Abstract
Nucleophilic fluorination of aromatic rings can be done via a cross-coupling reaction catalyzed by palladium and biaryl monophosphine ligands such as AlPhos. Nevertheless, aromatic fluorination via palladium catalysis can lead to regioisomers, a serious problem for this kind of reaction. An ortho-deprotonation mechanism was proposed for this reaction in previous studies. However, this mechanism does not explain why the ortho product is not formed from para and meta substrates, and the details of the mechanism are not fully understood yet. This theoretical work discloses the mechanism behind regioisomers formation, which takes place via unimolecular ortho-elimination of HF. The computed free energy profile of the reaction was followed by a detailed microkinetic analysis, which explain the experiments quantitatively. The present study shows that the rotation of the aryne coordinated to the palladium to form a complex leading to the ortho product is critical for regioselectivity. This rotation has a high free energy barrier due to steric repulsion with the adamantane group of the ligand. Such a feature impedes the formation of ortho product from para and meta substrates and allows the formation of the ortho product selectively from the ortho substrate.
Graphical Abstract
Similar content being viewed by others
References
Inoue M, Sumii Y, Shibata N (2020) Contribution of Organofluorine Compounds to Pharmaceuticals. ACS Omega 5:10633–10640
Han J, Remete AM, Dobson LS, Kiss L, Izawa K, Moriwaki H, Soloshonok VA, O’Hagan D (2020) Next generation organofluorine containing blockbuster drugs. J Fluorine Chem 239:109639
Yerien DE, Bonesi S, Postigo A (2016) Fluorination methods in drug discovery. Org Biomol Chem 14:8398–8427
Khandelwal M, Pemawat G, KanwarKhangarot R (2022) Recent Developments in Nucleophilic Fluorination with Potassium Fluoride (KF): A Review. Asian J Org Chem 11:e202200325
Ajenjo J, Destro G, Cornelissen B, Gouverneur V (2021) Closing the gap between (19)F and (18)F chemistry. EJNMMI Radiopharm Chem 6:33
Priyadarsini A, Mallik BS (2023) Electrocatalytic Mechanism of Water Splitting by Ultralow Content of RuO2-supported on Fluorine-Doped Graphene Using a Constant Potential Method. J Phys Chem C 127:18350–18364
Milián-Medina B, Gierschner J (2017) “Though It Be but Little, It Is Fierce”: Excited State Engineering of Conjugated Organic Materials by Fluorination. J Phys Chem Lett 8:91–101
Nishibori S, Hara N, Ogasawara S, Sasaki S-i, Tamiaki H (2024) Synthesis of C3-fluoroalkylated chlorophyll-a derivatives and fine tuning of their optical properties by the fluorination degree. J Photochem Photobiol, A 446:115118
Zhang C, Wu H, Feng S, Meng J (2023) Fluorination as a powerful tool for improving water/salt selectivity of hydrophilic polyethersulfone. J Membr Sci 687:122030
Champagne PA, Desroches J, Hamel J-D, Vandamme M, Paquin J-F (2015) Monofluorination of Organic Compounds: 10 Years of Innovation. Chem Rev 115:9073–9174
Campbell MG, Ritter T (2014) Late-Stage Formation of Carbon-Fluorine Bonds. Chem Rec 14:482–491
Patel C, André-Joyaux E, Leitch JA, de Irujo-Labalde XM, Ibba F, Struijs J, Ellwanger MA, Paton R, Browne DL, Pupo G, Aldridge S, Hayward MA, Gouverneur V (2023) Fluorochemicals from fluorspar via a phosphate-enabled mechanochemical process that bypasses HF. Science 381:302–306
Lee J-W, Oliveira MT, Jang HB, Lee S, Chi DY, Kim DW, Song CE (2016) Hydrogen-bond promoted nucleophilic fluorination: concept, mechanism and applications in positron emission tomography. Chem Soc Rev 45:4638–4650
Melo AS, Valle MS, Pliego JR (2023) Accelerating SN2 nucleophilic fluorination of primary alkyl bromide using an 18-crown-6 and fluorinated bulky alcohol phase transfer system. J Fluor Chem 269:110146
Pliego JR (2021) The Role of Intermolecular Forces in Ionic Reactions: The Solvent Effect, Ion-Pairing, Aggregates and Structured Environment. Org Biomol Chem 19:1900–1914
Silva SL, Valle MS, Pliego JR (2020) Nucleophilic Fluorination with KF Catalyzed by 18-Crown-6 and Bulky Diols: A Theoretical and Experimental Study. J Org Chem 85:15457–15465
Silva SL, Valle MS, Pliego JR (2020) Micro-solvation and counter ion effects on ionic reactions: Activation of potassium fluoride with 18-crown-6 and tert-butanol in aprotic solvents. J Mol Liq 319:114211
Dalessandro EV, Pliego JR (2020) Theoretical design of new macrocycles for nucleophilic fluorination with KF: thiourea-crown-ether is predicted to overcome [2.2.2]-cryptand. Mol Syst Des Eng 5:1513–1523
Kang SM, Kim CH, Lee KC, Kim DW (2019) Bis-triethylene Glycolic Crown-5-calix[4]arene: A Promoter of Nucleophilic Fluorination Using Potassium Fluoride. Org Lett 21:3062–3066
Jadhav VH, Choi W, Lee S-S, Lee S, Kim DW (2016) Bis-tert-Alcohol-Functionalized Crown-6-Calix[4]arene: An Organic Promoter for Nucleophilic Fluorination. Chem Eur J 22:4515–4520
Jadhav VH, Jang SH, Jeong H-J, Lim ST, Sohn M-H, Kim J-Y, Lee S, Lee JW, Song CE, Kim DW (2012) Oligoethylene Glycols as Highly Efficient Mutifunctional Promoters for Nucleophilic-Substitution Reactions. Chem Eur J 18:3918–3924
Lee JW, Yan H, Jang HB, Kim HK, Park SW, Lee S, Chi DY, Song CE (2009) Bis-Terminal Hydroxy Polyethers as All-Purpose, Multifunctional Organic Promoters: A Mechanistic Investigation and Applications. Angew Chem, Int Ed 48:7683–7686
Kim DW, Jeong HJ, Lim ST, Sohn MH, Katzenellenbogen JA, Chi DY (2008) Facile nucleophilic fluorination reactions using tert-alcohols as a reaction medium: Significantly enhanced reactivity of alkali metal fluorides and improved selectivity. J Org Chem 73:957–962
Oh Y-H, Kim DW, Lee S (2022) Ionic Liquids as Organocatalysts for Nucleophilic Fluorination: Concepts and Perspectives. Molecules 27:5702
Hong CM, Whittaker AM, Schultz DM (2021) Nucleophilic Fluorination of Heteroaryl Chlorides and Aryl Triflates Enabled by Cooperative Catalysis. J Org Chem 86:3999–4006
Lee WC, Kang SM, Lee BC, Kim SE, Kim DW (2020) Multifunctional Crown-5-calix[4]arene-based Phase-Transfer Catalysts for Aromatic 18F-Fluorination. Org Lett 22:9551–9555
Morales-Colón MT, See YY, Lee SJ, Scott PJH, Bland DC, Sanford MS (2021) Tetramethylammonium Fluoride Alcohol Adducts for SNAr Fluorination. Org Lett 23:4493–4498
Sather AC, Buchwald SL (2016) The Evolution of Pd0/PdII-Catalyzed Aromatic Fluorination. Acc Chem Res 49:2146–2157
Pliego JR (2021) Catalytic Cycle and off-Cycle Steps in the Palladium-Catalyzed Fluorination of Aryl Bromide with Biaryl Monophosphine Ligands: Theoretical Free Energy Profile. Mol Catal 506:111540
Sharninghausen LS, Brooks AF, Winton WP, Makaravage KJ, Scott PJH, Sanford MS (2020) NHC-Copper Mediated Ligand-Directed Radiofluorination of Aryl Halides. J Am Chem Soc 142:7362–7367
Mu X, Zhang H, Chen P, Liu G (2014) Copper-catalyzed fluorination of 2-pyridyl aryl bromides. Chem Sci 5:275–280
Pliego JR (2022) Copper-Catalyzed Aromatic Fluorination of 2-(2-bromophenyl)pyridine via Cu(I)/Cu(III) Mechanism in Acetonitrile Solvent: Cluster-Continuum Free Energy Profile and Microkinetic Analysis. Mol Catal 529:112560
Pliego JR (2022) Copper-mediated aromatic fluorination using N-heterocycle-carbene ligand: Free energy profile of the Cu(I)/Cu(III) and Cu(II) radical mechanisms. J Organomet Chem 973–974:122397
Sather AC, Lee HG, De La Rosa VY, Yang Y, Müller P, Buchwald SL (2015) A Fluorinated Ligand Enables Room-Temperature and Regioselective Pd-Catalyzed Fluorination of Aryl Triflates and Bromides. J Am Chem Soc 137:13433–13438
Milner PJ, Yang Y, Buchwald SL (2015) In-Depth Assessment of the Palladium-Catalyzed Fluorination of Five-Membered Heteroaryl Bromides. Organometallics 34:4775–4780
Milner PJ, Kinzel T, Zhang Y, Buchwald SL (2014) Studying Regioisomer Formation in the Pd-Catalyzed Fluorination of Aryl Triflates by Deuterium Labeling. J Am Chem Soc 136:15757–15766
Lee HG, Milner PJ, Buchwald SL (2014) Pd-Catalyzed Nucleophilic Fluorination of Aryl Bromides. J Am Chem Soc 136:3792–3795
Lee HG, Milner PJ, Buchwald SL (2013) An Improved Catalyst System for the Pd-Catalyzed Fluorination of (Hetero)Aryl Triflates. Org Lett 15:5602–5605
Senecal TD, Parsons AT, Buchwald SL (2011) Room Temperature Aryl Trifluoromethylation via Copper-Mediated Oxidative Cross-Coupling. J Org Chem 76:1174–1176
Maimone TJ, Milner PJ, Kinzel T, Zhang Y, Takase MK, Buchwald SL (2011) Evidence for in Situ Catalyst Modification during the Pd-Catalyzed Conversion of Aryl Triflates to Aryl Fluorides. J Am Chem Soc 133:18106–18109
Grushin VV (2010) The Organometallic Fluorine Chemistry of Palladium and Rhodium: Studies toward Aromatic Fluorination. Acc Chem Res 43:160–171
Watson DA, Su M, Teverovskiy G, Zhang Y, García-Fortanet J, Kinzel T, Buchwald SL (2009) Formation of ArF from LPdAr(F): Catalytic Conversion of Aryl Triflates to Aryl Fluorides. Science 325:1661–1664
Yandulov DV, Tran NT (2007) Aryl-Fluoride Reductive Elimination from Pd(II): Feasibility Assessment from Theory and Experiment. J Am Chem Soc 129:1342–1358
Perdew JP, Burke K, Ernzerhof M (1996) Generalized Gradient Approximation Made Simple. Phys Rev Lett 77:3865–3868
Zheng JJ, Xu XF, Truhlar DG (2011) Minimally augmented Karlsruhe basis sets. Theor Chem Acc 128:295–305
Weigend F, Ahlrichs R (2005) Balanced basis sets of split valence, triple zeta valence and quadruple zeta valence quality for H to Rn: Design and assessment of accuracy. Phys Chem Chem Phys 7:3297–3305
Andrae D, Häußermann U, Dolg M, Stoll H, Preuß H (1990) Energy-adjustedab initio pseudopotentials for the second and third row transition elements. Theor Chim Acta 77:123–141
Mardirossian N, Head-Gordon M (2016) ωB97M-V: A combinatorially optimized, range-separated hybrid, meta-GGA density functional with VV10 nonlocal correlation. J Chem Phys 144:214110
Neese F (2022) Software update: The ORCA program system—Version 5.0. Wiley Interdiscip Rev Comput Mol Sci 12:e1606
Neese F, Wennmohs F, Becker U, Riplinger C (2020) The ORCA quantum chemistry program package. J Chem Phys 152:224108
Mardirossian N, Head-Gordon M (2017) Thirty years of density functional theory in computational chemistry: an overview and extensive assessment of 200 density functionals. Mol Phys 115:2315–2372
Iron MA, Janes T (2019) Evaluating Transition Metal Barrier Heights with the Latest Density Functional Theory Exchange-Correlation Functionals: The MOBH35 Benchmark Database. J Phys Chem A 123:3761–3781
Cances E, Mennucci B, Tomasi J (1997) A new integral equation formalism for the polarizable continuum model: Theoretical background and applications to isotropic and anisotropic dielectrics. J Chem Phys 107:3032–3041
Su P, Li H (2009) Continuous and smooth potential energy surface for conductorlike screening solvation model using fixed points with variable areas. J Chem Phys 130:074109–074113
Pliego JR Jr, Riveros JM (2002) Parametrization of the PCM model for calculating solvation free energy of anions in dimethyl sulfoxide solutions. Chem Phys Lett 355:543–546
Luque FJ, Zhang Y, Aleman C, Bachs M, Gao J, Orozco M (1996) Solvent effects in chloroform solution: Parametrization of the MST/SCRF continuum model. J Phys Chem 100:4269–4276
Luque FJ, Bachs M, Aleman C, Orozco M (1996) Extension of MST/SCRF method to organic solvents: ab initio and semiempirical parametrization for neutral solutes in CCl 4. J Comput Chem 17:806–820
Barca GMJ, Bertoni C, Carrington L, Datta D, Silva ND, Deustua JE, Fedorov DG, Gour JR, Gunina AO, Guidez E, Harville T, Irle S, Ivanic J, Kowalski K, Leang SS, Li H, Li W, Lutz JJ, Magoulas I, Mato J, Mironov V, Nakata H, Pham BQ, Piecuch P, Poole D, Pruitt SR, Rendell AP, Roskop LB, Ruedenberg K, Sattasathuchana T, Schmidt MW, Shen J, Slipchenko L, Sosonkina M, Sundriyal V, Tiwari A, Vallejo JLG, Westheimer B, Włoch M, Xu P, Zahariev F, Gordon MS (2020) Recent developments in the general atomic and molecular electronic structure system. J Chem Phys 152:154102
Stevens WJ, Krauss M, Basch H, Jasien PG (1992) Relativistic Compact Effective Potentials and Efficient, Shared-Exponent Basis-Sets for the 3Rd-Row, 4Th-Row, and 5Th-Row Atoms. Can J Chem 70:612–630
Marenich AV, Cramer CJ, Truhlar DG (2009) Universal Solvation Model Based on Solute Electron Density and on a Continuum Model of the Solvent Defined by the Bulk Dielectric Constant and Atomic Surface Tensions. J Phys Chem B 113:6378–6396
Sciortino G, Maseras F (2023) Microkinetic modelling in computational homogeneous catalysis and beyond. Theor Chem Acc 142:99
Besora M, Maseras F (2018) Microkinetic modeling in homogeneous catalysis. Wiley Interdiscip Rev Comput Mol Sci 8:e1372
Janse van Rensburg W, Petersen MA, Datt MS, van den Berg J-A, van Helden P (2015) On the Kinetic Interpretation of DFT-Derived Energy Profiles: Cu-Catalyzed Methanol Synthesis. Catal Lett 145:559–568
Ianni JC (2019) Kintecus. Version 6.8 edn. http://www.kintecus.com
Acknowledgements
The authors thank the agencies CNPq, FAPEMIG, and CAPES for their support.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of Interest
There are no conflicts to declare.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
10562_2024_4706_MOESM1_ESM.docx
Supplementary file1 The coordinates of the optimized structures and the Tables with the calculations are available. (DOCX 217 KB)
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Pliego, J.R. Elucidating the Origin of Regioselectivity in Palladium-Catalyzed Aromatic Fluorination: Mechanistic Investigation and Microkinetic Analysis. Catal Lett (2024). https://doi.org/10.1007/s10562-024-04706-x
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s10562-024-04706-x