Although we successfully developed Model I for the prediction of the catalyst activity of B xy , the calculation of GH ‡ via the DFT-based optimization of a possible transition state is relatively inefficient in terms of costs. We thus pursued the use of a different theoretical parameter for the construction of a regression-based model for the prediction of the TOF values. This parameter should be related to the steric properties of the metasubstituents with respect to the boron centers in B xy , given that the GPR using the intrinsic electronic properties of the boranes failed to construct reliable prediction models (vide supra). In this context, we have recently proposed that the deformation energy (EDEF) [kcal mol ] can be used to evaluate the degree of remote back-strain, where EDEF represents the energetic penalty associated with the change in the conformation at the boron center from trigonal planar to tetrahedral upon the formation of LB-borane adducts. These results prompted us to examine whether the EDEF value could serve as an adequate index for designing boranes B xy for the catalytic reductive alkylation of amino acids and peptides. We calculated the EDEF values for the boranes shown in Figure via the gas-phase optimization of their H2O adducts followed by energy-decomposition analysis at the RI-DSD-PBEP86-D3BJ/ma-Def2-QZVPP//PBEh-3c/Def2-SVP level (Figure ). The GPR analysis with EDEF and Gw° using the experimental TOF values shown in Figure With the optimal triarylborane B 4b in hand, we modified the reaction conditions to reduce its environmental impact and thus establish a greener and more sustainable system. In this context, the use of an alternative reaction solvent that could also act as a Lewis base to generate an FLP with B 4b was initially explored, given the recent demand for the replacement of hazardous THF with alternative ethereal compounds that exhibit lower toxicity combined with high chemical and thermal stability. In the presence of 40 atm H2, the reductive alkylation of 1a with 2a was carried out using THF, 2-methyltetrahydrofurane (2-MeTHF), cyclopentyl methyl ether (CPME), 4-methyltetrahydropyrane (MTHP), or 2,2,4-trimethyl-1,3-dioxolane (TMD) (Figure ). While THF provided a superior result (50%) compared to 2-MeTHF (38%) and CPME (18%), 3aa was generated in 59% yield when MTHP was used. Prolongation of the reaction time to 24 h resulted in the formation of 3aa in 72% yield; however, the removal of the 4Å MS caused a significant decrease in the yield of 3aa to 42%. Finally, increasing the H2 pressure to 60 atm resulted in the formation of 3aa in 95% yield. The use of TMD did not furnish any 3aa. It should be noted that MTHP can be easily separated from water (its solubility in H2O is ~1.5 wt%) and removed under reduced pressure due to its strong hydrophobicity and low heat of vaporization, although its employment as a greener solvent has been limited in organic synthesis compared with the use of 2-MeTHF and CPME. Moreover, to clarify the benefit of using MTHP over THF, we compared the activation energies for the heterolytic cleavage of H2 by the combination of B 4b and THF or MTHP at the B97X-D/6-311+G(d,p)//B97X-D/6-31G(d,p) level (Figure ). A possible transition state was found in both cases, and that in the case of MTHP was found to be more stabilized (TSMTHP = +21.8 kcal mol -1 ) than that in the case involving THF (TSTHF = +23.2 kcal mol -1 ). We attribute this stabilization to the increased structural flexibility of the tetrahydropyrane motif relative to THF, which allows the formation of efficient non-covalent interactions (NCIs) between the F/Cl atoms in B and the H atoms in MTHP. The participation of such NCIs was confirmed using the quantum theory of atoms in molecules (AIM) method (for details, see Figure ). The B 4b -catalyzed reductive alkylation of 1a with 2a in MTHP using H2 (40 atm) demonstrated remarkable compatibility toward a variety of additives (A0-A21) (Figure ). All these experiments were carried out twice, and mean values [%] are given for the yield of 3aa, the recovered additive, and the imine intermediate 4-(benzylideneamino)benzoic acid formed in situ through the B 4b -catalyzed condensation of 1a and 2a. Initially, we carried out a control experiment using A0, which confirmed that the yields of 3aa and the remaining imine were consistent (72% and 28%, respectively) with those of the reaction conducted without A0 (Figures and). Relative to the control experiment, the reductive alkylation among 1a, 2a, and H2 proceeded without a significant change in the yield of 3aa, the recovered additives, or imine intermediates for additives with ketone (A3/A13), primary amide (A4), aryl bromide/iodide including alkyl ether (A6/A7), allylic ether (A8), terminal alkyne (A9), enone (A12), nitrile (A15), and ester (A20) moieties. It is also noteworthy that additives including sulfhydryl (A16) and sulfide (A17) moieties did not affect present reaction, whereas such sulfur-containing compounds can be critical inhibitors in transition-metal-based catalysis and organocatalysis. On the other hand, the hydrogenation of the imine intermediates was obviously suppressed in the presence of aliphatic/aromatic carboxy (A1/A14), aliphatic hydroxyl (A2), bulky silyl ether (A10), pinacolatoboryl (A18), and N-tertbutoxycarbonyl (Boc) (A21) moieties, as these functional groups include either a Lewis-basic or -acidic site that can kinetically inhibit the formation of the FLP consisting of B 4b and MTHP. In fact, the quantitative recovery of the additives after a period of 24 h was confirmed, without the generation of any other significant byproduct, i.e., the sum of the yields of 3aa and the imine was always ~95%). In contrast, the formation of 3aa was largely suppressed under reaction conditions including N-heteroaromatic moieties such as an imidazole (A5) and an indole (A19), as these heteroaromatic units can react with B 4b to form classical Lewis adducts and/or aldehydes to complicate the system. In the case of A11, which includes an epoxide moiety, 3aa was only produced in 13% yield, and a significant loss of A11 was confirmed after the reaction. Given that Lewisacidic triarylboranes mediate the ring-opening transformation of epoxides, the B 4b -catalyzed ring-opening reaction of A11 to give the corresponding aldehyde can be expected to compete with the targeted reaction (see Supporting Information for details).