Introduction
The transition metal catalyzed cross-coupling reactions such as Negishi,1 Heck,2
Suzuki-Miyaura,3 Stille,4 Kumada,5 Hiyama,6 and Sonogashira7 are extremely powerful tools for making C−C bonds. These methods have been extensively used in wide range of academic areas including material product synthesis, materials science, medicinal, biological, supramolecular chemistry, catalysis and coordination chemistry. Some of these reactions are also useful in pharmaceutical, agrochemical and fine chemical industries.8 Among these powerful transformations, the Suzuki-Miyaura cross-coupling (Scheme 1) (defined as transition-metal catalyzed cross-coupling between an organoboron compound and an organic halide or pseudo halide) is the most widely applied transition-metal catalyzed C−C bond forming reaction since its discovery in 1979.9

Scheme 1. Suzuki-Miyaura cross-coupling reaction.
Suzuki reaction has become the most attractive approach for C−C bond formation due to many reasons. Firstly, the mild reaction conditions and broad functional group tolerance of this transformation. Secondly, the use of organoboron reagents has many advantages such as they are inexpensive, some are thermally stable and inert to water and oxygen, thus easy to handle (industry), they transmetallate with a variety of metal compounds under exceptionally mild reaction conditions, low toxicity, good availability of diverse organoboron reagent and easy separation of boron containing by-products from the reaction mixtures.
The importance of Suzuki-Miyaura cross-coupling reaction has been well recognized with 2010 Nobel Prize in Chemistry together with Heck and Negishi couplings.10

Ni-Catalyzed Suzuki-Miyaura Cross-Coupling of Alkyl Halides with Alkyl Borane
Reagents
Equally significant to aryl and alkenyl (pseudo)halides, the transition metal catalyzed cross-coupling of alkyl halides and their equivalents also represents an important class of coupling reactions. However, the reactions of alkyl electrophiles are considerably more challenging as compared to corresponding aryl and alkenyl analogues due to the difficulties to

1|P a g e

undergo oxidative addition as well as the tendency to participate in some side reactions such as β-H elimination and hydro dehalogenation.
In 2007, Fu and Saito achieved the more challenging alkyl-alkyl Suzuki cross coupling with a Ni catalyst (Scheme 2).11 Interestingly, 2 equivalents of i-BuOH coupled with 1.2 equivalents of KOtBu base was essentially required, which was proposed to activate the alkyl borane for transmetallation with the Ni metal.

Scheme 2. Ni-catalyzed Suzuki coupling of alkyl bromides with alkyl borane reagents.

Ni-Catalyzed Asymmetric Suzuki-Miyaura Cross-Coupling of Alkyl Halides with
Borane Reagents
The first successful asymmetric Suzuki coupling was reported by Fu and Saito in 2008
(Scheme 3). 12

Scheme 3. Ni-catalyzed asymmetric Suzuki-Miyaura cross-coupling.
Later, secondary alkyl fluorides were synthesized via Suzuki cross-coupling reaction of 1-halo-1-fluoroalkanes (Scheme 4).13

Scheme 4. Synthesis of secondary alkyl fluorides via Suzuki cross coupling reaction.

2|P a g e

In the above reaction, 1-halo-1-fluoroalkanes are utilized in the catalytic C−C cross coupling process. Using this reaction, site-selective fluorination of alkyl chain can be done, without any activating functional group next to the C−F. This method can be extended to its asymmetric version by using a suitable chiral catalyst (Scheme 5).14

Scheme 5. Enantioselective cross-coupling of unactivated 1-fluoro-1-haloalkanes.

We started investigating the above reaction using computational (DFT) methods to unravel the mechanism and to elucidate the role of additives such as KOt-Bu and i-BuOH. In addition to that, we wanted to give more insights into the stereoinduction and enantioselectivity. Motivation
Organofluorine compounds have substantial applications in various areas of chemistry.
Organic fluorides are extremely important tools in drug discovery and biomedical investigations. Therefore, selective fluorination of organic molecules has rapidly become a field of great synthetic interest. Despite having various methods for preparation of organofluorine compounds, the enantioselective construction of stereogenic centers bearing a fluorine substituent remains a challenging task. Mechanistic investigation is important to establish the role played by the additives and to gain insights into the stereoinduction and enantioselectivity in Suzuki coupling reactions. Role of Ni(I) is also not well studied in the sense that whether it is the resting state of the catalyst or is directly participating in the catalytic cycle.
Objective
To establish the mechanistic pathway and to investigate the potential role of additives in all steps of the reaction. To determine the origin of enantioselectivity and to find the role of
Ni(I) in the catalytic cycle.

3|P a g e

Computational Methods
GAUSSIAN0915 program was used for doing all the calculations. All the stationary points such as reactants, intermediates and transition states were optimized using hybrid density functional B3LYP with 6-31G* basis set for all atoms except Ni.16 For Ni atom
LANL2DZ17 basis set with effective core potential (ECP) was used. Furthermore, frequency calculations were done on all the stationary states. The transition state was characterized by unique imaginary frequency which verified that they were first order saddle points on the potential energy curve. Intrinsic Reaction Coordinate (IRC) calculations were further done on the transition state to ascertain that the transition state obtained was connected to reactants and products. Results and Discussions
Formation of active catalyst:
Different possible pathways for the formation of possible active catalysts have considered which is explained in this session. In first step, ligand exchange takes place. Glyme is replaced by the diammine ligand. In next step, the catalyst undergoes transmetallation with 2 moles of alkyl 9BBN which further undergoes reductive elimination to form Ni0 (Scheme 6).
Ligand Exchange

Transmetallation and reductive elimination

Scheme 6: Formation of Ni(0).
Formation of Ni(I) from Ni(0) and alkyl halide
There are different possible pathways for formation of Ni(I) active catalyst from Ni(0) and alkyl halide (Scheme 7). These are following:

4|P a g e

(1) Radical Pathway

(2) Bimetallic Oxidative Addition

(3) Comproportionation

Scheme 7: Possible pathways for formation of Ni(I).
Optimized geometries and relative free energies of possible active catalysts are give in
Figure 1.

Ni(I)
-65.32

Ni(0) {singlet}
11.54

Ni(0) {triplet}
-9.10
5|P a g e

Figure 1. Optimized geometries and relative free-energies (kcal/mol) of proposed active species.18 The following possible mechanistic pathways are proposed for Ni-catalyzed alkylalkyl Suzuki coupling:
Pathway A and B involves NiI-NiIII catalytic cycle in which pathway A has transmetallation as first step and pathway B has oxidative addition as first step. On the other hand, pathway C and D involves Ni0-NiII catalytic cycle with pathway C having singlet Ni and pathway D having triplet Ni.
Pathway A: NiI – NiIII catalytic cycle with transmetallation as the first step (Scheme 8).

Scheme 8. NiI – NiIII catalytic cycle with transmetallation as the first step.
The transmetallation of 1 with 9-BBN is proposed to proceed by two possible pathways. One pathway is the direct transmetallation of 1 with 9-BBN via transition state [13]‡. In second pathway, the added base reacts with 9-BBN to form potassium boronate salt, which reacts with 1 to give 2 and Br leaves as KBr. 2 gives 3 via transition state [2-3]‡. Alkyl halide coordinates with 3 to give four-coordinated NiI complex, 4. For oxidative addition, two possible pathways are proposed. In first pathway, the Br and C atoms concertedly add to Ni center with a three-centered transition state [4-6]‡ to give 6 in one step. In the second pathway, the Ni atom in 4 abstracts the Br atom via transition state [4-5]‡. The product of [4-5]‡ is 5. 5

6|P a g e

gives 6 via transition state [5-6]‡ . 6 undergoes reductive elimination to give the product via transition state [6-1]‡ and catalyst is regenerated. (Scheme 9)

Scheme 9. Pathway A for NiI-NiIII catalytic cycle with transmetalation as first step.
The optimized geometries and relative free-energies of various transition states involved in pathway A are given in Figure 2.

7|P a g e

[2-3]‡

[1-3]‡

[4-5]‡

[4-6]‡

[6-1]‡

[6-1]‡ (with i-BuO-)

Figure 2. Optimized geometries and relative free energies (in kcal/mol) of transition states for pathway A. The distances are in Å.

Figure 3. Free energy profile for pathway A. Relative free energies are in kcal/mol.

8|P a g e

The energy barrier for transmetallation without any base is 39.4 kcal/mol. On the other hand, the energy barrier with t-BuO- and i-BuO- is 21.1 and 19.8 kcal/mol respectively.
Therefore, the pathway involving coordination to i-BuO- is more favored. The activation barrier for concerted addition transition state [4-6] is higher as compared to stepwise addition via transition state [4-5]. This implies that concerted addition of C and Br to Ni is not favored.
Further, the activation barrier for reductive elimination with both t-BuO- and i-BuO- is 12.7 kcal/mol (Figure 3).
Pathway B: NiI – NiIII catalytic cycle with oxidative addition as the first step (Scheme 10).

Scheme 10. NiI – NiIII catalytic cycle with oxidative addition as the first step.
Catalytic cycle B starts with addition of 1 with 1-bromo-1-fluoroalkanes to give 2b.
There are two possible pathways for oxidative addition of 2. One is concerted addition of C and Br to Ni via transition state [2b-4b]‡. The other pathway is the Br abstraction to give 3 via transition state [2b-3b]‡. The radical then adds to Ni via transition state [3b-4A]‡ to give 4A.
One of the Br is then substituted (leaves as KBr) by activated alkyl-9BBN in 4b and 4A to give 5b and 5A respectively. 5b and 5A then undergo transmetallation readily to give 6b and
6A via transition states [5b-6b]‡ and [5A-6A]‡ respectively. 6b and 6A then undergo reductive elimination via transition states [6b-1]‡ and [6A-1]‡ to give the product and catalyst is regenerated. (Scheme 11)

9|P a g e

Scheme 11. Pathway B for NiI-NiIII catalytic cycle with oxidative addition as first step.
The optimized geometries and relative free-energies of various transition states involved in pathway B are given in Figure 4.

10 | P a g e

[2b-4b]‡

[5b-6b]‡

[6b-1]‡

[2b-3b]‡

[3b-4A]‡

[6A-1]‡

[5A-6A]‡
Figure 4. Optimized geometries and relative free energies (in kcal/mol) of transition states for pathway B. The distances are in Å.

11 | P a g e

Figure 5. Free energy profile for pathway B. Relative free energies are in kcal/mol.
Coordination with i-BuO- lowers the energy by ~10-15 kcal/mol. Therefore, pathway with Ni coordinating to i-BuO- is favoured over t-BuO- (Figure 5).
Pathway C: Ni0-NiII catalytic cycle (singlet) (Scheme 12).

Scheme 12. Ni0-NiIIcatalytic cycle for singlet Ni.
Catalytic cycle C starts with oxidative addition of alkyl halide to singlet Ni, 1c. The oxidative addition occurs in a concerted way via transition state [2c-3c]‡ to give 3c. The Br is then displaced by activated alkyl-9BBN to give intermediate 4c. Intermediate 4c then
12 | P a g e

undergoes transmetallation via transition state [4c-5c]‡ to give intermediate 5c. 5c then undergoes reductive elimination via transition state [5c-1c]‡ to give the product and the catalyst is regenerated. (Scheme 13)

Scheme 13. Pathway C for singlet Ni0-NiII catalytic cycle.
The optimized geometries and relative free-energies of various transition states involved in pathway C are given in Figure 6.

[2c-3c]‡

[4c-5c]‡

[4c-5c]’‡

13 | P a g e

[5c-1c]‡

[4c-5c]‡(with i-BuO-)

[4c-5c]’‡(with i-BuO-)

Figure 6. Optimized geometries and relative free energies (in kcal/mol) of transition states for pathway B. The distances are in Å.

Figure 7. Free energy profile for pathway D. Relative free energies are in kcal/mol.
The activation barrier for the reductive elimination step is 54.4 kcal/mol which is too high for the reaction to occur at room temperature. Therefore, pathway D is not favored.(Figure 7)
Pathway D:Ni0-NiII catalytic cycle (triplet).
Catalytic cycle D starts with oxidative addition of alkyl halide to triplet Ni, 1d. The oxidative addition occurs in a step-wise manner. Firstly, Br is abstracted via transition state
[1d-d2]‡ to give 2d. The radical then adds to Ni via transition state [2d-3d]‡ to give intermediate 3d. Rest of the pathway is same as that of pathway C. (Scheme 14)

14 | P a g e

Scheme 14. Pathway D for triplet Ni0-NiII catalytic cycle.
The optimized geometries and relative free-energies of various transition states involved in pathway D are given in Figure 8.

[1d-2d]‡

[2d-3d]‡

[5d-1d]‡

15 | P a g e

[4d-5d]‡

[4d-5d]‡ (with i-BuO-)

Figure 8. Optimized geometries and relative free energies (in kcal/mol) of transition states for pathway D. The distances are in Å.

Figure 9. Free energy profile for pathway D. Relative free energies are in kcal/mol.
The activation barrier for the reductive elimination step is 54.4 kcal/mol which is too high for the reaction to occur at room temperature. Therefore, pathway D is not favoured
(Figure 9).
Conclusion
The Ni0-NiII catalytic cycle is not favored because the activation barriers of reductive elimination for singlet and triplet are as high as 41.5 and 54.4 kcal/mol respectively.
Coordination of i-BuO- to Ni lowers the activation barrier compared to coordination of t-BuO. The activation barrier for transmetallation without any base is 45.4 kcal/mol in pathway A.
On the other hand, the activation barrier with t-BuO- and i-BuO- is 25.7 and 12.8 kcal/mol respectively. Therefore, the role of base is to lower down the activation barrier for the

16 | P a g e

transmetallation step. At this stage, pathway A with transmetallation as first step and pathway
B with oxidative addition as first step and both involving NiI-NiIII catalytic cycle is recommended. Future Plans
We intend to follow the scheme proposed at this stage and also look for all other probable schemes. Also we want to gain insights into the stereoinduction and enantioselectivity. References
(1) (a) Negishi,E. Acc. Chem. Res. 1982, 15, 340. (b) Erdik,E. Tetrahedron, 1992, 48, 9577.
(2) Heck, R. F. Org. React. 1982, 27, 345.
(3) Suzuki,A. Pure Appl. Chem. 1985, 57, 1749.
(4) (a) Milstein,D.; Stille,J. K. J. Am. Chem. Soc. 1979, 101, 4981. (b) MilsteinD.; Stille,J. K.
J. Am. Chem. Soc.1979, 101, 4992. (c) Milstein D.; Stille,J. K. J. Org. Chem. 1979, 44,
1613.
(5) Negishi,E. I.; Liu,F. in Metal-Catalyzed Cross-Coupling Reactions, ed. Diederich, F.;
Stang,P. J. Wiley-VCH, Weinheim, Germany, 1998, 1–47.
(6) Nakao, Y.; Hiyama,T. Chem. Soc. Rev.2011, 40, 4893.
(7) Sonogashira,K. Comp. Org. Synth., ed. Trost, B. M.; Fleming, I., Pergamon, Oxford,
1991, 3, 521.
(8) Torborg, C.; Beller, M. Adv. Synth.Catal., 2009, 351, 3027.
(9) (a) Miyaura, N.; Suzuki, A. J. Chem. Soc. Chem.Commun., 1979, 866. (b) Miyaura, N.;
Yamada, K.; Suzuki, A. Tetrahedron Lett.,1979, 20, 3437. (c) Miyaura, N.; Yanagi, T.;
Suzuki, A. Synth. Commun.,1981, 11, 513.
(10) Wu, X.-F.; Anbarasan, P.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed.,2010, 49,
9047.
(11)Saito, B.; Fu,G. C. J. Am. Chem. Soc., 2007, 129, 9602.
(12)Saito, B.; Fu, G. C. J. Am. Chem. Soc., 2008, 130, 6694.

17 | P a g e

(13)Jiang, X.; Sakthivel, S.; Kulbitski, K.; Nisnevich, G.; Gandelman, M. J. Am. Chem. Soc.,
2014, 136, 9548.
(14) Jiang, X.; Gandelman, M. J. Am. Chem. Soc., 2014, 137, 2542.
(15) Gaussian 09, Revision A.02, Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Menucci, B.; Petersson, G. A.; Nakatsuji,
H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.;
Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.;
Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, Jr., J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.;
Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.;
Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyenger, S. S.; Tomasi, J.; Cossi, M.; Rega, N.;
Milliam, N. J.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts,
R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R.
L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.;
Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian, Inc.,
Wallingford CT, 2009.
(16) (a) Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys. 1972, 56, 2257. (b) Hariharan, P.
C.; Pople, J. A. Theor. Chim. Acta 1973, 28, 213. (c) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B
1988, 37, 785. (d) Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
(17) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 299.
(18) Guard, L. M.; Beromi, M. M.; Brudvig, G. W.; Hazari, N.;Vinyard, J. D, Angew. Chem. Int.
Ed., 2015, 54, 1.

18 | P a g e