Ligand‐Mediated Regioselective Rhodium‐Catalyzed Benzotriazole–Allene Coupling: Mechanistic Exploration and Quantum Chemical Analysis

Abstract The ligand‐controlled rhodium‐catalyzed regioselective coupling of 1,2,3‐benzotriazoles and allenes was investigated by DFT calculations. Because allylation can occur at either the N1 or N2 position of the 1,2,3‐benzotriazole, the complete Gibbs free energy profiles for both pathways were computed. A kinetic preference emerged for the experimentally observed N1 allylation with the JoSPOphos ligand, whereas N2 allylation was favored with DPEphos. Analysis of the regiodetermining oxidative addition step by using the activation strain model in conjunction with a matching energy decomposition analysis has revealed that the unprecedented N2 reaction regioselectivity is dictated by the strength of the electrostatic interactions between the 1,2,3‐benzotriazole and the rhodium catalyst. The nature of the electrostatic interaction was rationalized by analysis of the electrostatic potential maps and Hirshfeld charges: a stabilizing electrostatic interaction was found between the key atoms involved in the oxidative addition for the N2 pathway, analogous interactions are weaker in the N1 case.

Abstract: The ligand-controlled rhodium-catalyzed regioselective coupling of 1,2,3-benzotriazoles and allenesw as investigated by DFTc alculations. Because allylation can occur at eithert he N1 or N2 position of the 1,2,3-benzotriazole, the complete Gibbs free energyp rofiles for both pathways were computed. Ak inetic preference emerged for the experimentally observed N1 allylation with the Jo-SPOphos ligand, whereas N2 allylation was favored with DPEphos. Analysis of the regiodetermining oxidative addition step by using the activation strain modeli nc onjunction with am atching energy decomposition analysis has revealedt hat the unprecedented N2 reactionr egioselectivity is dictatedb yt he strength of the electrostatic interactionsb etween the 1,2,3-benzotriazole and the rhodium catalyst. The nature of the electrostatic interaction was rationalized by analysis of the electrostatic potential maps and Hirshfeldc harges:astabilizing electrostatic interaction was found between the keyatoms involved in the oxidative additionf or the N2 pathway,a nalogous interactions are weaker in the N1 case.
Major advances have been forgedf or N1-selective methods. [3] N2-selective modification is underdeveloped,p rimarily becauseo fd ifficulties in shifting the equilibrium toward 1b tautomer. As ac onsequence,t he structurals pace aroundv aluable N2-substituted 1,2,3-benzotriazoles that often occuri n pharmaceutical agents,a grochemicals and advancedm aterials is limited. [3,4] The rareexamples of N2 procedures reported duringt he last decade mostly rely on structural modification of the coupling partners. [3] These methods are usually based on sterically bulky groups on the benzotriazole or alkylating agent that block access to the terminal nitrogens N1/N3, thereby making the N2 position the preferred site of nucleophilic attack. Despite beingp ractically successful, theses trategiesa re restricted in functional-group tolerance and require prefunctionalized reactants. Transition-metalc atalysis offers an alternative approach that circumvents these previously mentioned issues as it involves the direct activation of XÀHb onds for functionalizing molecules. In 2014, we proposed an unprecedented rhodium (Rh) catalyzed allylation of 1,2,3-benzotriazoles. This methodology was attractive in the sense that it gave high N1/N2 regioselectivity and had ah igh tolerance toward ab road range of 1,2,3-benzotriazole and allene derivatives. [5] Importantly,t he N1 or N2 regioselectivity could be tuned by judiciousc hoice of the ligand on the Rh center.A mongaseries of diphosphine ligands used for the initial screening, we found that JoSPOphos (L1) gave the preference of N1 product, whereas DPEphos (L2) gave exclusive formation of the desired N2 substituted benzotriazole (Scheme 1b). Intrigued by this fact, we performed additional experiments [5] to probe the reaction mechanism and proposed the catalytic cycle illustrated in Scheme2.T he reaction involves three steps and beginsw ith oxidative addition of benzotriazole tautomers 1a/b to the Rh I complex. The generated Rh III ÀHi ntermediates Aa nd Bp roceed through hydrometalation and transform into s-allyl complexes Ca nd D. Intermediates Co rDthen undergo reductive elimination with the contaminantr elease of N-allylated products 4 and 3,r espectively.
Despite the plausibility of the reaction mechanism outlined in the Scheme 2, the factors determining the unusual N2 regioselectivity remainu nclear.T his facth as motivated us to study the reaction mechanism using density functional theory (DFT) calculations. To provideg eneral concepts for the rational design of other complementary approaches for the regioselective synthesis of valuable N-substituted synthons, the following questionsm ust be addressed:1 )What is the reaction mechanism?2 )Which step of the catalytic cycle is regiodetermining? 3) What are the physical factors behind the regioselectivity?T o answer these questions, we have performed as ystematic indepth theoretical investigation based on the accountso ft he previously reported experimental data. [5] The coordinationo fRhtoL1' was initially investigated to determinet he active form of the catalyst. Figure 1i llustrates the two possible binding modes of the JoSPOphos ligand (L1')t o the Rh center. [6] The large difference in computed Gibbs free energies (DDG = 17.4 kcal mol À1 )r esultsf rom af avorable Ptype of binding in Rh-L1'.H avingd etermined the structure of the catalyst, we then investigated the reaction mechanism.
All relevant mechanistic pathways (ford etails, see the Supporting Information, Figure S1) were computationally [7] explored and the Gibbs free energy profiles of the mostf avorable catalytic process were constructed (Scheme 3a). DFT calculations revealed ak inetic preference for N1 allylation (black color pathway) overN 2, which is in line with experimental results of N1-substituted benzotriazole (3)b eing the major product when JoSPOphos is employed.
The reaction is initiated by coordination of the substrate 1a/ b to Rh-L1' to form the pre-reactant complexes INT1 and INT2. Notably,t he hydroxy group on the Rh-L1' catalysta cts as ad irecting group for the incoming benzotriazole and resultsi na n OH···N1/N2 hydrogen-bonding interaction. Either the N1ÀH( 1a tautomer) or N2ÀHb ond( 1b tautomer) can undergo oxidative addition depending on the tautomeric form of the benzotriazole. The oxidative addition involves the classical 3-membered TSs (TS1-3, TS2-4) with relative free energies of 20.3 and 19.2 kcal mol À1 .C omputed structures of TS1-3 and TS2-4 are illustrated in Scheme3ba nd reveal al ate, product-likec haracter for TS1-3 with an early formedR hÀNb ond at 2.36 and an earlier TS structure for TS2-4, in which the RhÀNb ond is still relativelyl ong 3.04 .B ecause formation of INT3 and INT4 is downhill with respectt oI NT1,I NT2 by 15.4 kcal mol À1 in both cases, the oxidative addition step is predicted to be irreversible. To provideacoordination site necessary for the subsequent hydrometalation of the allene, the Cl ligand migratest o an axial position, whereas the allene binds to the Rh via an external C=Cd ouble bond in the equatorial plane. This ligand transformation raises energies to À1.0 and 0.6 kcal mol À1 to form INT5 and INT6, respectively.T he catalytic cycle continues with the hydrometalation and passes over transition states TS5-7, TS6-8 with Gibbs free activation barriers of 8.9 and 4.9 kcal mol À1 ,r espectively.T he resulting intermediates INT7, INT8 are asymmetrical p-type complexesl ocated at À11.9 and À15.3 kcal mol À1 ,w hich further isomerize to more stable s-allyl intermediates [8] INT9, INT10 with relative free energies of À21.8 and À23.7 kcal mol À1 .The reductivee limination traversing transition states TS9-11, TS10-12 and affords the product complexes INT11, INT12. It is worth pointingout that the calculated activation barriero fr eductive eliminationf or the N1-selective pathway (Scheme3a, in black) is significantly lower (DDG°= Scheme2.Proposed reaction mechanism for Rh catalyzedcoupling of 1,2,3benzotriazoles with allenes. .4 kcal mol À1 )c ompared to the N2 route. The optimized transition structures (Scheme 3c)r eveal as tabilizing hydrogenbondingi nteractioni nT S10-12 that is absent in TS9-11, which may be the origin of the lower barrier for the former.R elease of products 3' and 4' allows the Rh catalyst to reenterthe catalytic cycle and bind an ew substrate. The Gibbs free energy profile provided in Scheme3ar eveals that the oxidative addition is the regioselectivity determining step, while the reductive elimination is the rate-determining step. Our DFT calculations support the experimental observation [5] of N1-allylated regioisomer( 3')b eing ap referred product as aT S2-4 associated with N1-selective path is more stable than ac ompetitive TS1-3 for1.1 kcal mol À1 .
To understand why simply changing the JoSPOphosl igand (L1) with DPEphos (L2) completely switches the regioselectivity from N1 to N2, we again sampled variousm echanistic possibilities (see the Supporting Information, Figures S2, S3) and outlined the lowest-energy reactionp rofiles corresponded to N1 and N2 pathways (Scheme 4a). In contrastt oL 1 ' (Scheme 3a), now the N2 reaction channel (red curve,S cheme 4a)i sk inetically favored, which is in line with the experimental regioselective allylation at N2 atom of the benzotriazole.
The first elementary step of the catalytic cycle (Scheme4a), namely,o xidative addition takes place from INT13 or INT14, in which the substrates 1a or 1b are pre-coordinated to the catalyst via aw eak hydrogen-bond interaction between N1/2À H···Cl. From the substrate-coordinatedc omplexes INT13 and INT14, the N1/N2ÀHa ctivation is taking place via TS13-15/ TS14-16 located at 20.9 and 22.8 kcal mol À1 .O ptimized structures of TS13-15,T S14-16 are provided in Scheme 4b and are Scheme3.(a) Gibbs free energyprofile for coupling oft he 1,2,3-benzotriazoles with allenes catalyzedb yRh-L1' at 80 8Cand as tandard state of 1mol L À1 ; (b) Regioselectivity determining transition states;( c) Rate-determining transitions tates. Bond lengthsi n,Gibbs free energies in kcal mol À1 .T oreducec omputational cost the cyclohexyl group of allene(2) was replaced by the methylgroup( 2 ')a nd tert-butyl groupo ft he ligand( L1) was replaced with methyl (L1'). The formationo ft hese speciesise xergonic relative to the pre-reactive complexes (INT13,I NT14) by 1.9a nd 5.5 kcal mol À1 ,r espectively,s uggesting oxidative addition to be irreversible. Binding of the incoming allene 2' during the second stage of the catalytic cycle is uphill in terms of Gibbs free energy by 9.9 (INT17) and 10.3 (INT18) kcal mol À1 .D uring this process, the coordination geometry at theRhc enterc hanges from square pyramidal to octahedral, in which Cl and Hl igands occupy apical positions. The reaction continues with af ast hydrometalation pro-cess via TS17-19, TS18-20 with activation free energies of 6.0 and 6.9 kcal mol À1 to give s-allyl complexes( INT19, INT20). Finally,t he hydrometalation adducts undergo reductivee limination with barriers of 13.1 and 13.4 kcal mol À1 (TS19-21 and TS20-22), and deliver the product complexesI NT21 and INT22. The catalytic cyclec ompletes upon dissociation of the N-allylated products 3' or 4' from the coordination sphere of the metal with the regeneration of the catalyst. Considering the full Gibbs free energy profile illustratedi nS cheme 4a,t he key step determining the regioselectivity of the allylation is the oxidative addition step. Our DFT results showT S13-15 to be more stable than TS14-16b y1 .9 kcal mol À1 .T his DDG°between the regiodetermining TSs corresponds to ar atio of N1/N2 4:96 with predominance of N2 allylated regioisomer 4',w hich is in To understand why DPEphos (L2) leads to N2 regioselectivity, we quantitatively analyzed the regiodetermining oxidative addition step catalyzed by Rh-L2 using the activation strain model ASM (Figure 2). [9] Within the ASM, the relative energy in solution DE solution along the reactione nergy profile is separated into the energy of the solute DE solute (reaction system in vacuum with the solution phase geometry) and the solvation energy DE solvation [Eq. 1].
The intrinsic energy of the solute DE solute is split further into two terms: DE solute,strain (energy required for deformationo ffragments from their starting geometriest ot he geometries they obtain over the course of the reaction) and DE solute,int (energy of interaction between deformed fragments) [Eq. 2].
Next, the interactione nergy DE solute,int is decomposed into three terms using ac anonical energyd ecomposition analysis (EDA) [Eq. 3]: in which DV solute,elstat correspondst ot he electrostatic interaction between unperturbed charges of the deformed reactants, DE solute,Pauli accounts fort he repulsion between occupied orbitals, DE solute,oi is responsible for interaction between occupied and unoccupied orbitalsa nd polarization. The ASM and EDA terms were projected on the N1/N2ÀHb ond stretch, as this geometrical parameter is critically involved in the reactiona nd undergoes aw ell-defined change [9] over the course of the oxidative addition step. Figure 2a shows that the interaction energies (DE solute,int )control the reaction regiochemistry,w hereas the strain energy required for deformation of catalyst( Rh-L2) and substrate (one of the two 1,2,3-benzotriazole tautomers, 1a/b)d uring oxidative addition (DE solute,strain )i sn early identicalf or both N1-(black) and N2-selective (red) pathways. Similar DE solute,strain curvesi sa consequence of breakingt he same NÀHb ond at either N1 or N2 during the oxidative addition. Because the DE solute,int is decisive in determining the trend in DE solute and thus the observed reactivity trends, it was further analyzed by using the EDA, and the results are plotted in Figure 2b.D ifferences in the orbitalinteraction curves( DE solute,oi )a re minimal. Thus, it becomes evident that the predominance of the N2-selective pathway can be attributed to the more stabilizinge lectrostatic interaction (DV solute,elstat ), which effectively overrules the less destabilizing Pauli repulsion (DE solute,Pauli )p reference for the N1 pathway.
Next, to understand the trend in DV solute,elstat ,w ee xamined the electrostatic potential maps (ESP) and Hirshfeld charges [10] of Rh and N1, N2, N3 atoms of 1,2,3-benzotriazole fragments (1a/b). Figure 2c and di llustrate the ESP and charge analysis for the 1,2,3-benzotriazole tautomers at their equilibrium and TSs geometries. Our analysis has identified acausal relationship between the charge of the Na tom of the benzotriazole involvedi nt he regiodetermining oxidative additions tep and the degree of electrostatic stabilization: am ore electronegative N atom leads to as tronger,m ore stabilizing electrostatic interaction with the electropositive Rh metal center.T hus, the more reactive tautomer 1a has an N1 atom positioned between a carbon atom and nitrogen N2. This results in ar elativelye lectronegative N1 (À36 ma.u.), which leads to as trongly stabilizing electrostatic interaction with Rh (20 ma.u.) metal center (Figure 2c). In contrast, the less reactive tautomer 1b has a partially positive (44 ma.u.) N2 atom (Figure 2d)a saresult of being positioned between two nitrogens (N1 and N3 atoms). This leads to less stabilizing electrostatic interaction between the N2 atom and the electropositive Rh. The electrostatic interactions are more stabilizing for the reaction of N2 compared with N1 over the entire reactionc oordinate (Figure 2b), thus this chargea nd molecular electrostatic potential( MEP) analysis can be performed at any point.
In summary,w eh ave computationally analyzed the reaction mechanism of an ewly developed coupling of 1,2,3-benzotriazoles with allenesc atalyzed by Rh-diphosphine ligand (JoSPOphos/DPEphos) complexes.O ur DFT calculations revealt hat regardlesso ft he ligand being used, the reactionp roceeds via a three-step catalytic cycle, comprised of first an oxidative addition, then hydrometalation, and finally ar eductive elimination. Our activation strain and energy decompositiona nalyses on the regiodetermining oxidative addition step catalyzed by Rh-DPEphoss how that the preference for the N2-selective reaction channel arises from ap reviouslyu nrecognized electronic mechanism, namely,amore stabilizing electrostatic interaction between the electron-enriched region at the N1 atom of tautomer 1a with the positively charged Rh during N1ÀRh bond formation in the rate-determining N1ÀHo xidativea ddition step. We envisage that the newly identified electrostatic interactions can be used to further tune the 1,2,3-benzotriazole and catalyst interaction through the introductiono fv arious functionalities, whichm ay allow new reactions with tailored N2 regioselectivity trend.