, Switzerland
,
Subhabrata Sen∗
a   Dept. of Chemistry, School of Natural Sciences, Shiv Nadar Institution of Eminence Deemed to be University, Tehsil Dadri, Gautam Buddha Nagar, U.P. 201314, India
,
Debajit Maiti∗
a   Dept. of Chemistry, School of Natural Sciences, Shiv Nadar Institution of Eminence Deemed to be University, Tehsil Dadri, Gautam Buddha Nagar, U.P. 201314, India
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Funding and facility for this research have been provided by Shiv Nadar Institution of Eminence deemed to be University.
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Abstract

Most of the reactivities of donor–acceptor (D–A) singlet carbenes are similar to metal carbenoids. However, the lone pair at the carbenoid carbon, coordinated with metal, is free in D–A carbene thereby making it nucleophilic as well. Herein, DFT-optimized structural features of D–A carbene has been investigated and is compared with rhodium carbenoid. It was observed that, when a D–A carbene reacts with cyclic-1,3-diones in different ethereal solvents, it is the lone pair at the sp2 orbital of the carbene that abstracts the proton from the enol form (of the cyclic-1,3-diones) to form a benzylic carbocation and an enolate. Subsequently, the carbocation undergoes nucleophilic attack by O of the ether solvents and then by the enolate to afford the desired ether-linked products. Accordingly, herein the reaction in THF, which otherwise had failed to work as a substrate in reported amino etherification reactions, worked well. DFT-calculated orbital energy levels and reaction profile support this reverse reactivity of singlet carbenes. Furthermore, HOMO–LUMO calculations indicated that electron-rich arenes in D–A carbene stabilizes the LUMO and destabilizes the HOMO which increases yield. Additionally, a library of 37 enol ether and 39 ether-linked compounds of potential medicinal relevance have been synthesized with good to excellent yields using numerous cyclic-1,3-diones.


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Key words

carbene chemistry - singlet carbene - DFT calculation - photochemical reaction

Carbene chemistry has laid to the foundation of numerous attractive areas of research with respect to organic transformation.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] Metal carbenoids generated from donor–acceptor (D–A) diazo compounds (like aryl diazoacetates) have been investigated extensively.[14–23] Aryl ring adjacent to carbene contributes as a donor moiety and the ester part imposes an electron-withdrawing effect to the carbene carbon thus constructing the acceptor moiety. The X-ray crystal structures of metal carbenoids and their corresponding intermediates unveiled the stereoelectronic nature of such species and subsequently strengthened the mechanistic proposals behind their reactivities.[24] In addition, DFT calculations along with experimental evidence have invigorated the fundamental chemistry of metal carbenoids.[25] [26] Among transition metals, rhodium carbenoid complexes are one of the most explored ones.[27] [28] [29] [30] [31] [32] [33] In the recent past, blue LED induced metal-free D–A carbenes have emerged as a promising tool towards the development of various synthetic transformations.[34] [35] [36] [37] [38] [39] [40] [41] [42] [43] However, one of the limitations of D–A singlet-carbene research is that these species are not stable enough to generate crystal structure. Consequently, theoretical prediction and experimental evidence complemented each other to elucidate mechanistic possibilities in most of the cases. However, in some reactions, even such approaches fail to explain their reactivity.

Bivalent singlet carbenes generated from photolysis of alkyl aryl diazoesters are sp2 -hybridized where spin-paired electrons are in a hybridized nonbonded sp2 orbital and the unhybridized p-orbital remains vacant.[44] Most of the singlet-carbene reactivities are explained by considering it as an electrophilic species similar to the metal carbenoids.[35] [36] [37] , [40] [42] In metal carbenoids the lone pair is coordinated with the transition metal leaving the p-orbital vacant.[24] However, singlet carbenes possess a lone pair (two spin-paired electrons in sp2 orbital) which creates an ambiguity about whether this could impart nucleophilicity to the carbene carbon contributing to the ambiphilic nature of singlet carbene or could the electrophilicity of carbene prevail due to the vacant p-orbital. Here lies the difference of metal carbenoid and carbenes and this contrasting electronic behaviour prompts them to react in a different way and at times antithetical to each other.

Reactivity of D–A carbene with the nucleophiles has been investigated in a number of reports.[36] [37] , [39] [40] [41] Most of them indicated that the lone pair at the nucleophiles (such as O or N etc.) attack the empty p-orbital of carbene generating O/N–H inserted products in a concerted manner. On the contrary, few reports demonstrated that nucleophiles like R–OH react with singlet carbenes through hydrogen bonding.[39] [45] Also in a number of recent reports, it has been shown that during the reaction with a cyclic ether the lone pair at O attacks the carbene to generate an oxonium ylide followed by a nucleophilic attack to the resulting ylide for further transformation.[46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58]

In this context there are some failed reactions where the underlying reason for the failure was not well understood. For example, Koenigs et al. and we had reported amino etherification reactions of aryl diazo esters with NFSI in ethereal solvents.[46] [48] The proposed mechanism involved the ylide-mediated pathway where the electron-poor aryl diazoesters worked better than their electron-rich counterpart. However, it could not explain the yield variation in the reaction with respect to substitutions at aryl moiety, and why the reaction worked with 1,4-dioxane but failed with tetrahydrofuran (THF). Recently Koenigs et al. had reported computational analysis of O–H functionalization of alcohols with D–A diazo esters under blue LED highlighting the possible reaction pathways.[45] In this context, as the crystal structure of a singlet carbene is not obtainable due to its highly reactive nature, visualizing structural parameters through computational calculation would be pertinent in carbene research specially to understand the unexplained reactivities of singlet carbene, which has not been revealed yet. Herein we have computationally investigated the unexplored electronic structure of metal-free D–A carbene, compared their structural features with Rh carbenoid crystal structure and correlated several structural parameters such as bond lengths, bond angles, dihedral angles, HOMO–LUMO localization, and orbital energy levels with experimental findings in terms of reactivity and yield variation. In this way, we tried to rationalize the apparently unorthodox trend of reactivity for cyclic ethers like 1,4-dioxane, THP, and THF in the ring-opening reactions with cyclic-1,3-diones in comparison to their general reactivity.

Table 1 Structural Comparison between Di-Rh Carbenoid A, Singlet Free Carbene B, and Carbocation C

Entry

Parameters

A

B

C

 1

C7–C6 bond length (Å)

1.406

1.407

1.372

 2

C7–C8 bond length (Å)

1.477

1.421

1.494

 3

C6–C7–C8 bond angle (°)

118.7

124.2

123.7

 4

C6–C7–M/H bond angle (°)

127.6

–

125.4

 5

C8–C7–M/H bond angle (°)

123.7

–

119.1

 6

C4–C5–C6–C7 dihedral

coplanar

coplanar

coplanar

 7

C6–C7–C7–O8 dihedral (°)

orthogonal

–84.6

–81.0

 8

C7–M/H bond with arene plane

coplanar

–

coplanar

 9

C1–C2 bond length (Å)

–

1.382

1.371

10

C4–C5 bond length (Å)

–

1.379

1.369

Earlier, Fürstner et al. had reported structural parameters of di-Rh carbene complexes based on their crystal structures.[24] We have revisited these findings and carefully compared them with our computationally optimized structure of D–A carbene (Table [1]). The important attributes are presented in Table [1]. As expected, many of the parameters were comparable between the metal carbenoid A and D–A carbene B which imparts similarity in reactions like cyclopropanation, cyclopropenation, C–H insertion, etc. For example, the arene moiety is coplanar with the carbene carbon (C7), suggesting maximal orbital overlap. It further indicated the donating nature of arene π-electron cloud to the empty p-orbital of carbene thereby constructing the major lobe of the LUMO (Figure S1 in the Supporting Information). In both the cases, these interactions resulted in the contraction of the C6–C7 bond (ca. 1.41 Å). However, there are some differences as well. The bond angle of C6–C7–C8 in B is 124.2° whereas it is 118.7° for A (Table [1], entry 3). Possibly, the bulky Rh–ligand complex resulted this with contraction in bond angle. Though, the carbonyl C=O bond lied almost orthogonal to the arene-carbene carbon plane in both the structures (Table [1], entry 7), interestingly the C7–C8 bond length in B (1.42 Å) is significantly shorter than the metal carbenoid (1.48 Å, Table [1], entry 2).

These findings indicate that in B the coplanar electron-rich aryl ring strongly stabilizes the empty p-orbital at C7 and the orthogonal position of C=O minimizes any electronic destabilizing effect which is similar to A. However, the lone pair at the C7 in sp2 orbital is delocalized to the carbonyl π-cloud which results in contraction of the C7–C8 bond length in metal-free carbene. This contraction is much less compared to A (1.48 Å) as the lone pair over C7 in A is coordinated with the π-acceptor metal complex. Thus, the singlet carbene differs from the metal carbenoids in two ways. First, the lone pair at the sp2 orbital of the singlet-carbene carbon is available to impart nucleophilic nature to the carbene at the same time it is delocalized to the adjacent carbonyl. Next, the contracted C7–C8 bond length exerts larger restricted rotation barrier in comparison to the di-Rh carbenoids which could contribute to the stereoselectivity in singlet-carbene reactions.

Next, while examining the HOMO orbital delocalization of B, we found that the HOMO major lobe is also delocalized majorly around the C7 carbon (Figure S1).

Thus, the delocalization of both the major lobes of HOMO and LUMO of the whole molecule over same C7 induce the diametric nature of singlet carbene. We tested this using electronically different substituents at different positions over the phenyl ring of B (electron-donating substitutions: o-methyl, p-tertiary butyl; withdrawing substitutions: m-fluoro and p-fluoro). Interestingly, in all cases this orbital delocalization was similar (Figure S1). We examined the structural features in the energy-optimized structures of other differently substituted singlet carbenes (Figure S2 and Table S1 in the Supporting Information). We observed similar bond distances, bond angles, and dihedral angles in all cases. However, the bond lengths between C6–C7 were slightly contracted in singlet carbenes with electron-donating substituents (B_2f, B_2k′, B_2r, B_2k, B_2e) compared to electron-withdrawing substitutions (B_2c, B_2d, B_2g, B_2i, B_2y) at the arene moiety. This could possibly result from larger stabilization of empty p-orbital at C7 by more electron-rich arenes. The bond lengths between C7–C8 are almost constant in all cases (ca. 1.42 Å) even with bulky ester substitutions like in B-2r, B_2k, B_2w (Table S1 and Figure S2).

Zoom Image
Scheme 1 Scope and yield trend in OH-insertion and ether-linking reaction

Now, to explore the ambiphilic nature of carbene we reacted dimedone 1a with aryl diazo esters in ethyl acetate and cyclic ethers as solvent. We have chosen such reaction because it is known that the singlet carbene reacts with alcohol functionality by protonation and H-bond formation[45] (nucleophilic activity of carbene), and on the other hand, with cyclic ethers like 1,4-dioxane form ylide (electrophilic reactivity of carbene) which subsequently react with suitable nucleophile (like O- or N-containing species) to undergo ring-opening reactions to generate ether-linked products.[46] [48] Dimedone was chosen as it is a nucleophile and also, in its enol form there is an H-bond donor (–OH) which could complement the nucleophilicity of the singlet carbene.

When we performed the reaction in ethyl acetate as solvent, we observed formation of the OH insertion products 4a–x, 5a–i, 6a–d, where electron-donating substitutions in the phenyl ring of 2 produced higher yields compared to electron-withdrawing substitutions (Scheme [1]). Next, we analyzed and explored the etherification reactions in tetrahydrofuran (THF, 3a), tetrahydropyran (THP, 3b), and 1,4-dioxane (3c). Accordingly, when we reacted 1a with numerous aryl diazoesters 2 (Scheme S1 in the Supporting Information) in 3a as solvent, the ether-linked products 7a–w were obtained exclusively in high yield. This was contrary to the earlier reports by Koenigs et al. and by us where similar reactions in THF failed to generate the desired products.[46] [48] We explored the scope of this reaction using different types of substituents at the para, meta, and ortho position of the aryl moiety at 2. The reaction was also performed with diverse methyl, ethyl, benzyl, and cyclohexyl ester at the aryl diazoacetate 2 (Scheme S1). Herein, we observed opposite trends in yields with respect to the electronic nature of the substituents as observed in earlier reports.[46] [48] Electron-donating groups at the phenyl ring (7a,c,d,h,n–t in Scheme [1]) favored the reaction over the electron-withdrawing groups (7e,f,j,l,v,w in Scheme [1]) as seen in OH-insertion reactions.

Next, the reactions were conducted in 3b and 3c (the reported solvents for successful amino etherification reactions) and in 2-methyl THF (3d). Interestingly, the reaction in 3b afforded both the 4a and 7x in a ratio of 5:4. With 3d the ether-linked product 7y was obtained in 50% yield but with 3c no formation of ether-linked product was observed, however, the OH-inserted product was formed with 62% yield. Reactions with cyclohexane dione 1b and cyclopentane dione 1c with 2 in THF provided exclusive ether-linked products 8a–i and 9a–e (Scheme [1]) in high yields. It is noteworthy here, when stochiometric amount of 3a was added to the reaction of 1a and 2a in ethyl acetate, ca. 50:50 ratio of 4a:7a were obtained. Therefore, unlike the previous reports, herein we observed that electron-rich aryl diazoacetates favored the reaction over their electron-poor counterparts, and the ring opening of THF happened exclusively, whereas, in 1,4-dioxane only formation of enol ether (4a) happened (no ring-opened product).

To investigate this further, we explored the HOMO–LUMO energy gap of the reactants with respect to their reactivity (Figure [1]). Interestingly, we found a decrease in reactivity towards the desired product formation when there was a decrease in the orbital energy gap (3.59 eV to 3.26 eV) between the HOMO of cyclic ethers 3a–c and the LUMO of the singlet carbene B_2a (carbene from 2a). It is noteworthy that in the reported mechanism for the amino etherification reaction the formation of oxonium ylide happened via the attack of 1,4-dioxane at the empty p-orbital of the carbene and subsequent nucleophilic attack prompted the ring opening. However, in Figure [1] we can see that the gap between the HOMO (of 3a) and the LUMO (of B_2a) is highest in case of THF (3a). This explains why THF was not productive in earlier reports. Furthermore, when we assessed the orbital energy gap between the HOMO of singlet carbenes with respect to the substitutions at the arene moiety (electron-rich B_2k, B_2e, neutral B_2a, and electron-poor B_2d, B_2c, and B_2y) and the LUMO of 1a, we found that the yield increased with decrease in orbital energy gap in both enol functionalization and etherification reaction (as in 4k,e and 7a,d). This strongly indicates that in both the cases, the reaction is proceeding through the interaction between the HOMO of B (consisting of lone pair at C7) and the low-lying LUMO of 1a (in the O–H bond of 1a-enol) which result in the formation of cationic intermediate C in both enol functionalization and ether linking. Therefore, electron-rich arenes destabilize the HOMO (HOMO energy rises, Figure [1]), making the carbene more nucleophilic, and stabilize the LUMO (C7–C6 bond contracts as shown earlier, Table S1). This facilitates the reaction towards higher yields (Scheme [1]).

Zoom Image
Figure 1 Hydrogen bonding and formation of benzylic carbocation C

To support the reaction mechanism, we performed solvent-phase DFT calculations of a possible reaction pathway (Figures S3 and S4 in the Supporting Information). From the DFT calculations it could be stipulated that the lone pair of carbene (HOMO) attacks the O–H bond LUMO in 1a to generate a carbocation C as depicted in Table [1]. This is an electrophile (unlike the diametric carbene B in Table [1]) which is being attacked by either 3a or 1a-anion to generate the desired product 7a or 4a. In the absence of 3a the reaction proceeds towards exclusive formation of 4a (Figure S3 in the Supporting Information, Scheme [1]). When 3a was present in excess (as solvent), the reaction favors toward formation of 7a. We observed elongation of the C7–C8 bond length when C7 was engaged in hydrogen bonding with 1a, while the C7–C6 bond was not altered (Figure [2]). The coplanarity of carbenes with the arene ring remained intact. This indicated the extended stabilization of sp2 carbene’s empty p-orbital by arene π-cloud. As observed in the structural parameters of C (Table [1] and Figure [2]), the C7–C6 bond has contracted more in C (1.37 Å) compared to that of B (1.41 Å), and also the C7–C6 bond length in C is similar to that of C1–C2 and C4–C5 bond lengths (Figure [2] and Table [1]). This suggested that the cationic charge at C7 is highly stabilized by the aromatic π-electron cloud forming a benzylic carbocation resembling a resonance structure C (Figure [2]). The extent of this stabilization is more with electron-rich arene rings and less among electron-poor arene rings, as predicted and perceived through the yields of 7a,c,d,h,i,n–t where methyl, tert-butyl, and methoxy substitutions at the phenyl ring provided better yields compared to 7j–l,v,w with fluoro, chloro, trifluoromethyl, and nitro substitutions (Scheme [1]). It is noteworthy that the orthogonal orientation of ester carbonyl should be imposing least effect on the empty p-orbital of C7 of B and C (Table [1]). This is further corroborated in Scheme [1], where different esters at 2 did not contribute to any notable yield variation.

Zoom Image
Figure 2HOMO–LUMO analysis of reactants with respect to yield variation (B_2: carbene generated from 2; for corresponding structures refer to Schemes S1 and S2 in the Supporting Information)

In summary, we have discussed the structural parameters of D–A singlet carbenes via DFT calculation, compared them with di-Rh carbenoids (based on their crystal structure data from literature) and correlated those parameters with experimental findings in terms of reactivity and yield. In the reactions of singlet carbene with cyclic 1,3-diones in different ethereal solvents such as THF, THP, and 1,4-dioxane, a different trend in reactivity was observed from the previously reported ether-linking reactions. Computational calculation including the HOMO–LUMO analysis established mechanistic rationale for such reactivities where nucleophilicity of carbene prevails to generate benzylic carbocation intermediate through H-bonding with enol of cyclic 1,3-diones, which further explains the yield variation with respect to substitutions in D–A carbenes. Electron-rich arene in D–A carbene stabilizes the LUMO and destabilizes the HOMO which improves the yield. This work provides a structural basis for the unique electronic nature of donor–acceptor singlet carbene which would help chemists to construct newer mechanistic insights and synthetic applications. Additionally, 76 new compounds of biological interests were synthesized in good to excellent yields.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

S. Singh and D.M. are thankful to Shiv Nadar Institution of Eminence, deemed to be University for funding and facility. Authors are thankful to Magus Supercomputing Facility of HCL technologies Ltd for computational works. D.M. is thankful to Dr Ranajit Das and Dr Sayantan Maity for assisting in computational calculation.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2153-6819.
  • Supporting Information

Corresponding Authors

Subhabrata Sen
Dept. of Chemistry, School of Natural Sciences, Shiv Nadar University
Tehsil Dadri, Gautam Buddha Nagar, U.P. 201314
India   

Debajit Maiti
Dept. of Chemistry, School of Natural Sciences, Shiv Nadar University
Tehsil Dadri, Gautam Buddha Nagar, U.P. 201314
India   

Publication History

Received: 07 July 2023

Accepted after revision: 14 August 2023

Accepted Manuscript online:
14 August 2023

Article published online:
28 September 2023

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Zoom Image
Scheme 1 Scope and yield trend in OH-insertion and ether-linking reaction
Zoom Image
Figure 1 Hydrogen bonding and formation of benzylic carbocation C
Zoom Image
Figure 2HOMO–LUMO analysis of reactants with respect to yield variation (B_2: carbene generated from 2; for corresponding structures refer to Schemes S1 and S2 in the Supporting Information)