Silicon-fluorine non-covalent interaction guided distal functionalization of di- and tri- fluoro alkyl benzene

Silicon-fluorine non-covalent interaction guided distal functionalization of di- and tri- fluoro alkyl benzene | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Silicon-fluorine non-covalent interaction guided distal functionalization of di- and tri- fluoro alkyl benzene Debabrata Maiti, Suman Maji, Amal Sebastian, Partha Mondal, Kartic Manna, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6523406/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Fluoroalkyl arenes are essential in pharmaceutical development, with groups like CF3, CF2H, CH2CF3, and cyclopropyl-CF3 significantly enhancing medicinal properties. However, current methodologies that rely on metal-catalyzed cross-coupling reactions face challenges such as reductive elimination and limited reagent availability. This study introduces an alternative approach, leveraging Si/F non-covalent interactions for the first time in transition metal catalysis. This enables distal C−H functionalization of di- and tri-fluoroalkyl arenes using commercially available fluoroalkyl reagents and coupling partners, achieving meta-selectivity. The process facilitates the efficient synthesis of pharmacologically relevant compounds, including Cinacalcet, TrxR1, and the herbicide tetflupyrolimet, advancing sustainable and economical drug discovery. By employing a silicon-containing directing ligand, the approach ensures site-selective functionalization, marking a significant step toward green and efficient synthetic strategies. Physical sciences/Chemistry/Catalysis/Homogeneous catalysis Physical sciences/Chemistry/Catalysis/Catalyst synthesis Physical sciences/Chemistry/Catalysis/Catalytic mechanisms Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Introduction Fluoroalkyl arenes play a pivotal role in the development of life-saving medications. The trifluoromethyl (CF 3 ), difluoromethyl (CF 2 H), trifluoroethyl (CH 2 CF 3 ), and cyclopropyl-CF 3 groups act as bioisosteres, enhancing efficacy, stability, and pharmacokinetic profile (Fig. 1 A ). 1 – 5 A substantial number of current fluorinated pharmaceuticals are synthesized through metal-catalyzed cross-coupling reactions. Despite their effectiveness in introducing fluoroalkyl groups, the cross-coupling methodology behind this process is still evolving, facing challenges such as reductive elimination and the availability of this fluoroalkylating reagent, which is more difficult to prepare commercially (Fig. 1 B ). 6 – 11 We envisioned an alternative methodology using readily available fluoroalkyl arenes as the base structure. By commencing with fluoroalkyl arenes, chemists can potentially introduce other substituents into the arene ring directly through C-H activation, including the potentially exciting and elusive distal C-H functionalization. This strategy utilizes existing fluorinated groups, thereby simplifying the synthesis process and enhancing the overall efficiency and selectivity of the process. This hypothesis opens new avenues for advancing drug discovery and creating new pharmaceuticals with enhanced therapeutic properties. In this work, we visualized to promote metal catalyzed distal C-H functionalization 12 – 16 by relying on upon Lewis acid-base non-covalent interactions 17 – 22 between silicon and fluorine. Silicon-fluorine weak interactions authenticated by Fujiki fluoroalkylated rod-like polysilanes in 2006. 23 This non-covalent interaction has been primarily restricted to organo-catalysis. Shibata and co-workers in 2014 utilized Si/F weak interaction through-space for C-F bond cleavage in their stereoselective allylic stereoselective allylic trifluoromethylation protocol. 24 This pioneering work demonstrated the potential of Si/F interactions in facilitating complex chemical transformations. More recently, in 2023, Companyó and co-workers elegantly demonstrated Si/F weak interactions could induce reactivity and govern selectivity in the asymmetric defluorinative allylation of silyl enol ethers. 25 Their findings highlighted the utility of Si/F interactions in asymmetric synthesis, providing a new dimension to the role of non-covalent interactions in chemical reactivity. However, metal-catalysed transformation relying on the formation of Si/F weak interactions remains elusive. In our methodology, we hypothesized the presence of multiple adjacent fluorine atoms in trifluoromethyl arene may prompt alpha-effect which will induce a nucleophilic characteristic to fluorine atoms, surpassing their inherent electronegative traits and will enable the use of metal catalysis for elusive remote olefination process. Apart from trifluoromethyl arenes, we further hypothesized our methodology may be further extended to other fluoroalkyl arenes, such as difluoromethyl (CF 2 H), trifluoroethyl (CH 2 CF 3 ), and cyclopropyl-CF 3 , thereby may demonstrate the generality of our approach. Such a weak interaction controlled distal C-H functionalization methodology will pave the first instance of transition metal-catalyzed functionalization governed by silicon-fluorine non-covalent interactions (Fig. 1 C ). RESULTS AND DISCUSSION Optimization of the Reaction Conditions Our initial focus was on designing an appropriate directing template ( DT ) that could drive the reaction and promote the Si/F interaction. The directing template system that we envisaged had to accommodate three major components; a directing core for efficient binding of the transition metal to induce the C-H activation, a Si-atom containing moiety attached to an electronegative atom thereby inducing electron deficiency at the silicon center and finally, a linker to couple the aforementioned components in such a fashion so as to ensure an ideal balance between the steric and electronic parameters. This becomes the cardinal principle to ensure proximity of the transition metal towards our desired site of activation which in turn ensures streamlined reactivity and selectivity in our protocol (Fig. 2 A ). Our initial investigations included various biaryl systems hosting a weakly coordinating cyano-group (Fig. 2 B ). We selected trifluorotoluene as our model substrate and explored a wide range of silyl protecting groups attached to an oxygen atom. Initially the reactions were carried out at 80 o C for 24 hours. Control reactions without the directing group were carried out simultaneously and comparison of the results sadly showed no variation in selectivity and yield in presence of the simple biaryl-DT hosting a triisopropylsilyl (TIPS) protection ( DT 1 ). Consequently, we then carried out the reaction at room temperature in hopes that weak interactions could be facilitated by the lower temperatures. Much to our pleasure, the reaction gave initial selectivities up to 1:5.2:1.3 ( o : m : p ) and yields around 32% in presence of the directing template ( DT 1 ) whereas only a trace amount of product was observed in absence of any directing ligand. We were keen on fine-tuning the ligand to its utmost capabilities. Various silyl protecting groups such as tert -butyldimethylsilyl (TBDMS) ( DT 2 ), triisopropylsilyl (TIPS) ( DT 1 , DT 4 to DT 7 ) and tert -butyldiphenylsilyl (TBDPS) ( DT 3 ), we found that triisopropylsilyl (TIPS) protection offered the finest balance between steric and electronic factors, thereby enabling better yield and selectivity. We then set out to fine tune the ligand further by switching into a strongly coordinating pyrimidine directing core. But thorough evaluation of various ligands hosting a pyrimidine core ( DT 11 to DT 16 ) revealed them to be ineffective in our given protocol, affording little to no yield or selectivity. Further investigation with various cyano-containing biaryls were implemented by varying the electronic parameters ( DT 4 to DT 6 ). Although electron donating and withdrawing substituents were incorporated at various positions of directing template, the best results were obtained in absence of any additional substituents i.e., our default biaryl ligand DT 1 . We were then intrigued to probe into the effects of varying the linker length. After meticulous optimization, the mono aryl ligand DT 8 hosting the silicon moiety and cyano-directing core adjacent to each other, was found to be the superior ligand affording the desired meta -selective product at 62% yield. Rigorous optimization of other reaction conditions revealed the superiority of N -acetyl phenyl alanine over various monoprotected amino acids and other pyridone based systems as auxiliary ligands. Additionally, the reaction protocol was also found to be obsolete in the presence of any other solvent except HFIP. Optimization of other reaction parameters held parallel later revealed the selectivities to be as high as 1:30:3 ( o : m : p ), underlining the capabilities of this directing template ( DT 8 ). Substrate scope With the optimized conditions in hand (see supporting information for full optimization data), we then set out to explore the scope of this transformation (Fig. 3). Unbiased trifluorotoluene ( 3a ) gave us the desired meta -selective product with a selectivity of 1:30:3 ( o : m : p ). We then tried varying the substitution pattern at the 2-position of trifluorotoluene. Incorporation of electron donating groups such as methyl ( 3b ) and methoxy ( 3c ) were found to enhance the efficacy of our protocol, giving good to excellent yields and selectivities. Increasing the chain length of the substitution at 2nd position were also well tolerated as in the case of n -propyl ( 3d ) and n -butyl ( 3e ) substituents. Substitutions at the 3-position was also compatible in our protocol as chloromethyl ( 3f ) afforded the meta -selective product, overriding the inherent ortho and para directing tendency of chloromethyl. As we tried to further modulate the substitution patterns, we found that our protocol was hampered by the presence of a substitution at the 4-position. Elevating the reaction temperature to 60 o C enabled us to override this snag. This could be attributed to steric factors, hindering the close proximity required for site-selectivity. Introduction of methyl group ( 3g ) and electron withdrawing halogens ( 3h and 3i ) and ester group ( 3j and 3k ) at the 4-position were well tolerated at the elevated temperatures. Subsequently, we evaluated the site-selective nature of this protocol with substrates hosting two different trifluorotoluene motifs ( 3m and 3n ). Interestingly, we observed exclusive mono-functionalization with the meta -selective olefination occurring only at one of the rings even in the presence of excess amounts of the olefin partner. An ortho directing ketone group ( 3l ) gave way for Si/F weak interaction driven meta- selective product, albeit in moderate yield and selectivity. We then started probing into the generality of our protocol in case of long chain esters. Analogues from adamantyl acetic acid ( 3o ) and pelargonic acid ( 3p) were compatible and meta -olefination was observed with good yields and selectivities although it required the elevated temperature of 60 ο C. Further investigations were done on the efficacy of our protocol in case of complex entries and gratifyingly, trifluorotoluene tagged with borneol ( 3q ) gave us the meta -selective product. We then investigated the robustness of the method by varying the trifluoroalkyl-arene linker length. To out satisfaction, 4-bromo substituted trifluoroethyl derivatives ( 3r and 3s ) were well tolerated in the given protocol although corresponding Heck-product was also observed in minor amounts. Additionally, fully unbiased cyclopropyl derivatives ( 3t and 3u ) also gave the meta -olefinated product. Both these substrate classes demonstrate how the given protocol overrides the ortho and para directing tendency due to hyperconjugative effects of the benzylic proton as well as the + I effect. Additionally, the comparable yields and selectivities obtained on using fluorine-containing coupling partners ( 3u vs 3t ) point towards dominant Si/F interaction with DT 8 and arene. To further probe into the versatility of our protocol, we turned our focus to difluoromethyl derivatives. This protocol was well compatible with difluoromethyl arenes albeit with a lower selectivity in comparison to trifluoromethyl derivatives (Fig. 4). This observation can be attributed of acrylates with varied chain lengths. Ethyl ( 5a ), n -butyl ( 5b ), dodecyl acrylate ( 5c ), and docosyl acylate ( 5d ) gave satisfactory and comparable yields, demonstrating that the variation of chain length in coupling partners has no effect on the efficacy of the protocol. We then moved on to fluorine-containing acylates, such as 2,2,2-trifluoroethyl acrylate ( 5e ) and dodecafluoroheptyl acrylate ( 5f ) which once again gave moderate yields. Cyclic ( 5g ) & bicyclic acrylates ( 5h , 5i ), acrylic esters ( 5j ), acrylamides ( 5k ) and maleimides ( 5l ) were found to be compatible with our given protocol, demonstrating its functional group tolerance. Much less activated coupling partners such as methyl vinyl ketone ( 5m ) and sulphones ( 5n and 5o ) were also well tolerated. Interestingly, 1-acetyl cyclohexene ( 5p ) afforded the allylic product. Perfluorohexyl ethylene ( 5q ), another inactivated olefin partner, also gave the meta -selective product in good selectivities. Incorporation of electron-withdrawing substitutions such as bromide at the 2nd and 4th position of the arene ring was also compatible with the given protocol ( 5r and 5s ). Applications After observing an exclusive mono-functionalization on substrates hosting more than one trifluoromethyl motifs ( 3m and 3n ), we were intrigued by the possibility of a sequential/iterative di-functionalization (Fig. 5 B ). We prepared the mono-olefinated compound 3m using our Si/F weak interaction and then utilized this as the substrate for a second olefination using a different olefin coupling partner but by exploiting the same strategy ( 7a - 7c ). Gratifyingly, di-functionalization at both the meta -positions was feasible in satisfactory yields. Additionally, the large-scale synthesis (1 mmol) of 3a was carried out, affording 40% of the desired meta -olefinated product (Fig. 5 A ). We then wanted to explore the possibilities to extend our protocol towards the creation of diverse synthetic handles. The simple meta -olefinated trifluorotoluene substrate 3a easily underwent hydrolysis ( 8a ), reduction ( 8b ) and 1,4-addition ( 8c ) to afford the corresponding a , b –unsaturated acid 26 , primary alcohol 27 and nitromethane adduct 28 , respectively (Fig. 5 C ). These systems hold diverse potential in the construction of pharmacologically and industrially relevant compounds. 28 – 29 One such example can be demonstrated where we utilized the resultant primary alcohol towards the synthesis of the calcimimetic drug cinacalcet (Fig. 5 D ). Cinacalcet is a widely used drug for diseases and conditions induced by hypercalcemia, especially for treating chronic kidney malfunction. We begin with our Si/F interaction-controlled C−H olefination of trifluorotoluene, followed by its NaBH 4 mediated reduction into the aforementioned primary alcohol 8b which in turn is brominated using NBS ( 8d ). 30 The brominated product undergoes coupling with ( R )-1-(naphthalen-1-yl)ethan-1-amine to afford the desired drug 8e in significant yields. 31 To gain insight into the mechanistic narratives of our protocol, we began with a series of control reactions (Fig. 6 A ). Replacing the trifluoromethyl substrate 1a with toluene, we did not observe any olefination product. Similarly, no product formation was observed when the triisopropylsilyl (TIPS) protection of DT 1 was changed to the methyl protection of DT 17 . These reactions justify the requirement of the fluorine-containing substrate as well as the presence of a silicon containing directing group, which accounts to our basic hypothesis of Si/F interaction. To accumulate further evidence, we then carried out the NMR titration studies to probe the interaction between Si and F. We began with 19 F NMR studies where we took a mixture of trifluorotoluene and 0.5 equivalents of DT 8 in CDCl 3 which showed a significant shift of 6.2 Hz which further increased to 8.9 Hz on using equimolar quantities of DT 8 (Fig. 6 B ). Additionally, a similar shift was observed in the 1 H NMR spectrum probing the isopropyl protons of DT 8 (Fig. 6 C ). Addition of equimolar quantities of the substrate to DT 8 in CDCl 3 prompted a notable shift of 11.7 Hz. Addition of HFIP to this mixture did not show a consequential shift (~ 0.9 Hz), thereby nullifying the possibility of the fluorine atoms of HFIP participating in the Si/F interaction. To Further verify this postulate, we carried out NMR titration studies where equimolar quantities of DT 8 and substrate were taken in various other solvents. Apart from HFIP, we found that there was a significant peak shift in solvents like THF and toluene (see supporting information). This shows that the Si/F weak interaction is prevalent in other solvents as well although the reactions are not facilitated in them. This can be explained by the established crucial role of HFIP in Pd-catalysis in facilitating C−H activation, making the reaction feasible. 32 All these experiments help account for the proposed Si/F non-covalent interaction. We then set out to delve deeper into the intricate details and kinetics of our protocol. The primary kinetic isotope effect was evaluated by carrying out parallel reactions using 1d as well as its deuterated counterpart under standard conditions (Fig. 6 D ). The quantified K H /K D value of 1.24 suggests that C−H activation may not be the rate determining step. 33 Subsequently we carried out the reversibility experiment under D 2 -HFIP which demonstrated the reversibility of the C−H activation step which once again suggests improbability of it being the rate determining step (Fig. 6 E ). 34 To gain further insight into the reaction kinetics we carried out the order determination with respect to all variable parameters in the protocol (Fig. 6 F ). Notably, the order with respect to substrate and the olefin partner were both found to be ~ 1 which, corroborates with our assumption of C−H activation not being the rate determining step (see supporting information file for full data regarding order determination). 35 Additionally, we performed a case study comparing our protocol to a non-directed approach (no DTx ) (Fig. 6 G ). Gratifyingly, we found much superior yields and selectivities in all explored cases, demonstrating the supremacy of our protocol. Computational Studies To elucidate the mechanism of regioselective meta -olefination computational studies were performed employing density functional theory (DFT). The DFT calculations are performed using the Gaussian 16 B.01 36 suite of programs and geometry optimizations were performed at the ωB97X-D 37 /def2-SVP 38 level of theory. The choice of functional is based on its superior performance in modeling transition-metal-catalyzed reactions and non-covalent interactions. 39 – 40 The effect of solvation by solvent HFIP is also incorporated by implicit SMD 41 solvation model in the computed (single-point calculations) Gibbs free energy profile at the ωB97X-D/def2-TZVP 38 level of theory. The computations were performed on substrate 1a along with directing ligand DT 8 . The free energy profile for meta -selective olefination is shown in figure 7 . The reaction starts with C-H activation step. The C-H activation steps are calculated using both with MPAA and without MPAA ligands. Without the MPAA ligands meta -C-H activation occurs via TS-I m which has 7.6 kcal/mol more energy barrier than the MPAA ligand promoted meta -C-H activation state TS-1 m . The stabilization of TS-1 m over TS-I m is attributed to the formation of a [5,6]-membered palladacycle in TS-1 m . This palladacycle facilitates C-H bond activation by positioning the amide oxygen of the MPAA ligand optimally for the concerted metalation-deprotonation (CMD) mechanism. This observation is consistent with the experimental findings which suggests crucial role of external ancillary MPAA ligands to facilitate functionality of the reaction. The C-H activation state for both meta and para bond activations are similar in energy with ΔΔG ‡ (TS1m− TS1p) = 0.3 kcal/mol which suggests that C-H activation step is not the regioselectivity determining transition state. Also, we have calculated meta -C-H activation step without directing group (TS-1 m ") which is also energetically unfavored than TS-1 m by 3.6 kcal/mol. After the C-H activation step co-ordination of olefin takes place to form Int-3 m/p . The transfer of olefin moiety to the Pd at meta position occurs via TS-2 m with activation barrier of 5.4 kcal/mol and for the para position via TS-2 m with ΔG ‡ = 8.1 kcal/mol to produce Int-4 m/p . Next b -hydride elimination assisted by the MPAA ligand takes place via Int-5 m/p where b -hydrogen is slightly activated by Pd. Then Int-5 m/p undergoes ligand assisted b -hydride elimination step via TS-3 m/p and form the final product Int-6 m/p which is a Pd 0 complex. According to energy span model (50) b -hydride elimination step is the turnover frequency-determining transition state (TDTS) that determines regioselectivity ( meta over para ) for the overall reaction. Consistent with the experiment, the meta - TS-3 m is 5.2 kcal/ mol more stable than the para - TS-3 p (Fig. 9). The Si/F distances for TS-3 m and TS-3 p are 4.58 Å and 5.22 Å respectively. The Si/F interaction is usually observed when the distance is between the range 3–4.5Å. So, stabilization of TS-3 m is because of weak Si/F non-covalent interaction whereas in case of TS-3 p this Si/F interaction is completely absent. We have also calculated the b -hydride elimination step without the directing group and observed that the regioselectivity vanishes as energy difference between meta (TS-III m ) and para (TS-III p ) is only 0.7 kcal/mol. This finding again reaffirms the role of directing group in the regioselective C-H activation. The oxidation of Pd(0) with the Ag(I) oxidant take place to regenerate the Pd(II) catalyst. The recovery of catalyst Pd(OAc) 2 , using two molecules of oxidant AgOAc, is a complicated redox process and this process is expected to be highly exergonic and require low activation barriers. 42 Conclusion In summary, we present the first report of utilizing Si/F non-covalent interactions in the domain of transition metal catalysis for the meta -olefination of di- and tri- fluoroalkyl arenes at ambient temperatures. A simple mono-aryl directing template hosting an electron-deficient Si-moiety is found to establish a Lewis acid-base type interaction with the fluorine atoms of the substrate to drive functionalization at the meta -position. Comprehensive experimental and computational analysis gave profound insights on the significant role played by Si/F non-covalent interactions on dictating site-selectivity. The wide array of functionalized di- and tri- fluoroalkyl arenes enable access to a larger chemical space significant for the construction of valuable pharmacological skeletons which has been demonstrated by the total synthesis of the drug Cinacalcet. The concept of utilizing such weak interactions in the domain of metal catalysis will guide future development of sustainable distal C-H functionalization devoid of covalently attached directing template. METHODS SUMMARY General Procedure for the meta -selective olefination of di/trifluoromethyl arenes: In an oven-dried screw capped reaction tube charged with magnetic stir-bar, substrate (fluoro alkyl arene) (1 equiv., 0.1 mmol), Pd(OAc) 2 (10 mol%, 2.24 mg), N -Ac-Phe-OH (20 mol%, 4.1 mg), Directing Template ( DT 8 ) (1 equiv .), AgOAc (3 equiv .) in 1 mL of HFIP were added. After that, olefin (2.75 equiv .) was added to that reaction mixture. The reaction tube was well capped and placed in a RT (35 o C) or preheated oil bath at 60 o C with stirring (1000 rpm) for 36 h or 48 h. Upon completion of the reaction, the mixture was diluted with ethyl acetate and filtered through a celite pad. The filtrate was evaporated under reduced pressure and the crude mixture was purified by column chromatography using silica (100-200 mesh size) and petroleum ether/ethyl acetate as the eluent. The final meta -olefinated product was characterized by different spectroscopic techniques ( 1 H, 13 C, 19 F etc.). Declarations Acknowledgements Financial support received from SERB-India (CRG/2022/004197) is greatly acknowledged. Financial support received CSIR-India for S.M. and IIT Bombay (fellowship to K.M.). Author contributions D.M., and S.M. conceived the concept. S.M., A.T.S., and K.M. performed the reactions and analyzed the products. A.D., P.M., and A.K.P. carried out the computational investigation. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Competing interests: The authors declare no conflict of interest. Additional information Supplementary Information is linked to the online version of the paper Correspondence and requests for materials should be addressed to D.M. ( [email protected] ). Reprints and permissions information is available at www.nature.com/reprints References Müller, K., Faeh, C. & Diederich, F. Fluorine in pharmaceuticals: looking beyond intuition. Science 317 , 1881–1886 (2007). Sap, J. B. et al. Organophotoredox hydrodefluorination of trifluoromethylarenes with translational applicability to drug discovery. J. Am. Chem. Soc. 142 , 9181–9187 (2020). Gouverneur, V. & Müller, K. Fluorine in pharmaceutical and medicinal chemistry: From biophysical aspects to clinical applications . World Scientific (2012). Wang, J. et al. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6523406","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":457228898,"identity":"9b765e2a-0397-4d1f-aaa0-c03492d1af4e","order_by":0,"name":"Debabrata Maiti","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAuUlEQVRIiWNgGAWjYDCCAyBkYMPDxsAD5vMQp+WAQRoPGxspWoD4MAMDGxGKwYDv2uGHhz8UnJfhk+89wPCjhkHGnJAWydtpBkCH3QY6jC+BsecYA49lAwEtBrcTYFp4DBh4Gxh4DA4Q1JL+AajlHFgL41/itOSAbDkA1sJMlC2St3MKDpwxSAZqyUs4LHNMgrAWvtvpmz9U/LGzl28+e/Dhmxobe4JaUABQsQQp6kfBKBgFo2AU4AIAthQ90pcsB+wAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0001-8353-1306","institution":"Indian Institute of Technology Bombay","correspondingAuthor":true,"prefix":"","firstName":"Debabrata","middleName":"","lastName":"Maiti","suffix":""},{"id":457228899,"identity":"c797a839-ab7a-4b0b-b76e-fd3f03052939","order_by":1,"name":"Suman Maji","email":"","orcid":"","institution":"Iit Bombay","correspondingAuthor":false,"prefix":"","firstName":"Suman","middleName":"","lastName":"Maji","suffix":""},{"id":457228900,"identity":"ccd1d17e-722c-4874-b011-bf258290bd13","order_by":2,"name":"Amal Sebastian","email":"","orcid":"","institution":"Iit Bombay","correspondingAuthor":false,"prefix":"","firstName":"Amal","middleName":"","lastName":"Sebastian","suffix":""},{"id":457228901,"identity":"85ca0ab8-2f60-4606-84ab-3695ee203bc4","order_by":3,"name":"Partha Mondal","email":"","orcid":"","institution":"Indian Association for the Cultivation of Science","correspondingAuthor":false,"prefix":"","firstName":"Partha","middleName":"","lastName":"Mondal","suffix":""},{"id":457228902,"identity":"c1ff9ebf-8928-4b55-9aa7-178ee26e8eb3","order_by":4,"name":"Kartic Manna","email":"","orcid":"","institution":"Iit Bombay","correspondingAuthor":false,"prefix":"","firstName":"Kartic","middleName":"","lastName":"Manna","suffix":""},{"id":457228903,"identity":"d12a66a1-ab7a-4ffb-924d-927ef62c1032","order_by":5,"name":"Arun Pal","email":"","orcid":"","institution":"Indian Association for the Cultivation of Science","correspondingAuthor":false,"prefix":"","firstName":"Arun","middleName":"","lastName":"Pal","suffix":""},{"id":457228904,"identity":"979a6af0-8f10-4b09-8ed9-9e2aea9bec2c","order_by":6,"name":"Ayan Datta","email":"","orcid":"https://orcid.org/0000-0001-6723-087X","institution":"IACS Kolkata","correspondingAuthor":false,"prefix":"","firstName":"Ayan","middleName":"","lastName":"Datta","suffix":""}],"badges":[],"createdAt":"2025-04-24 19:50:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6523406/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6523406/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82860653,"identity":"5d41df4b-60d2-49a7-83f0-b6cba02b2aa9","added_by":"auto","created_at":"2025-05-16 06:49:12","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":614278,"visible":true,"origin":"","legend":"\u003cp\u003e(A) Representative molecules containing di- and tri- fluoroalkyl benzene. (B) Traditional cross-coupling methodology for di- and tri- fluoroalkylation and our proposed strategy. (C) This work: utilizing Si/F weak interaction for olefination of di/tri fluoroalkyl arenes\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6523406/v1/9ca58ef0ca1e9590b9091458.png"},{"id":82860654,"identity":"2fbd0632-1d3e-4c34-84db-d0ddbd47ca04","added_by":"auto","created_at":"2025-05-16 06:49:12","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":633307,"visible":true,"origin":"","legend":"\u003cp\u003eDesign and evaluation of various Si-embedded directing templates (\u003cstrong\u003eDT\u003c/strong\u003e). \u003csup\u003ea\u003c/sup\u003eYield and regioselectivity were determined by \u003csup\u003e1\u003c/sup\u003eH-NMR analysis with reference to 1,3,5-trimethoxy benzene as an internal standard.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6523406/v1/8b398acd77d7b8a0fd5920f3.png"},{"id":82861493,"identity":"d843ef70-d9c9-48de-bbb7-77c1eaf40941","added_by":"auto","created_at":"2025-05-16 06:57:12","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":579088,"visible":true,"origin":"","legend":"\u003cp\u003eScope with trifluoromethyl arenes. Isolated yields are reported. Stndard condition: trifluoromethyl arene (0.1 mmol), olefin (2.75 \u003cem\u003eequiv\u003c/em\u003e.), DT\u003csub\u003e8 \u003c/sub\u003e(1 \u003cem\u003eequiv\u003c/em\u003e.), Pd(Opiv)\u003csub\u003e2\u003c/sub\u003e (10 mol%), \u003cem\u003eN\u003c/em\u003e-Ac-Phe-OH (20 mol%), AgOAc (3 \u003cem\u003eequiv\u003c/em\u003e.), HFIP (1 mL), rt, 36 h. \u003csup\u003ea\u003c/sup\u003e48 h. \u003csup\u003eb\u003c/sup\u003e60 \u003csup\u003eo\u003c/sup\u003eC\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6523406/v1/81ff01b2b03d1907deb9a2a9.png"},{"id":82860656,"identity":"14e86303-24a7-4833-adc0-7bba17143456","added_by":"auto","created_at":"2025-05-16 06:49:12","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":440318,"visible":true,"origin":"","legend":"\u003cp\u003eScope with difluoromethyl arene. Isolated yields are reported. Difluoromethyl arene (0.1 mmol), olefin (2.75 \u003cem\u003eequiv\u003c/em\u003e.), DT\u003csub\u003e8\u003c/sub\u003e (1 \u003cem\u003eequiv\u003c/em\u003e.), Pd(Opiv)\u003csub\u003e2\u003c/sub\u003e (10 mol%), \u003cem\u003eN\u003c/em\u003e-Ac-Phe-OH (20 mol%), AgOAc (3 \u003cem\u003eequiv\u003c/em\u003e.), HFIP (1 mL), rt, 36 h. \u003csup\u003ea\u003c/sup\u003e48 h. \u003csup\u003eb\u003c/sup\u003e60 \u003csup\u003eo\u003c/sup\u003eC.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6523406/v1/deb5fa0a3a00d97084e758f3.png"},{"id":82860669,"identity":"4eb58c8e-7ad1-4d68-9a64-71ff3147320c","added_by":"auto","created_at":"2025-05-16 06:49:12","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":581676,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA\u003c/strong\u003e. Large scale synthesis \u003cstrong\u003eB.\u003c/strong\u003e Iterative/sequential olefination of substrates with two different trifluoromethyl moieties \u003cstrong\u003eC.\u003c/strong\u003e Exploring other synthetic transformations of the olefinated products \u003cstrong\u003eD.\u003c/strong\u003e The 4-step total synthesis of cinacalcet. Conditions: (I) \u003cstrong\u003e3a\u003c/strong\u003e (0.2 mmol), NaOH (6 \u003cem\u003eequiv\u003c/em\u003e.), EtOH/H\u003csub\u003e2\u003c/sub\u003eO (1:1), 120 \u003csup\u003eo\u003c/sup\u003eC, 24 h. (II) \u003cstrong\u003e3a\u003c/strong\u003e (0.2 mmol), NaBH\u003csub\u003e4\u003c/sub\u003e (3 \u003cem\u003eequiv\u003c/em\u003e.), PEG 400, 65 \u003csup\u003eo\u003c/sup\u003eC, 10 h. (III) \u003cstrong\u003e3a \u003c/strong\u003e(0.2 mmol), CH\u003csub\u003e3\u003c/sub\u003eNO\u003csub\u003e2\u003c/sub\u003e (2 \u003cem\u003eequiv\u003c/em\u003e.), DBU (3 \u003cem\u003eequiv\u003c/em\u003e.), 0 \u003csup\u003eo\u003c/sup\u003eC to rt, 3 h. (IV) \u003cstrong\u003e3a\u003c/strong\u003e (0.2 mmol), NBS (1.2 equiv.), PPh\u003csub\u003e3 \u003c/sub\u003e(1.2 \u003cem\u003eequiv\u003c/em\u003e.), DCM, rt, 1 h. (V) 3a (0.2 mmol), (\u003cem\u003eR\u003c/em\u003e)-1-(naphthalen-1-yl)ethan-1-amine (1.5 \u003cem\u003eequiv\u003c/em\u003e.), K\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e (4 \u003cem\u003eequiv\u003c/em\u003e.), toluene, 120 \u003csup\u003eo\u003c/sup\u003eC, 64 h.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-6523406/v1/f714bc0069548430b7486b99.png"},{"id":82860668,"identity":"e2352ba0-a072-41d8-8175-64d05e6cb2e8","added_by":"auto","created_at":"2025-05-16 06:49:12","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":897807,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA.\u003c/strong\u003e Control experiments investigating the proposed Si/F interaction \u003cstrong\u003eB.\u003c/strong\u003e \u003csup\u003e19\u003c/sup\u003eF NMR titration study results using varied amounts of \u003cstrong\u003eDT\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e8\u003c/strong\u003e\u003c/sub\u003e with the substrate \u003cstrong\u003eC.\u003c/strong\u003e \u003csup\u003e1\u003c/sup\u003eH NMR titration studies using equimolar quantities of substrate, \u003cstrong\u003eDT\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e8\u003c/strong\u003e\u003c/sub\u003e and HFIP \u003cstrong\u003eD.\u003c/strong\u003e Evaluation of kinetic isotope effect \u003cstrong\u003eE.\u003c/strong\u003e Reversibility experiment to check the reversibility of C-H activation \u003cstrong\u003eF.\u003c/strong\u003e Order determination studies with respect to substrate and olefin \u003cstrong\u003eG.\u003c/strong\u003e Comparative evaluation of yields and selectivities between this approach and non-directed approach.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-6523406/v1/1e514b3fc09704e34bb66090.png"},{"id":82861501,"identity":"d0369628-fc51-46af-84a9-fb510e25b84e","added_by":"auto","created_at":"2025-05-16 06:57:12","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":717777,"visible":true,"origin":"","legend":"\u003cp\u003eRelative free energy profile diagram for non-covalent interaction induced Pd-catalyzed \u003cem\u003emeta\u003c/em\u003e-olefination\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-6523406/v1/5026fc34b004b39dffe5c176.png"},{"id":82860675,"identity":"dfbe80f4-cfde-4de3-9797-c4cdfc6df5dc","added_by":"auto","created_at":"2025-05-16 06:49:12","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":296638,"visible":true,"origin":"","legend":"\u003cp\u003eThe natural bond orbital (NBO) analysis of \u003cstrong\u003eTS-1m\u003c/strong\u003e. Bond distances are in Å.\u003c/p\u003e","description":"","filename":"8.png","url":"https://assets-eu.researchsquare.com/files/rs-6523406/v1/3b38207ca669a845fd56c136.png"},{"id":82861494,"identity":"740461bc-27ee-429d-97b6-d4c18b20c4e7","added_by":"auto","created_at":"2025-05-16 06:57:12","extension":"png","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":283614,"visible":true,"origin":"","legend":"\u003cp\u003eOptimized geometries of \u003cstrong\u003eTS-3m\u003c/strong\u003e and \u003cstrong\u003eTS-3p\u003c/strong\u003e with Si/F distances in Å.\u003c/p\u003e","description":"","filename":"9.png","url":"https://assets-eu.researchsquare.com/files/rs-6523406/v1/a3d6d917a67db0989d8b2c72.png"},{"id":87020138,"identity":"3a52f32f-5e82-498f-870f-5785290b335c","added_by":"auto","created_at":"2025-07-18 10:59:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5163371,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6523406/v1/fd1376ef-2381-46c5-97a8-72cdc45a0762.pdf"},{"id":82860662,"identity":"6573d534-bec2-4aec-8add-60057f3c4cc3","added_by":"auto","created_at":"2025-05-16 06:49:12","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":14718525,"visible":true,"origin":"","legend":"supporting information","description":"","filename":"supportinginformation.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6523406/v1/43c841aa2913e0f15f875eea.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Silicon-fluorine non-covalent interaction guided distal functionalization of di- and tri- fluoro alkyl benzene","fulltext":[{"header":"Introduction","content":"\u003cp\u003eFluoroalkyl arenes play a pivotal role in the development of life-saving medications. The trifluoromethyl (CF\u003csub\u003e3\u003c/sub\u003e), difluoromethyl (CF\u003csub\u003e2\u003c/sub\u003eH), trifluoroethyl (CH\u003csub\u003e2\u003c/sub\u003eCF\u003csub\u003e3\u003c/sub\u003e), and cyclopropyl-CF\u003csub\u003e3\u003c/sub\u003e groups act as bioisosteres, enhancing efficacy, stability, and pharmacokinetic profile (Fig.\u0026nbsp;1\u003cstrong\u003eA\u003c/strong\u003e).\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e–\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e A substantial number of current fluorinated pharmaceuticals are synthesized through metal-catalyzed cross-coupling reactions. Despite their effectiveness in introducing fluoroalkyl groups, the cross-coupling methodology behind this process is still evolving, facing challenges such as reductive elimination and the availability of this fluoroalkylating reagent, which is more difficult to prepare commercially (Fig.\u0026nbsp;1\u003cstrong\u003eB\u003c/strong\u003e).\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e–\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e We envisioned an alternative methodology using readily available fluoroalkyl arenes as the base structure. By commencing with fluoroalkyl arenes, chemists can potentially introduce other substituents into the arene ring directly through C-H activation, including the potentially exciting and elusive distal C-H functionalization. This strategy utilizes existing fluorinated groups, thereby simplifying the synthesis process and enhancing the overall efficiency and selectivity of the process. This hypothesis opens new avenues for advancing drug discovery and creating new pharmaceuticals with enhanced therapeutic properties.\u003c/p\u003e\n\u003cp\u003eIn this work, we visualized to promote metal catalyzed distal C-H functionalization\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e–\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e by relying on upon Lewis acid-base non-covalent interactions\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e–\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e between silicon and fluorine. Silicon-fluorine weak interactions authenticated by Fujiki fluoroalkylated rod-like polysilanes in 2006.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e This non-covalent interaction has been primarily restricted to organo-catalysis. Shibata and co-workers in 2014 utilized Si/F weak interaction through-space for C-F bond cleavage in their stereoselective allylic stereoselective allylic trifluoromethylation protocol.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e This pioneering work demonstrated the potential of Si/F interactions in facilitating complex chemical transformations. More recently, in 2023, Companyó and co-workers elegantly demonstrated Si/F weak interactions could induce reactivity and govern selectivity in the asymmetric defluorinative allylation of silyl enol ethers.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e Their findings highlighted the utility of Si/F interactions in asymmetric synthesis, providing a new dimension to the role of non-covalent interactions in chemical reactivity. However, metal-catalysed transformation relying on the formation of Si/F weak interactions remains elusive.\u003c/p\u003e\n\u003cp\u003eIn our methodology, we hypothesized the presence of multiple adjacent fluorine atoms in trifluoromethyl arene may prompt alpha-effect which will induce a nucleophilic characteristic to fluorine atoms, surpassing their inherent electronegative traits and will enable the use of metal catalysis for elusive remote olefination process. Apart from trifluoromethyl arenes, we further hypothesized our methodology may be further extended to other fluoroalkyl arenes, such as difluoromethyl (CF\u003csub\u003e2\u003c/sub\u003eH), trifluoroethyl (CH\u003csub\u003e2\u003c/sub\u003eCF\u003csub\u003e3\u003c/sub\u003e), and cyclopropyl-CF\u003csub\u003e3\u003c/sub\u003e, thereby may demonstrate the generality of our approach. Such a weak interaction controlled distal C-H functionalization methodology will pave the first instance of transition metal-catalyzed functionalization governed by silicon-fluorine non-covalent interactions (Fig.\u0026nbsp;1\u003cstrong\u003eC\u003c/strong\u003e).\u003c/p\u003e\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n"},{"header":"RESULTS AND DISCUSSION","content":"\u003cp\u003e\u003cstrong\u003eOptimization of the Reaction Conditions\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eOur initial focus was on designing an appropriate directing template (\u003cstrong\u003eDT\u003c/strong\u003e) that could drive the reaction and promote the Si/F interaction. The directing template system that we envisaged had to accommodate three major components; a directing core for efficient binding of the transition metal to induce the C-H activation, a Si-atom containing moiety attached to an electronegative atom thereby inducing electron deficiency at the silicon center and finally, a linker to couple the aforementioned components in such a fashion so as to ensure an ideal balance between the steric and electronic parameters. This becomes the cardinal principle to ensure proximity of the transition metal towards our desired site of activation which in turn ensures streamlined reactivity and selectivity in our protocol (Fig.\u0026nbsp;2\u003cstrong\u003eA\u003c/strong\u003e).\u003c/p\u003e\u003cp\u003eOur initial investigations included various biaryl systems hosting a weakly coordinating cyano-group (Fig.\u0026nbsp;2\u003cstrong\u003eB\u003c/strong\u003e). We selected trifluorotoluene as our model substrate and explored a wide range of silyl protecting groups attached to an oxygen atom. Initially the reactions were carried out at 80 \u003csup\u003eo\u003c/sup\u003eC for 24 hours. Control reactions without the directing group were carried out simultaneously and comparison of the results sadly showed no variation in selectivity and yield in presence of the simple biaryl-DT hosting a triisopropylsilyl (TIPS) protection (\u003cstrong\u003eDT\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/sub\u003e). Consequently, we then carried out the reaction at room temperature in hopes that weak interactions could be facilitated by the lower temperatures.\u003c/p\u003e\u003cp\u003eMuch to our pleasure, the reaction gave initial selectivities up to 1:5.2:1.3 (\u003cem\u003eo\u003c/em\u003e:\u003cem\u003em\u003c/em\u003e:\u003cem\u003ep\u003c/em\u003e) and yields around 32% in presence of the directing template (\u003cstrong\u003eDT\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/sub\u003e) whereas only a trace amount of product was observed in absence of any directing ligand. We were keen on fine-tuning the ligand to its utmost capabilities. Various silyl protecting groups such as \u003cem\u003etert\u003c/em\u003e-butyldimethylsilyl (TBDMS) (\u003cstrong\u003eDT\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/sub\u003e), triisopropylsilyl (TIPS) (\u003cstrong\u003eDT\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/sub\u003e, \u003cstrong\u003eDT\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e4\u003c/strong\u003e\u003c/sub\u003e to \u003cstrong\u003eDT\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e7\u003c/strong\u003e\u003c/sub\u003e) and \u003cem\u003etert\u003c/em\u003e-butyldiphenylsilyl (TBDPS) (\u003cstrong\u003eDT\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e3\u003c/strong\u003e\u003c/sub\u003e), we found that triisopropylsilyl (TIPS) protection offered the finest balance between steric and electronic factors, thereby enabling better yield and selectivity. We then set out to fine tune the ligand further by switching into a strongly coordinating pyrimidine directing core. But thorough evaluation of various ligands hosting a pyrimidine core (\u003cstrong\u003eDT\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e11\u003c/strong\u003e\u003c/sub\u003e to \u003cstrong\u003eDT\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e16\u003c/strong\u003e\u003c/sub\u003e) revealed them to be ineffective in our given protocol, affording little to no yield or selectivity. Further investigation with various cyano-containing biaryls were implemented by varying the electronic parameters (\u003cstrong\u003eDT\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e4\u003c/strong\u003e\u003c/sub\u003e to \u003cstrong\u003eDT\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e6\u003c/strong\u003e\u003c/sub\u003e). Although electron donating and withdrawing substituents were incorporated at various positions of directing template, the best results were obtained in absence of any additional substituents i.e., our default biaryl ligand \u003cstrong\u003eDT\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/sub\u003e. We were then intrigued to probe into the effects of varying the linker length. After meticulous optimization, the mono aryl ligand \u003cstrong\u003eDT\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e8\u003c/strong\u003e\u003c/sub\u003e hosting the silicon moiety and cyano-directing core adjacent to each other, was found to be the superior ligand affording the desired \u003cem\u003emeta\u003c/em\u003e-selective product at 62% yield. Rigorous optimization of other reaction conditions revealed the superiority of \u003cem\u003eN\u003c/em\u003e-acetyl phenyl alanine over various monoprotected amino acids and other pyridone based systems as auxiliary ligands. Additionally, the reaction protocol was also found to be obsolete in the presence of any other solvent except HFIP. Optimization of other reaction parameters held parallel later revealed the selectivities to be as high as 1:30:3 (\u003cem\u003eo\u003c/em\u003e:\u003cem\u003em\u003c/em\u003e:\u003cem\u003ep\u003c/em\u003e), underlining the capabilities of this directing template (\u003cstrong\u003eDT\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e8\u003c/strong\u003e\u003c/sub\u003e).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eSubstrate scope\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eWith the optimized conditions in hand (see supporting information for full optimization data), we then set out to explore the scope of this transformation (Fig.\u0026nbsp;3). Unbiased trifluorotoluene (\u003cstrong\u003e3a\u003c/strong\u003e) gave us the desired \u003cem\u003emeta\u003c/em\u003e-selective product with a selectivity of 1:30:3 (\u003cem\u003eo\u003c/em\u003e:\u003cem\u003em\u003c/em\u003e:\u003cem\u003ep\u003c/em\u003e). We then tried varying the substitution pattern at the 2-position of trifluorotoluene. Incorporation of electron donating groups such as methyl (\u003cstrong\u003e3b\u003c/strong\u003e) and methoxy (\u003cstrong\u003e3c\u003c/strong\u003e) were found to enhance the efficacy of our protocol, giving good to excellent yields and selectivities. Increasing the chain length of the substitution at 2nd position were also well tolerated as in the case of \u003cem\u003en\u003c/em\u003e-propyl (\u003cstrong\u003e3d\u003c/strong\u003e) and \u003cem\u003en\u003c/em\u003e-butyl (\u003cstrong\u003e3e\u003c/strong\u003e) substituents. Substitutions at the 3-position was also compatible in our protocol as chloromethyl (\u003cstrong\u003e3f\u003c/strong\u003e) afforded the \u003cem\u003emeta\u003c/em\u003e-selective product, overriding the inherent \u003cem\u003eortho\u003c/em\u003e and \u003cem\u003epara\u003c/em\u003e directing tendency of chloromethyl. As we tried to further modulate the substitution patterns, we found that our protocol was hampered by the presence of a substitution at the 4-position. Elevating the reaction temperature to 60 \u003csup\u003eo\u003c/sup\u003eC enabled us to override this snag. This could be attributed to steric factors, hindering the close proximity required for site-selectivity. Introduction of methyl group (\u003cstrong\u003e3g\u003c/strong\u003e) and electron withdrawing halogens (\u003cstrong\u003e3h\u003c/strong\u003e and \u003cstrong\u003e3i\u003c/strong\u003e) and ester group (\u003cstrong\u003e3j\u003c/strong\u003e and \u003cstrong\u003e3k\u003c/strong\u003e) at the 4-position were well tolerated at the elevated temperatures. Subsequently, we evaluated the site-selective nature of this protocol with substrates hosting two different trifluorotoluene motifs (\u003cstrong\u003e3m\u003c/strong\u003e and \u003cstrong\u003e3n\u003c/strong\u003e). Interestingly, we observed exclusive mono-functionalization with the \u003cem\u003emeta\u003c/em\u003e-selective olefination occurring only at one of the rings even in the presence of excess amounts of the olefin partner. An \u003cem\u003eortho\u003c/em\u003e directing ketone group (\u003cstrong\u003e3l\u003c/strong\u003e) gave way for Si/F weak interaction driven \u003cem\u003emeta-\u003c/em\u003e selective product, albeit in moderate yield and selectivity. We then started probing into the generality of our protocol in case of long chain esters. Analogues from adamantyl acetic acid (\u003cstrong\u003e3o\u003c/strong\u003e) and pelargonic acid (\u003cstrong\u003e3p)\u003c/strong\u003e were compatible and \u003cem\u003emeta\u003c/em\u003e-olefination was observed with good yields and selectivities although it required the elevated temperature of 60 \u003csup\u003eο\u003c/sup\u003eC. Further investigations were done on the efficacy of our protocol in case of complex entries and gratifyingly, trifluorotoluene tagged with borneol (\u003cstrong\u003e3q\u003c/strong\u003e) gave us the \u003cem\u003emeta\u003c/em\u003e-selective product.\u003c/p\u003e\u003cp\u003eWe then investigated the robustness of the method by varying the trifluoroalkyl-arene linker length. To out satisfaction, 4-bromo substituted trifluoroethyl derivatives (\u003cstrong\u003e3r\u003c/strong\u003e and \u003cstrong\u003e3s\u003c/strong\u003e) were well tolerated in the given protocol although corresponding Heck-product was also observed in minor amounts. Additionally, fully unbiased cyclopropyl derivatives (\u003cstrong\u003e3t\u003c/strong\u003e and \u003cstrong\u003e3u\u003c/strong\u003e) also gave the \u003cem\u003emeta\u003c/em\u003e-olefinated product. Both these substrate classes demonstrate how the given protocol overrides the \u003cem\u003eortho\u003c/em\u003e and \u003cem\u003epara\u003c/em\u003e directing tendency due to hyperconjugative effects of the benzylic proton as well as the + I effect. Additionally, the comparable yields and selectivities obtained on using fluorine-containing coupling partners (\u003cstrong\u003e3u\u003c/strong\u003e vs \u003cstrong\u003e3t\u003c/strong\u003e) point towards dominant Si/F interaction with \u003cstrong\u003eDT\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e8\u003c/strong\u003e\u003c/sub\u003e and arene.\u003c/p\u003e\u003cp\u003eTo further probe into the versatility of our protocol, we turned our focus to difluoromethyl derivatives. This protocol was well compatible with difluoromethyl arenes albeit with a lower selectivity in comparison to trifluoromethyl derivatives (Fig. 4). This observation can be attributed of acrylates with varied chain lengths. Ethyl (\u003cstrong\u003e5a\u003c/strong\u003e), \u003cem\u003en\u003c/em\u003e-butyl (\u003cstrong\u003e5b\u003c/strong\u003e), dodecyl acrylate (\u003cstrong\u003e5c\u003c/strong\u003e), and docosyl acylate (\u003cstrong\u003e5d\u003c/strong\u003e) gave satisfactory and comparable yields, demonstrating that the variation of chain length in coupling partners has no effect on the efficacy of the protocol. We then moved on to fluorine-containing acylates, such as 2,2,2-trifluoroethyl acrylate (\u003cstrong\u003e5e\u003c/strong\u003e) and dodecafluoroheptyl acrylate (\u003cstrong\u003e5f\u003c/strong\u003e) which once again gave moderate yields. Cyclic (\u003cstrong\u003e5g\u003c/strong\u003e) \u0026amp; bicyclic acrylates (\u003cstrong\u003e5h\u003c/strong\u003e, \u003cstrong\u003e5i\u003c/strong\u003e), acrylic esters (\u003cstrong\u003e5j\u003c/strong\u003e), acrylamides (\u003cstrong\u003e5k\u003c/strong\u003e) and maleimides (\u003cstrong\u003e5l\u003c/strong\u003e) were found to be compatible with our given protocol, demonstrating its functional group tolerance. Much less activated coupling partners such as methyl vinyl ketone (\u003cstrong\u003e5m\u003c/strong\u003e) and sulphones (\u003cstrong\u003e5n\u003c/strong\u003e and \u003cstrong\u003e5o\u003c/strong\u003e) were also well tolerated. Interestingly, 1-acetyl cyclohexene (\u003cstrong\u003e5p\u003c/strong\u003e) afforded the allylic product. Perfluorohexyl ethylene (\u003cstrong\u003e5q\u003c/strong\u003e), another inactivated olefin partner, also gave the \u003cem\u003emeta\u003c/em\u003e-selective product in good selectivities. Incorporation of electron-withdrawing substitutions such as bromide at the 2nd and 4th position of the arene ring was also compatible with the given protocol (\u003cstrong\u003e5r\u003c/strong\u003e and \u003cstrong\u003e5s\u003c/strong\u003e).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eApplications\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eAfter observing an exclusive mono-functionalization on substrates hosting more than one trifluoromethyl motifs (\u003cstrong\u003e3m\u003c/strong\u003e and \u003cstrong\u003e3n\u003c/strong\u003e), we were intrigued by the possibility of a sequential/iterative di-functionalization (Fig.\u0026nbsp;5\u003cstrong\u003eB\u003c/strong\u003e). We prepared the mono-olefinated compound \u003cstrong\u003e3m\u003c/strong\u003e using our Si/F weak interaction and then utilized this as the substrate for a second olefination using a different olefin coupling partner but by exploiting the same strategy (\u003cstrong\u003e7a\u003c/strong\u003e-\u003cstrong\u003e7c\u003c/strong\u003e). Gratifyingly, di-functionalization at both the \u003cem\u003emeta\u003c/em\u003e-positions was feasible in satisfactory yields. Additionally, the large-scale synthesis (1 mmol) of \u003cstrong\u003e3a\u003c/strong\u003e was carried out, affording 40% of the desired \u003cem\u003emeta\u003c/em\u003e-olefinated product (Fig.\u0026nbsp;5\u003cstrong\u003eA\u003c/strong\u003e). We then wanted to explore the possibilities to extend our protocol towards the creation of diverse synthetic handles. The simple \u003cem\u003emeta\u003c/em\u003e-olefinated trifluorotoluene substrate \u003cstrong\u003e3a\u003c/strong\u003e easily underwent hydrolysis (\u003cstrong\u003e8a\u003c/strong\u003e), reduction (\u003cstrong\u003e8b\u003c/strong\u003e) and 1,4-addition (\u003cstrong\u003e8c\u003c/strong\u003e) to afford the corresponding \u003cem\u003ea\u003c/em\u003e,\u003cem\u003eb\u003c/em\u003e–unsaturated acid\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e, primary alcohol\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e and nitromethane adduct\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e, respectively (Fig.\u0026nbsp;5\u003cstrong\u003eC\u003c/strong\u003e). These systems hold diverse potential in the construction of pharmacologically and industrially relevant compounds.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e–\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e One such example can be demonstrated where we utilized the resultant primary alcohol towards the synthesis of the calcimimetic drug cinacalcet (Fig. 5\u003cstrong\u003eD\u003c/strong\u003e). Cinacalcet is a widely used drug for diseases and conditions induced by hypercalcemia, especially for treating chronic kidney malfunction. We begin with our Si/F interaction-controlled C−H olefination of trifluorotoluene, followed by its NaBH\u003csub\u003e4\u003c/sub\u003e mediated reduction into the aforementioned primary alcohol \u003cstrong\u003e8b\u003c/strong\u003e which in turn is brominated using NBS (\u003cstrong\u003e8d\u003c/strong\u003e).\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e The brominated product undergoes coupling with (\u003cem\u003eR\u003c/em\u003e)-1-(naphthalen-1-yl)ethan-1-amine to afford the desired drug \u003cstrong\u003e8e\u003c/strong\u003e in significant yields.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eTo gain insight into the mechanistic narratives of our protocol, we began with a series of control reactions (Fig.\u0026nbsp;6\u003cstrong\u003eA\u003c/strong\u003e). Replacing the trifluoromethyl substrate \u003cstrong\u003e1a\u003c/strong\u003e with toluene, we did not observe any olefination product. Similarly, no product formation was observed when the triisopropylsilyl (TIPS) protection of \u003cstrong\u003eDT\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e1\u003c/strong\u003e\u003c/sub\u003e was changed to the methyl protection of \u003cstrong\u003eDT\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e17\u003c/strong\u003e\u003c/sub\u003e. These reactions justify the requirement of the fluorine-containing substrate as well as the presence of a silicon containing directing group, which accounts to our basic hypothesis of Si/F interaction. To accumulate further evidence, we then carried out the NMR titration studies to probe the interaction between Si and F. We began with \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003eF NMR studies where we took a mixture of trifluorotoluene and 0.5 equivalents of \u003cstrong\u003eDT\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e8\u003c/strong\u003e\u003c/sub\u003e in CDCl\u003csub\u003e3\u003c/sub\u003e which showed a significant shift of 6.2 Hz which further increased to 8.9 Hz on using equimolar quantities of \u003cstrong\u003eDT\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e8\u003c/strong\u003e\u003c/sub\u003e (Fig. 6\u003cstrong\u003eB\u003c/strong\u003e). Additionally, a similar shift was observed in the \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003eH NMR spectrum probing the isopropyl protons of \u003cstrong\u003eDT\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e8\u003c/strong\u003e\u003c/sub\u003e (Fig. 6\u003cstrong\u003eC\u003c/strong\u003e). Addition of equimolar quantities of the substrate to \u003cstrong\u003eDT\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e8\u003c/strong\u003e\u003c/sub\u003e in CDCl\u003csub\u003e3\u003c/sub\u003e prompted a notable shift of 11.7 Hz. Addition of HFIP to this mixture did not show a consequential shift (~ 0.9 Hz), thereby nullifying the possibility of the fluorine atoms of HFIP participating in the Si/F interaction.\u003c/p\u003e\u003cp\u003eTo Further verify this postulate, we carried out NMR titration studies where equimolar quantities of \u003cstrong\u003eDT\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003e8\u003c/strong\u003e\u003c/sub\u003e and substrate were taken in various other solvents. Apart from HFIP, we found that there was a significant peak shift in solvents like THF and toluene (see supporting information). This shows that the Si/F weak interaction is prevalent in other solvents as well although the reactions are not facilitated in them. This can be explained by the established crucial role of HFIP in Pd-catalysis in facilitating C−H activation, making the reaction feasible.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e All these experiments help account for the proposed Si/F non-covalent interaction. We then set out to delve deeper into the intricate details and kinetics of our protocol. The primary kinetic isotope effect was evaluated by carrying out parallel reactions using \u003cstrong\u003e1d\u003c/strong\u003e as well as its deuterated counterpart under standard conditions (Fig. 6\u003cstrong\u003eD\u003c/strong\u003e). The quantified K\u003csub\u003eH\u003c/sub\u003e/K\u003csub\u003eD\u003c/sub\u003e value of 1.24 suggests that C−H activation may not be the rate determining step.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e Subsequently we carried out the reversibility experiment under D\u003csub\u003e2\u003c/sub\u003e-HFIP which demonstrated the reversibility of the C−H activation step which once again suggests improbability of it being the rate determining step (Fig.\u0026nbsp;6\u003cstrong\u003eE\u003c/strong\u003e).\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e To gain further insight into the reaction kinetics we carried out the order determination with respect to all variable parameters in the protocol (Fig. 6\u003cstrong\u003eF\u003c/strong\u003e). Notably, the order with respect to substrate and the olefin partner were both found to be ~ 1 which, corroborates with our assumption of C−H activation not being the rate determining step (see supporting information file for full data regarding order determination).\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e Additionally, we performed a case study comparing our protocol to a non-directed approach (no \u003cstrong\u003eDTx\u003c/strong\u003e) (Fig.\u0026nbsp;6\u003cstrong\u003eG\u003c/strong\u003e). Gratifyingly, we found much superior yields and selectivities in all explored cases, demonstrating the supremacy of our protocol.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eComputational Studies\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eTo elucidate the mechanism of regioselective \u003cem\u003emeta\u003c/em\u003e-olefination computational studies were performed employing density functional theory (DFT). The DFT calculations are performed using the Gaussian 16 B.01\u003csup\u003e36\u003c/sup\u003e suite of programs and geometry optimizations were performed at the ωB97X-D\u003csup\u003e37\u003c/sup\u003e/def2-SVP\u003csup\u003e38\u003c/sup\u003e level of theory. The choice of functional is based on its superior performance in modeling transition-metal-catalyzed reactions and non-covalent interactions.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e39\u003c/span\u003e–\u003cspan class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e The effect of solvation by solvent HFIP is also incorporated by implicit SMD\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e solvation model in the computed (single-point calculations) Gibbs free energy profile at the ωB97X-D/def2-TZVP\u003csup\u003e38\u003c/sup\u003e level of theory.\u003c/p\u003e\u003cp\u003eThe computations were performed on substrate \u003cstrong\u003e1a\u003c/strong\u003e along with directing ligand \u003cstrong\u003eDT\u003csub\u003e8\u003c/sub\u003e\u003c/strong\u003e. The free energy profile for \u003cem\u003emeta\u003c/em\u003e-selective olefination is shown in \u003cstrong\u003efigure 7\u003c/strong\u003e. The reaction starts with C-H activation step. The C-H activation steps are calculated using both with MPAA and without MPAA ligands. Without the MPAA ligands \u003cem\u003emeta\u003c/em\u003e-C-H activation occurs via \u003cstrong\u003eTS-I\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003em\u003c/strong\u003e\u003c/sub\u003e which has 7.6 kcal/mol more energy barrier than the MPAA ligand promoted \u003cem\u003emeta\u003c/em\u003e-C-H activation state \u003cstrong\u003eTS-1\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003em\u003c/strong\u003e\u003c/sub\u003e. The stabilization of \u003cstrong\u003eTS-1\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003em\u003c/strong\u003e\u003c/sub\u003e over \u003cstrong\u003eTS-I\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003em\u003c/strong\u003e\u003c/sub\u003e is attributed to the formation of a [5,6]-membered palladacycle in \u003cstrong\u003eTS-1\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003em\u003c/strong\u003e\u003c/sub\u003e. This palladacycle facilitates C-H bond activation by positioning the amide oxygen of the MPAA ligand optimally for the concerted metalation-deprotonation (CMD) mechanism. This observation is consistent with the experimental findings which suggests crucial role of external ancillary MPAA ligands to facilitate functionality of the reaction. The C-H activation state for both \u003cem\u003emeta\u003c/em\u003e and \u003cem\u003epara\u003c/em\u003e bond activations are similar in energy with \u003cstrong\u003eΔΔG\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e‡\u003c/strong\u003e\u003c/sup\u003e\u003csub\u003e\u003cstrong\u003e(TS1m− TS1p)\u003c/strong\u003e\u003c/sub\u003e \u003cstrong\u003e=\u003c/strong\u003e 0.3 kcal/mol which suggests that C-H activation step is not the regioselectivity determining transition state. Also, we have calculated \u003cem\u003emeta\u003c/em\u003e-C-H activation step without directing group \u003cstrong\u003e(TS-1\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003em\u003c/strong\u003e\u003c/sub\u003e\u003cstrong\u003e\")\u003c/strong\u003e which is also energetically unfavored than \u003cstrong\u003eTS-1\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003em\u003c/strong\u003e\u003c/sub\u003e by 3.6 kcal/mol.\u003c/p\u003e\u003cp\u003eAfter the C-H activation step co-ordination of olefin takes place to form \u003cstrong\u003eInt-3\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003em/p\u003c/strong\u003e\u003c/sub\u003e. The transfer of olefin moiety to the Pd at \u003cem\u003emeta\u003c/em\u003e position occurs via \u003cstrong\u003eTS-2\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003em\u003c/strong\u003e\u003c/sub\u003e with activation barrier of 5.4 kcal/mol and for the \u003cem\u003epara\u003c/em\u003e position via \u003cstrong\u003eTS-2\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003em\u003c/strong\u003e\u003c/sub\u003e with \u003cstrong\u003eΔG\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e‡\u003c/strong\u003e\u003c/sup\u003e \u003cstrong\u003e=\u003c/strong\u003e 8.1 kcal/mol to produce \u003cstrong\u003eInt-4\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003em/p\u003c/strong\u003e\u003c/sub\u003e. Next \u003cem\u003eb\u003c/em\u003e-hydride elimination assisted by the MPAA ligand takes place via \u003cstrong\u003eInt-5\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003em/p\u003c/strong\u003e\u003c/sub\u003e where \u003cem\u003eb\u003c/em\u003e-hydrogen is slightly activated by Pd. Then \u003cstrong\u003eInt-5\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003em/p\u003c/strong\u003e\u003c/sub\u003e undergoes ligand assisted \u003cem\u003eb\u003c/em\u003e-hydride elimination step via \u003cstrong\u003eTS-3\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003em/p\u003c/strong\u003e\u003c/sub\u003e and form the final product \u003cstrong\u003eInt-6\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003em/p\u003c/strong\u003e\u003c/sub\u003e which is a Pd\u003csup\u003e0\u003c/sup\u003e complex. According to energy span model (50) \u003cem\u003eb\u003c/em\u003e-hydride elimination step is the turnover frequency-determining transition state (TDTS) that determines regioselectivity (\u003cem\u003emeta\u003c/em\u003e over \u003cem\u003epara\u003c/em\u003e) for the overall reaction. Consistent with the experiment, the \u003cem\u003emeta\u003c/em\u003e-\u003cstrong\u003eTS-3\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003em\u003c/strong\u003e\u003c/sub\u003e is 5.2 kcal/ mol more stable than the \u003cem\u003epara\u003c/em\u003e-\u003cstrong\u003eTS-3\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/sub\u003e (Fig. 9). The Si/F distances for \u003cstrong\u003eTS-3\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003em\u003c/strong\u003e\u003c/sub\u003e and \u003cstrong\u003eTS-3\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/sub\u003e are 4.58 Å and 5.22 Å respectively. The Si/F interaction is usually observed when the distance is between the range 3–4.5Å. So, stabilization of \u003cstrong\u003eTS-3\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003em\u003c/strong\u003e\u003c/sub\u003e is because of weak Si/F non-covalent interaction whereas in case of \u003cstrong\u003eTS-3\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/sub\u003e this Si/F interaction is completely absent.\u003c/p\u003e\u003cp\u003eWe have also calculated the \u003cem\u003eb\u003c/em\u003e-hydride elimination step without the directing group and observed that the regioselectivity vanishes as energy difference between \u003cem\u003emeta\u003c/em\u003e \u003cstrong\u003e(TS-III\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003em\u003c/strong\u003e\u003c/sub\u003e\u003cstrong\u003e)\u003c/strong\u003e and \u003cem\u003epara\u003c/em\u003e \u003cstrong\u003e(TS-III\u003c/strong\u003e\u003csub\u003e\u003cstrong\u003ep\u003c/strong\u003e\u003c/sub\u003e\u003cstrong\u003e)\u003c/strong\u003e is only 0.7 kcal/mol. This finding again reaffirms the role of directing group in the regioselective C-H activation. The oxidation of Pd(0) with the Ag(I) oxidant take place to regenerate the Pd(II) catalyst. The recovery of catalyst Pd(OAc)\u003csub\u003e2\u003c/sub\u003e, using two molecules of oxidant AgOAc, is a complicated redox process and this process is expected to be highly exergonic and require low activation barriers.\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, we present the first report of utilizing Si/F non-covalent interactions in the domain of transition metal catalysis for the \u003cem\u003emeta\u003c/em\u003e-olefination of di- and tri- fluoroalkyl arenes at ambient temperatures. A simple mono-aryl directing template hosting an electron-deficient Si-moiety is found to establish a Lewis acid-base type interaction with the fluorine atoms of the substrate to drive functionalization at the \u003cem\u003emeta\u003c/em\u003e-position. Comprehensive experimental and computational analysis gave profound insights on the significant role played by Si/F non-covalent interactions on dictating site-selectivity. The wide array of functionalized di- and tri- fluoroalkyl arenes enable access to a larger chemical space significant for the construction of valuable pharmacological skeletons which has been demonstrated by the total synthesis of the drug Cinacalcet. The concept of utilizing such weak interactions in the domain of metal catalysis will guide future development of sustainable distal C-H functionalization devoid of covalently attached directing template.\u003c/p\u003e"},{"header":"METHODS SUMMARY ","content":"\u003cp\u003e\u003cstrong\u003eGeneral Procedure for the \u003cem\u003emeta\u003c/em\u003e-selective olefination of di/trifluoromethyl arenes:\u0026nbsp;\u003c/strong\u003eIn an oven-dried screw capped reaction tube charged with magnetic stir-bar, substrate (fluoro alkyl arene) (1 equiv., 0.1 mmol), Pd(OAc)\u003csub\u003e2\u003c/sub\u003e (10 mol%, 2.24 mg), \u003cem\u003eN\u003c/em\u003e-Ac-Phe-OH (20 mol%, 4.1 mg), Directing Template (\u003cstrong\u003eDT\u003csub\u003e8\u003c/sub\u003e\u003c/strong\u003e) (1 \u003cem\u003eequiv\u003c/em\u003e.), AgOAc (3 \u003cem\u003eequiv\u003c/em\u003e.) in 1 mL of HFIP were added. After that, olefin (2.75 \u003cem\u003eequiv\u003c/em\u003e.) was added to that reaction mixture. The reaction tube was well capped and placed in a RT (35 \u003csup\u003eo\u003c/sup\u003eC) or preheated oil bath at 60 \u003csup\u003eo\u003c/sup\u003eC with stirring (1000 rpm) for 36 h or 48 h. Upon completion of the reaction, the mixture was diluted with ethyl acetate and filtered through a celite pad. The filtrate was evaporated under reduced pressure and the crude mixture was purified by column chromatography using silica (100-200 mesh size) and petroleum ether/ethyl acetate as the eluent. The final \u003cem\u003emeta\u003c/em\u003e-olefinated product was characterized by different spectroscopic techniques (\u003csup\u003e1\u003c/sup\u003eH, \u003csup\u003e13\u003c/sup\u003eC, \u003csup\u003e19\u003c/sup\u003eF etc.).\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFinancial support received from SERB-India (CRG/2022/004197) is greatly acknowledged. Financial support received CSIR-India for S.M. and IIT Bombay (fellowship to K.M.).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eD.M., and S.M. conceived the concept. S.M., A.T.S., and K.M. performed the reactions and analyzed the products. A.D., P.M., and A.K.P. carried out the computational investigation. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e The authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplementary Information\u003c/strong\u003e is linked to the online version of the paper \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorrespondence and requests for materials\u003c/strong\u003e should be addressed to D.M. ([email protected]).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eReprints and permissions information\u003c/strong\u003e is available at www.nature.com/reprints\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eM\u0026uuml;ller, K., Faeh, C. \u0026amp; Diederich, F. 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Chem.\u003c/em\u003e\u003cstrong\u003e78\u003c/strong\u003e, 2405\u0026ndash;2412 (2013). \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6523406/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6523406/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Fluoroalkyl arenes are essential in pharmaceutical development, with groups like CF3, CF2H, CH2CF3, and cyclopropyl-CF3 significantly enhancing medicinal properties. However, current methodologies that rely on metal-catalyzed cross-coupling reactions face challenges such as reductive elimination and limited reagent availability. This study introduces an alternative approach, leveraging Si/F non-covalent interactions for the first time in transition metal catalysis. This enables distal C−H functionalization of di- and tri-fluoroalkyl arenes using commercially available fluoroalkyl reagents and coupling partners, achieving meta-selectivity. The process facilitates the efficient synthesis of pharmacologically relevant compounds, including Cinacalcet, TrxR1, and the herbicide tetflupyrolimet, advancing sustainable and economical drug discovery. By employing a silicon-containing directing ligand, the approach ensures site-selective functionalization, marking a significant step toward green and efficient synthetic strategies.","manuscriptTitle":"Silicon-fluorine non-covalent interaction guided distal functionalization of di- and tri- fluoro alkyl benzene","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-16 06:49:07","doi":"10.21203/rs.3.rs-6523406/v1","editorialEvents":[{"type":"communityComments","content":1}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"108ed4e6-0453-4d28-94dd-1e428c251e9b","owner":[],"postedDate":"May 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":48596515,"name":"Physical sciences/Chemistry/Catalysis/Homogeneous catalysis"},{"id":48596516,"name":"Physical sciences/Chemistry/Catalysis/Catalyst synthesis"},{"id":48596517,"name":"Physical sciences/Chemistry/Catalysis/Catalytic mechanisms"}],"tags":[],"updatedAt":"2025-07-18T10:50:57+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-16 06:49:07","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6523406","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6523406","identity":"rs-6523406","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}