Theoretical Insight towards Mechanism, Role of NHC and DBU in the Synthesis of Substituted Quinolines

A plausible mechanism for the conversion of aldimine to 2‐phenyl‐4‐difluoromethylquinoline catalyzed by N‐heterocyclic carbene (NHC) in association with 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) is investigated in detail by using density functional theory (DFT) method. Six significant stages are proposed to be involved in the whole catalytic cycle, starting from the generation of NHC followed by its nucleophilic interaction with the carbon atom of C‐N in aldimine to generate corresponding aza‐Breslow intermediate. This aza‐Breslow intermediate further undergoes intramolecular umpolung addition followed by several proton transfers to regenerate the NHC along with 2‐phenyl‐4‐difluoromethylquinoline. The role of NHC in this intramolecular umpolung addition of aza‐Breslow intermediate has been investigated by using conceptual DFT. Apart from NHC; the role of DBU in this catalytic cycle has also been monitored carefully. These theoretical findings are in good agreement with experimental results and also provide a deeper insight into the mechanism of NHC catalyzed synthesis of 2‐phenyl‐4‐difluoromethylquinoline.

Keywords: Aldimine; aza-Breslow intermediate; DBU; NHC; 2-Phenyl-4-difluoromethylquinoline

A detail mechanistic investigation on N‐heterocyclic carbene (NHC) catalyzed synthesis of 2‐phenyl‐4‐difluoromethylquinoline from aldimine has been performed by using density functional theory (DFT) method. The proposed catalytic cycle is found to be comprised of six significant stages through the formation of an aza‐Breslow intermediate. Catalyst NHC and the base 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) have been cooperatively participated to accomplish this reaction efficiently.

Introduction

N‐heterocyclic carbenes (NHCs) have witnessed extraordinary growth in the field of catalysis, because of their versatile synthetic utility and excellent catalytic efficiency. Designing asymmetric catalyst capable of rendering nucleophilic aldehydes has been a fascinating area of research for last few decades, which leads to the discovery of NHC. First stable NHC was isolated by Arduengo et al.[1] in the year 1991. In NHCs, carbene carbon is located on a N‐heterocyclic ring residue and contains one unshared pair of electrons along with unhybridized empty p‐orbital. This unshared pair of electrons is mainly responsible for its σ‐donation capability, whereas the unhybridised empty p‐orbital is capable of accepting electron pair, which allows the development of new transformation based on polarity reversal or umpolung reactivity. NHCs find importance as organocatalyst because of their numerous potential applications, like, pronounced nucleophilicity, tunable electronic properties and potential as leaving groups. NHCs have extensive applications because of their ability to catalyze carbon‐carbon and carbon‐hetero atom bond formation in the synthesis of various important five and six member heterocyclic moties. In organic chemistry, two very important reactions such as Stetter reaction (1,4‐addition of an α,β‐ unsaturated carbonyl compounds) and Benzoin reaction (1,2‐addition of a carbonyl compound) are known to be catalyzed by NHCs. In the year 2006, Fu et al.[15] for the first time, used the NHCs in intramolecular umpolung organocatalysis towards various Michael acceptors. However, similar intermolecular umpolung activity was noticed separately by Glorius[16] and Matsuoka.[17] Umpolung efficiency of NHCs is mainly governed by the generation of various acyl anion equivalents called Breslow intermediates developed by Breslow in the year 1958.[18] Since then, various NHCs derived form triazolium, imidazolium and thiazolium salts have been employed in a variety of organic reactions.[19] In recent years, different types of Breslow intermediates have been developed with efficient organocatalytic activity. Jacobi von Wangelin developed deoxy‐Breslow intermediates by the addition of NHCs to alkyl halides but their catalytic activities are still not known. However, addition of NHCs to aldimine type of compounds, lead to the generation of aza‐Breslow intermediates. This type of intermediate was first developed by Douthwaite[23] in the year 2009 and found its potential application in the synthesis of important nitrogen containing heterocyclic moties like indoles. However, first aza‐Breslow intermediate was isolated by Rovis group[24] in the year 2012.

This report is mainly based upon mechanistic exploration in the in situ generation of aza‐Breslow intermediate and its efficiency in umpolung activity. On the basis of experimental results reported by Biju et al.[25] the model reaction used in this DFT investigation is mentioned in Scheme .

Catalytic cycle of Scheme  is represented in Scheme  and this catalytic cycle is initiated by nucleophilic attack of NHC to imine carbon of aldimine leads to the formation of a zwitterionic intermediate INT 1. INT 1 is further converted to aza‐Breslow intermediate INT 2 followed by intramolecular nucleophilic addition reaction to form another intermediate INT 5. INT 5 regenerates the catalyst NHC along with final product (2‐phenyl‐4‐difluoromethylquinoline) via several proton transfer steps. However, exact mechanism of this reaction remains elusive and several mechanistic questions are still remains unclear. For example: (1) How DBU plays a crucial role in the generation of key aza‐Breslow intermediate? (2) How NHC is responsible for umpolung activity? (3) What are the mechanism for protonation and deprotonation of several intermediates? Thus, it is very desirable to explore the mechanistic insight of this model reaction and answer these important questions by using DFT method. These investigations help to develop a generalized pathway for organocatalytic reaction involving aza‐Breslow intermediate.

The reported aldimine derived 2‐phenyl‐4‐difluoromethylquinoline is very attractive in biological research because of the presence of CF2H group. The impending biological properties of 2‐phenyl‐4‐difluoromethylquinoline is due to its H‐bond‐donor capability and high lipophilicity. On the contrary, some other important pharmacologically active chiral heterocyclic compounds can also be developed via several NHC‐catalyzed intermolecular [n + 2] (n=2, 3, and 4) cycloaddition/annulation reactions. Donghui et al. have performed numerous DFT investigations in order to understand their mechanisms and predicted the origin of chemo‐selectivity and stereo‐selectivity.

Computational Details: In this work, all the stationary points have been optimized by using Gaussian 09[34] software package at M06‐2X/6‐31G(d,p) level of theory (Level A). The transition states in this reaction are optimized by using Berny algorithm.[38] On the other hand, in order to confirm whether the stationary point is a transition state or a minimum, vibrational frequency for each stationary point has been evaluated at the same level. Each transition state has exhibited one and only one imaginary frequency, while minima are devoid of any imaginary frequencies. Furthermore, intrinsic reaction coordinate (IRC) calculations at the same level of theory ensure that the transition states are connected to two predictable minima. Afterward, energies of various intermediates and transition states are refined via single‐point calculation with M06‐2X/6‐311++G(d,p) level of theory (Level B) in N, N‐dimethyl formamide (ϵ=36.7) solvent at 1000 C by using IEF‐PCM solvent model. Finally, corrected Gibbs free energies are used in the following discussion.

Conceptual DFT (CDFT) based global electrophilicity index,[43] has been calculated by using the expression, ω=(μ2/2η), where, "μ" is chemical potential and "η" is chemical hardness. Both these parameters "μ" and "η" can be derived by calculating HOMO (ϵH) and LUMO (ϵL) energies, i. e. μ=1/2(ϵH + ϵL) and η=ϵL ‐ ϵH, respectively. On the other hand, nucleophilicity index, "N " defined as, N=ϵHOMO (Nu) ‐ ϵHOMO (TCE) was introduced by Domingo et al. Tetracyanoethylene (TCE) is considered as a reference compound, because in the context of polar reactions, it has lowest HOMO energy among a large series of compounds. Local reactivity parameters such as, local nucleophicity index, "Nk"[49] and local electrophilicity index, "ωk"[50] have also been determined by using the mathematical expressions, Nk=N Pk− and ωk=ω Pk+, where, Pk− and Pk+ are the calculated local electrophilic and local nucleophilic Parr functions. All the three dimensional structures represented in this report are developed by using CYL‐view.[53]

Results and Discussion

Catalytic mechanism for the formation of 2‐phenyl‐4‐difluoromethylquinoline

In organic chemistry "Umpolung" activity is one of the most vital strategies for the formation of various traditional bonds in an unconventional fashion. A number of NHC catalyzed organic reactions are known that precedes via umploung strategy like Benzion condensation, Stetter reaction, cycloaddition and annulation reactions etc. Umpolung activities of these catalytic cycles originate from the nucleophilic addition of NHCs to various organic molecules such as, aldehydes, ketones, ketenes etc. Our reported reaction for the development of 2‐phenyl‐4‐difluoromethylquinoline also proceeds via umpolung strategy but this umpolung activity originates from the nucleophilic addition of NHC to an aldimine. The catalytic cycle of this reaction comprises of six significant stages. First stage is the in situ generation of NHC from its precursor Pre‐NHC by using DBU, second stage is the nucleophilic addition of this NHC to C3 atom of reactant R, leads to the formation of a zwitterionic intermediate INT 1, third stage is the development of aza‐Breslow intermediate INT 2 form zwitterionic intermediate INT 1, INT 2 is the origin of umpolung activity in this catalytic cycle. Fourth stage of this catalytic cycle is the intramolecular umpolung addition of INT 2 to carbon centre C6 of R, fifth stage is the regeneration of NHC catalyst to initiate another catalytic cycle and finally sixth stage is the formation of product PR (2‐phenyl‐4‐difluoromethylquinoline). All these involved stages are discussed briefly in the following sections.

Stage‐1: Generation of catalyst NHC to initiate the catalytic cycle

This stage of catalytic cycle is based upon the in situ generation of NHC from its precursor Pre‐NHCvia abstraction of H2+ from carbon atom C1 of Pre‐NHC in presence of base DBU. This step proceeds through the transition state TS 1 with activation energy of 6.9 kcal/mole and corresponding C1−H2 and H2−DBU bond distances are 1.332 and 1.349 Å, respectively. Mechanistic representation and relative Gibbs free energy (kcal/mol) profile of this stage is shown in Scheme  and Figure , respectively.

Stage‐2: Initiation of catalytic cycle

Catalytic cycle of this reported reaction initiates with the nucleophilic addition of in situ generated NHC to reactant R. Three possible sites are present in the reactant R for the nucleophilic addition of NHC, viz. Site‐1, Site‐2 and Site‐3. Site‐1 represents the nucleophilic attack of NHC to carbon centre C3 of reactant R. On the other hand, Site‐2 and Site‐3 indicates the addition of NHC to carbon centre C6 and C7 respectively, as shown in Scheme . In order to identify the most preferable site of attack, Parr function (Pk+) of C3, C6 and C7 atoms are calculated and are found to be 0.26, 0.02 and 0.00, respectively. This finding clearly suggests that C3 is the most preferred and C7 is the least preferred site for the nucleophilic addition of NHC to R. Hence, Site‐3 is excluded, while, relative free energy change involved in the development of transition states and intermediates due to nucleophilic attack at Site‐1 and Site‐2 are evaluated. Mechanism of nucleophilic addition of NHC through Site‐1 and Site‐2 and the corresponding energy profile diagram is presented in Figure .

Optimized structures of all the stationary points with their selected geometrical parameters involved in most favorable pathway are presented in Figure  and the remaining stationary points are depicted in SI 2. In case of Site‐1, C1−C3 bond distance is reduced from 2.001 Å in TS 2 to 1.521 Å in INT 1 (Figure ), whereas, for Site‐2, C1−C6 bond distance is decreased from 1.990 Å in TS 2′ to 1.502 Å in INT 1′ (SI 2). Variation of bond lengths suggests that C1 atom of NHC can form bond with either C3 atom or C6 atom of R.

Relative energy profile diagram (Figure ) suggests that Site‐1 is more preferred site for the nucleophilic addition of NHC in comparison to Site‐2. Since, Site‐1 has activation energy barrier of 17.6 kcal/mol, which is smaller than the activation energy barrier (22.0 kcal/mol) for Site‐2. This difference in energy barrier is further confirmed by global electron density transfer (GEDT)[54] analysis (represented in SI 3). GEDT values for TS 2 and TS 2′ are found to be 0.38e and 0.29e, respectively. These values also suggest that TS 2′ has comparatively higher energy than TS 2, since, higher is the value of GEDT lower will be the energy of transition state and vice versa. Hence, DFT evaluated Parr function, Gibbs free energy profile and GEDT values imply that the nucleophilic addition of NHC to reactant R occurs smoothly through Site‐1 under experimental reaction conditions.

Stage‐3: Formation of aza‐Breslow intermediate

This stage of catalytic cycle is associated with the generation of key intermediate i. e. aza‐Breslow intermediate INT 2, which is responsible for "Umpolung" activity. The intermediate INT 2 is generated from the zwitterionic intermediate INT 1via direct (Path‐1) or DBU assisted proton transfer steps (Path‐2 and Path‐3). Path‐1 involves direct [1, 2]‐proton shift through a cyclic three membered transition state TS 3, while, path‐2 and path‐3 represent bimolecular proton transfer pathways assisted by protonated DBU (DBU‐H2+, which is generated during the formation of NHC from its precursor Pre‐NHC) and free DBU, respectively as shown in Scheme . Path‐1 is found to proceed with higher activation energy barrier in comparison to other two pathways (Path‐2 and Path‐3). Highly strained three membered cyclic transition state makes the Path‐1 energetically unfavorable. Detail discussion of these three pathways is given in the following sections:

• Path‐1: Path‐1 of this stage represents direct [1, 2]‐proton shift in _B_INT 1 to generate INT 2 through a cyclic three membered transition state TS 3 (Scheme ). Optimized geometries of all the stationary points involved in this pathway are shown in Figure  and SI 2. It has been observed that C3−H5, N4−H5 and C3−N4 bond distances in the case of TS 3 are 1.193, 1.371 and 1.527 Å, respectively. These results attested the formation of a cyclic three membered ring structure in TS 3. This strained cyclic structure results a high activation energy barrier of 52.7 kcal/mol, which infers the least possibility of H5+ proton transfer through this pathway under experimental reaction conditions. The relative energy profile diagram for Path‐1 is shown in Figure 

. Not only strained structure but also charge separation in TS 3 plays some crucial role in its instability. However, transfer of H5+ proton through this cyclic three membered TS 3 to generate the aza‐Breslow intermediate (INT 2) can be avoided with the incorporation DBU‐H2+ or DBU.

• Path‐2: This pathway represents the generation of _B_INT 2 from INT 1viaDBU‐H2+ assistance as shown in Scheme . This pathway is a two step processes, first step involves deprotonation of DBU‐H2+ or protonation of N4− to neutralize the negative charge on N4 atom, followed by the abstraction of H5+ by free DBU to generate INT 2 along with DBU‐H5+. First step leads to the transformation of INT 1 to INT 3 with barrierless activation energy and second step involves abstraction of H5+ from INT 3via transition state TS 4 (activation energy 10.7 kcal/mol) to generate the important intermediate INT 2. DFT derived important geometrical parameters of all the stationary points involve in this pathway are given in Figure  and the energy profile diagram is shown in Figure .
• Path‐3: This pathway involves free _B_DBU assisted transformation of INT 1 to INT 2. Path‐3 is also comprised of two elementary steps. First, abstraction of H5+ by free DBU to generate intermediate INT 4 and DBU‐H5+, followed by the neutralization of N4− in INT 4 by DBU‐H5+ to get back the free DBU and leads to the formation of required INT 2. Conversion of INT 1 to INT 4 proceed via transition state TS 5 with activation energy barrier of 32.878 kcal/mol, while, the second step involves the conversion of INT 4 to INT 2 with a barrierless reaction path. Important geometrical parameters of all the stationary points involves in this pathway evaluated at M06‐2X/6‐31G(d,p) level and the relative free energy profile diagram are given in SI 2 and Figure , respectively.

On detail comparison of energy profile diagrams derived from DFT calculation (Figure ) revealed that among the three possible pathways of Stage‐3, i. e. in the conversion of INT 1 to INT2, Path‐1 is least feasible because of higher activation barrier. On the other hand, DBU‐H2+ assisted pathway (Path‐2) in the formation of aza‐Breslow intermediate (INT2) from corresponding zwitterionic intermediate (INT 1) is found to be energetically more favorable in comparison to free DBU assisted pathway (Path‐3).

Stage‐4: Intramolecular umpolung addition of aza‐Breslow intermediate (INT 2)

Intramolecular umpolung addition of INT 2 to an unsaturated carbon centre C6 of the reactant R leads to the formation of a six membered cyclic intermediate (INT 5) shown in Scheme , with the subsequent release of a fluoride ion (F9− ion). This reaction requires an activation energy barrier of only 9.9 kcal/mol (TS 6). C3−C6 bond length evaluated at M06‐2X/6‐31G(d,p) level in the cases of TS 6 and INT 5 are found to be 1.993 and 1.549 Å, respectively. It is further seen that on the formation of C3−C6 bond, C8−F9 bond distance is elongated to 1.371 Å without affecting C8−F10 and C8−F11 distances. This elongation of C8‐F9 bond leads to the generation of F9− ion and this F9− ion further acts as a base in order to regenerate the NHC catalyst again to initiate next catalytic cycle. Schematic representation and relative free energy profile diagram of Stage‐4 are shown in Scheme  and in Figure , respectively.

Stage‐5: Regeneration of NHC catalyst

This particular stage is one of the most important stages of the entire catalytic cycle because of its involvement to regenerate the NHC catalyst along with the formation of INT 6. It proceeds through transition state TS 7, where, the released F9− ion abstract the H2/5+ atom attached with N4 atom of INT 5 and subsequently leads to the cleavage of C1−C3 bond (elongated from 1.544 Å in INT 5 to 2.103 Å in TS 7). As a result, free NHC is being released along with the formation of intermediate INT 6 and HF. H−F bond distance is shortened from 1.148 Å in INT 5 to 0.995 Å in TS 7 and finally 0.921 Å in liberated HF. Activation energy barrier of this transformation is found to be 2.7 kcal/mol (TS 7), which can easily be overcome under experimental reaction conditions. Calculated energy barrier suggests that the NHC catalyst acts as a very good leaving group. Schematic representation and energy profile diagram of Stage‐5 is presented in Scheme  and in Figure , respectively.

Stage‐6: Formation of 2‐phenyl‐4‐difluoromethylquinoline (PR)

Stage‐6 shows the conversion of intermediate INT 6 into final product PR. Similar to Stage‐3, Stage‐6 also involves proton transfer suggesting two pathways. Path‐1 involves direct proton transfer from C6 to C8 atom of INT 6, whereas, Path‐2 represents a bimolecular reaction mechanism of proton transfer assisted by DBU. Path‐1 proceeds via a strained cyclic four membered transition state TS 8 with activation energy of 60.7 kcal/mol (TS 8), and it is found to be least feasible under experimental reaction conditions. However, this high energy pathway can be avoided if the proton transfer is carried out in the presence of DBU (Path‐2). This DBU assisted proton transfer comprises of two steps, first, free DBU abstracts a proton (H12+) from C6 to form an intermediate INT 7 and DBU‐H12+, this step proceeds through the transition state TS 9 with a very low activation energy barrier (3.6 kcal/mol). In second step, DBU‐H12+ gets deprotonated by releasing H12+ to C8 with almost barrierless transition state TS 10 (0.1 kcal/mol). Thus, product PR is generated along with the regeneration of free DBU. Detail mechanistic representation and the relative free energy profile diagram derived from DFT method is given in Scheme  and Figure , respectively. Free energy profile diagram clearly reveals that Path‐2 of Stage‐6 is energetically more favorable in comparison to Path‐1. Therefore, it can be mentioned that DBU assisted pathway (Path‐2) is more prominent for conversion of intermediate INT‐6 to final product PR (2‐phenyl‐4‐difluoromethylquinoline).

DFT investigations confirm that the NHC catalyzed synthesis of 2‐phenyl‐4‐difluoromethylquinoline is composed of six significant stages, however, catalytic cycle mainly initiates from Stage‐2 after the generation of NHC from Stage‐1. The complete catalytic cycle of this model reaction is shown in Scheme , optimized geometry of all the stationary points with their selected geometrical parameters are mentioned in Figure  and SI 2. While, relative free energy profile diagram for the entire catalytic cycle is presented in Figure .

Role of NHC

It has been observed from experimental results that NHC has ability to invert the polarity of aldimine via the formation of aza‐Breslow intermediate. CDFT investigations suggest that NHC has much higher global nucleophilicty (N=3.23 eV) in comparison to global electrophilicity (ω=0.61 eV) (Table ). On the other hand, it is seen that substrate R may act both as electrophile and as nucleophile on the basis of calculated electrophilicity (ω=1.19 eV) and nucleophilicity (N=3.19 eV) values. Furthermore, local electrophilicity (ωk) and local nucleophilicity (Nk) of atoms C3 and C6 of R are found to be 0.31, −0.06 eV and 0.02, 0.22 eV, respectively (Table ). Therefore, in comparison to C6 atom, NHC prefers to attack at C3 atom of the substrate R. Again, DFT evaluated electrophilicity (ω) and nucleophilicity (N) of the aza‐Breslow intermediate (INT 2) are 0.47 and 5.17 eV, respectively. It is noticed that nucleophilic attack of NHC to the substrate R not only reduced the electrophilicity but also significantly increased the nucleophilicity of the generated aza‐Breslow intermediate (INT 2). Thus, aza‐Breslow intermediate acts a better nucleophile and favors to attack other electrophiles. On the contrary, local electrophilicity (ωk) and local nucleophilicity (Nk) values on C3 atom of INT 2 are calculated to be −0.02 and 2.79 eV, respectively, whereas, same quantities of C6 atom are 0.08 and 0.16 eV, respectively. These values revealed that on formation of INT 2, the polarity of C3 atom is significantly altered. Thus, the nucleophilicity of C3 atom in aldimine can be significantly enhanced upon addition of NHC to that atom.

Electronic chemical potential (μ, in a.u.), chemical hardness (η, in a.u.), global electrophilicity (ω, in eV), global nucleophilicity (N, in eV) for NHC, R and aza‐Breslow intermediate (INT 2).

	μ	η	ω	N
NHC	‐0.1174	0.3066	0.61	3.23
R	‐0.1478	0.2485	1.19	3.19
INT 2	‐0.0890	0.2286	0.47	5.17

DFT derived Parr functions (P k + and P k −), local electrophilicity (ω k, in eV), and local nucleophilicity (N k, in eV) for R and aza‐Breslow intermediate (INT 2).

	Pk+	Pk−	ωk	Nk
R (C3)	0.26	−0.02	0.31	−0.06
R (C6)	0.02	0.07	0.02	0.22
INT 2 (C3)	−0.04	0.54	−0.02	2.79
INT 2 (C6)	0.17	0.03	0.08	0.16

Role of 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU)

It has been observed that the base DBU plays an important role in entire catalytic cycle for the synthesis of 2‐phenyl‐4‐difluoromethylquinoline. Firstly, DBU participates in the reaction to generate the active catalyst NHC from its precursor Pre‐NHC by abstracting H2+via transition state TS 1 which leads to formation of DBU‐H2+. This DBU‐H2+ further participates in proton transfer steps to generate the most important aza‐Breslow intermediate INT 2. Careful analysis of Stage‐3 revealed that generation of INT 2 from zwitterionic intermediate INT 1 proceeds predominantly through DBU‐H2+ assisted pathway (Path‐2) in comparison to direct (Path‐1) and DBU assisted pathway (Path‐3). This DBU‐H2+ assisted proton transfer comprised of two steps, first, protonation at N4− of INT 1, proceeds with barrierless activation energy. Second, abstraction of H5+ by free DBU to form INT 2viaTS 4 with activation energy barrier of 10.7 kcal/mol. On the other hand, direct proton transfer pathway (Path‐1) is a single step process proceeds with an activation energy barrier of 52.7 kcal/mol (TS 3), while, DBU assisted proton transfer (Path‐2) comprises of two elementary steps, one goes through transition state TS 5 with activation energy of 32.8 kcal/mol and other one is barrierless. All these DFT evaluated results confirmed that DBU‐H2+ significantly lowered the activation energy in the proton transfer reaction to form aza‐Breslow intermediate INT 2 from INT 1. Again, in Stage‐6, DBU assisted proton transfer is found to be more energetically favorable over direct proton transfer to generate desired product PR. Similar to Stage‐3, in this stage also DBU assisted pathway is comprised of two steps, first, DBU abstract the proton H12+ from INT 6 through the transition state TS 9 with an activation energy barrier of 3.6 kcal/mol and second, DBU‐H12+ gets deprotonated through an activation energy barrier of 0.1 kcal/mol (TS 10) to form the product PR. On the contrary, direct proton transfer pathway needs much higher activation energy of 60.7 kcal/mol (TS 8). Therefore, it can be confirmed that additive DBU contributes significantly in this catalytic cycle and plays crucial roles in the formation of product PR (2‐phenyl‐4‐difluoromethylquinoline).

Conclusion

In this work, a most probable catalytic mechanism for NHC catalyzed conversion of aldimine to 2‐phenyl‐4‐difluoromethylquinoline is proposed by utilizing DFT method. DFT evaluated results suggest that the whole catalytic cycle is composed of six significant stages, starting from the generation of NHC from its precursor followed by the nucleophilic attack of NHC to unsaturated imine carbon of aldimine to generate zwitterionic intermediate INT 1, which then undergoes proton transfer reaction under the assistance of DBU‐H2+ to form corresponding aza‐Breslow intermediate INT 2. INT 2 then involves in intramolecular umpolung addition followed by several proton transfer steps to regenerate the NHC catalyst along with the formation of 2‐phenyl‐4‐difluoromethylquinoline. Global and local CDFT derived reactivity parameters confirm the role of NHC towards umpolung activity. DBU also found to play significant role in several proton transfer steps of the proposed catalytic cycle. Findings of this investigation are not only in good agreement with the experimental observations but also provide a detail understanding about the mechanism of this type of reaction to generate various other heterocyclic moieties.

Supporting Information Summary

Supporting information includes the most energetically favorable catalytic cycle of reported reaction (SI 1), DFT optimized structure of stationary points except most favorable pathways (SI 2), GEDT analysis of TS 2 and TS 2′ (SI 3) and absolute energies (SI 4) of all the optimized stationary points involved in this work along with their Cartesian coordinates (SI 5).

Acknowledgements

Author (AS) thanks Department of Science and Technology, New Delhi, India for the INSPIRE fellowship. PM thanks Science and Engineering Research Board, New Delhi, India for project grant (SERB/F/10750/2017‐2018).

Conflict of interest

The authors declare no conflict of interest.

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GRAPH: Supplementary

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