C−H•••F−C Interactions: A Guide for Designing Fluorous Monodentate Ligands for the Highly Linear-Selective Hydroformylation at Near-Ambient Pressure


 Organofluorine compounds often exhibit unique catalytic capabilities with novel structural scaffold, reactivity and mechanisms. Herein, we report a Rh-catalyzed hydroformylation under mild conditions using monodentate phosphite ligands P(OCH2CF3)3 (TTFP) and P(OCH2CF2CH3)3 (TDFP). The ligand were designed with the principle that the inclusion of fluorine-rich group can significantly change the physical and chemical properties of the complex through H•••F hydrogen bonds, the existence of which has been confirmed by crystal-packing studies. These monodentate phosphite ligands self-assemble to form bidentate ligands through C–H•••F–C interactions, and catalysts based on these ligands deliver extremely high regioselectivities in hydroformylation. Aldehydes were formed with up to 92% chemoselectivity, with linear aldehydes formed in high regioselectivity (n:iso=28/1) under a syngas pressure of only 2 atm.


Background
Fluorinated molecules have unique and important physicochemical properties 1,2 , which have been used extensively to develop medicines 3,4 and agrochemicals 5,6 . The introduction of uorine alters the physicochemical properties of a molecule by changing its chemical reactivity and the stability of adjacent functional groups, as well as its pK a and dipole moment 4,7,8 . Fluorous interactions (C-F···F-C, C-H···F-C, C-H···π) have been reported to signi cantly in uence the arrangements of molecules in molecular crystals [9][10][11] , photophysical 12 and solvation properties 13 . Several reported studies aimed at understanding the nature of these interactions, including approaches based on statistical analysis 14 , energy calculations 14 , crystal structure analysis 15 and charge-density analysis 16 . The different statisticalanalysis-based surface area correction approaches 17 have been applied to C-H···F-C and C-F···F-C interactions, revealing that the lighter uorine halogen favors the C-H···F-C interactions 18, 19 . The nature of C-H···F-C interactions in molecular crystals has been exhaustively investigated, and it behaves as a weak hydrogen bond that is dominated by electrostatic and dispersion components when the two fragments are neutral 15,20 . The C-H···F-C hydrogen bond plays an important role in the formation of self-assembled adlayers during crystal packing 10 , with intermolecular, molecule-substrate, and intramolecular interactions the driving forces that dominate the self-assembled structure. With this in mind, we asked the question: can these in-situ-generated interactions be applied to homogeneous catalytic reactions?
Hydroformylation is one of the most important homogeneous chemical processes, which converts ole ns into aldehydes. Novel catalysts with improved e ciency have been continually developed over the past four decades. Rh-based catalysts modi ed by phosphorus ligands are widely used, and the development of ligands has become the optimal way to improve the catalytic activity. In contrast to their monodentate counterparts, bidentate donor ligands generally lead to higher regio-and enantioselectivities in many homogeneous transition-metal catalysts due to the formation of a more rigid microenvironment at the catalytic metal center 21,22 . Ligands that self-assemble 23 via O-H···O and N-H···N hydrogen bonds to form a psuedo bidentate ligand has been reported to facilitate hydroformylation in a regioselective manner. Fluorous interactions can also be used to increase rigidity in the microenvironment of the catalytic metal center, thereby increasing the selectivity of the reaction. Generating a monodentate ligand with hydrogen bond donor/acceptor is more cost-effective than preparing a bidentate ligand with tedious synthetic steps 24 .
Monosubstituted HRh(CO) 3 L catalysts used in ethylene hydroformylation have been computationally simulated by the Jensen group 25 using density functional theory (DFT), which elucidated the electronic and steric factors governing the catalytic activity of the modi ed phosphite ligand (L). Electronwithdrawing ligands, such as P(OCH 2 CF 3 ) 3 , were predicted to be more active than those used for contemporary hydroformylation. Taken together the results of previous experimental 26, 27 and computational studies 25,28 on Rh-catalyzed hydroformylation, we designed a set of uorine-containing monodentate phosphite ligands in the present work. Experimental and computational studies suggest that these ligands self-assemble through the C-H···F-C interaction that increases the rigidity of the microenvironment around the Rh center and more effectively distinguishes between the reaction pathways for selectively forming linear aldehydes.

Initial Experiments and Optimizations
Fluorine-containing ligands were con rmed to exhibit high regioselectivity for linear aldehydes compared to other monodentate ligands through an initial set of experiments that used 1-decene as a benchmark substrate and various monodentate ligands in toluene under 2 atm of syngas at 70 °C ( Figure   1). As triphenylphosphine (TPP) is widely used in industry, we rst examined ligands L2 and L3, which are TPP derivatives with electron-withdrawing CF 3 groups. However, no satisfactory results were obtained (entries 2 and 3). Under the abovementioned mild conditions, partially uorinated ligands L4-L6 provided the same level of regioselectivity as Biphephos (L1), a classical and prominent bidentate ligand for hydroformylation (entries 1 and 4-7); however, the highest linear-to-branched aldehyde ratio (n:iso=40.1:1) was observed with L7 (entry 7).
With the optimal uorine-containing ligands L4-L7, we set to explore hydroformylation conditions using these ligands (Supplementary Information, Table S1-S4). We observed that the proportion of uorinecontaining ligand is a decisive factor for the linear selectivity ( Figure 2). The n:iso ratios above 10/1 were observed at L/Rh ratios above 5:1, which is higher than the regioselectivity observed for most currently used monodentate ligands. The desired undecaldehyde was obtained in excellent isolated yields, with 91% yield and 96% regioselectivity observed using 2.5 mol% tris(2,2-di uoropropyl)phosphite (TDFP, L/[Rh]=5).

Substrate Scope and Comparison with PPh 3 and TPPTS Ligands
With the optimal ligand in hand, we compared TTFP and TDFP with the widely used PPh 3 and the watersoluble monodentate ligand TPPTS. High yields and linear selectivities were obtained for C6-C10 ole ns when the electron-withdrawing TTFP and TDFP ligands were used (Figure 3). Under the same conditions, the water-soluble TPPTS provided high regioselectivities (>84%), however the yields were below 50% ( Figure 3). While the industrially relevant PPh 3 delivered an aldehyde yield of more than 85%, only 70-83% undecanal was obtained under mild hydroformylation conditions. By carefully optimizing the reaction conditions, we found that TDFP exhibited good catalytic activities and linear aldehyde selectivities for aliphatic ole n. However, TDFP did not work satisfactorily for aromatic ole ns or internal ole ns (Table S5-S7). The highly regioselective hydroformylations of terminal ole ns suggest that speci c interactions exist between these uorine-containing monodentate ligands, and that these interactions remain intact during the catalytic process. factors that affect aldehyde regioselectivity during hydroformylation 31,32 . It should be noted here that some of the reported computational work supports the notion that electron-withdrawing ligands are associated with low activation energies and trigonal-bipyramidal transition-state geometries 25,33,34 . The complete structures of Rh/TTFP complexes with phosphorus ligands containing hydrolysable bonds (e.g., P-O) and non-rigid groups are di cult to obtain by X-ray diffractometry. Therefore, alkene intermediate 2, which contains two bis-equatorially coordinated phosphorus ligands, was examined computationally.
Computational studies of intermediate 2" with 1-butene as the substrate were carried out using the Gaussian 09 suite of programs 35 . The geometries of all molecules were optimized using the B3LYP [36][37][38] and BP86 39,40 density functional with the Stuttgart-Dresden effective core potential (ECP28MWB) with the associated double-ζ basis set 41 for Rh and the 6-31G** 42 basis set used for all other elements. The solvation effect of toluene was incorporated through the self-consistent reaction eld (SCRF) approach using the integral equation formalism of the polarizable continuum model (IEFPCM). The nature of each  Table S8. We screened H···F distances below 2.7 Å (the sum of the van der Waals radii of H and F) 43 that correspond to intramolecular C−H···F−C interactions between the two ligands. It should be noted here that H···F distances for C−H···F−C interactions reported in the literature range between 2.00 and 4.00 Å 17 . The H···F distances between the two ligands were determined to lie in the 2.20-2.70 Å range (Table S8) with C−H···F and H···F−C angles of 90-180° (Table S9). The H···F interactions correspond to weak hydrogen bonds in these distance and angle ranges 17 . The optimized structures of alkene intermediates 2" bearing the TTFP and TDFP ligands (Figures 4b and 4c) reveal that the C−H bonds involved in H···F interactions are shorter than other C−H bonds on the same carbon atom, which is consistent with C−H bond shortening due to short-range repulsion. Moreover, a short distance in the 2.4-2.6 Å range was observed between the uorine and the α-hydrogen of 1-butene. The formation of C−H···F−C hydrogen bonds increases the rigidity of the microenvironment at the Rh center, with a P−Rh−P angle within the 100-110°r ange to energetically discriminate between competing reaction pathways, thus leads to higher regioselectivity 21,44 . This was consistent with our experimental results.
Furthermore, the FTIR peaks that correspond to the C-F and C-H bonds in the uorine-containing monodentate TTFP and TDFP were blue-shifted when Rh(acac)(CO) 2 was added (n L /n [Rh] =1, 3, 5 and 7).
The FTIR spectra at the optimized [Rh]/L ratio (1:5) ( Figure 5, spectra in red) exhibited a blue-shift of 3 cm -1 . Taken together with the DFT-optimized structure, we speculate that these shifts are due to the formation of C-H···F-C hydrogen bonds. A large number of studies into the blue-shifting C-H···X-type (X=F, Cl, N, O) 45-47 hydrogen bonding have been reported over the past two decades, and the magnitude of the blue-shift is the key factor that distinguishes it from conventional hydrogen bonding.

Conclusions
In conclusion, we have designed a class of monodentate uorine-containing phosphite ligands that are able to self-assemble through C-H···F-C interactions to form "pseudo" bidentate ligands. The Rh catalyst modi ed with the TTFP or TDFP ligand was proved highly active and regioselective for hydroformylation under extremely mild conditions. Experimental data and computational studies reveal that C-H···F-C hydrogen bonds are the key to the extremely high regioselectivity. Further synthetic applications of the C-H···F-C interactions are currently being investigated in our laboratory.

Methods
General procedure for the hydroformylation at near-ambient pressure Procedure A In a 5 mL vial equipped with a magnetic bar was added Rh(acac)(CO) 2 (0.01 mmol), ligand (0.01-0.1 mmol), alkene (2 mmol) and toluene (1 mL). After stirring for 5 min, the vial was transferred into an autoclave and replaced air with syngas over 5 times. Syngas (CO/H 2 =1:1, 1-2 atm) were charged in autoclave. The reaction mixture was stirred at 60-100 °C (oil bath) for 16 h. The pressure was carefully released in a fume hood after the reaction was cooled. The internal standard (n-dodecane, 1 mmol) was added to the collected reaction mixture (2 mmol scale). GC yield and n:iso ratios were calculated by GC-MS with an internal standard (n-dodecane).

Procedure B
In a 5 mL vial equipped with a magnetic bar was added Rh(acac)(CO) 2 (0.01 mmol), ligand TDFP (0.05 mmol), alkene (2 mmol) and toluene (1 mL). After stirring for 5 min, the vial was transferred into an autoclave and replaced air with syngas over 5 times. Syngas (CO/H 2 =1:1, 2 atm) were charged in autoclave. The reaction mixture was stirred at 70 °C (oil bath) for 16 h. The pressure was carefully released in a fume hood after the reaction was cooled. The collected reaction mixture (2 mmol scale) was dried under reduced pressure, and the mixture was subjected to column chromatography (silica gel, npentane/ether) to afford pure product. The nal product was weighed and characterized by 1 H NMR and GC-MS.

Data and code availability
There is no dataset and code associated with the paper. Characterization and spectra are included in the Supplemental information.   Optimizing the reaction conditions for the hydroformylation of 1-decene using various uorine-containing monodentate phosphite ligands.    ratio.