Communication pubs.acs.org/Organometallics
Transition-Metal-Mediated Nucleophilic Aromatic Substitution with Acids Matthew E. O’Reilly,† Samantha I. Johnson,‡ Robert J. Nielsen,‡ William A. Goddard, III,*,‡ and T. Brent Gunnoe*,† †
Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, United States Materials and Process Simulation Center, California Institute of Technology, Pasadena, California 91125, United States
‡
S Supporting Information *
ABSTRACT: Transition-metal-mediated nucleophilic aromatic substitution (SNAr) reactions prefer that a suitably strong nucleophile be in an aprotic medium. Usually, using protic nucleophile/medium requires high reaction temperatures (>180 °C) to overcome the attenuated nucleophilicity for attack on the arene π system. Surprisingly, we demonstrate herein a RhIII-mediated SNAr reaction of a fluoroarene moiety with RCO2H (R = CH3, CF3) in acid media that proceeds at moderate temperatures (2.5 Å).10 Importantly, the arene C−F bonds are situated near the coordinated TFA− ligands to allow for I-SNAr. Scheme 2 depicts the synthesis of the fluorinated ligand Q2FB (2) and the Rh complex 1. A palladium-catalyzed Suzuki
Figure 2. DFT optimized structure of (Q2FB)Rh(TFA)3 (1) depicting the fluorinated substrate near the “Rh(TFA)3” unit for I-SNAr.
Scheme 2. Synthesis of 8,8′-(4,5-Difluoro-1,2phenylene)diquinoline (Q2FB; 2), (Q2FB)Rh(TFA)(COE) (3), and (Q2FB)Rh(TFA)3 (1)a
DFT optimized structure of 1 with the Rh positioned above the C19 (2.656 Å) and C20 (2.524 Å) π bond. Consistent with our intended design, O6 of a coordinated TFA ligand is suitably positioned above the C−F unit (2.986 Å), ready to engage in a nucleophilic attack. When complex 1 was heated in HTFA to 90 °C and the experiment was monitored by 19F NMR spectroscopy, the fluorine signals attributable to the Q2FB ligand gradually disappear over 12 h, and two new resonances appear at −13.1 (q, 1F, 3JFF = 6 Hz) and −76.9 (d, 3F, 3JFF = 6 Hz) ppm that are consistent with formation of the acyl fluoride compound CF3C(O)F. Further supporting this assignment, selective decoupling of the −13.1 ppm resonance produces a singlet at −76.9 ppm (see the Supporting Information). Likewise, heating complex 1 in acetic acid at 90 °C yields the corresponding CH3C(O)F, whose 19F resonance is also a quartet at −49.29 ppm (q, 1F, 3JHF = 7 Hz). During the defluorination event in HTFA, the singly defluorinated intermediate 4 arose after 0.5 h of heating at 90 °C (Scheme 3). The remaining Ar−F signal of 4 resonates at −108.9 ppm in the 19F NMR spectrum. The 1H NMR spectrum containing the intermediate 4 has 14 aromatic resonances, consistent with the proposed asymmetric structure. A notable feature is that the capping arene Ar−H resonances appear as a singlet (8.18 ppm) and a doublet (8.25 ppm, 3JHF = 6 Hz). Further support for intermediate 4 comes from 2D NMR
a
Legend: (i) 10 mol % of Pd(PPh3)4, 15 equiv of K3PO4, DMF/H2O (1/1), 110 °C; (ii) 0.5 equiv of {Rh(COE)2(μ-TFA)}2, THF; (iii) 2.1 equiv of Ag(TFA), THF.
coupling appends 2 equiv of 8-quinolylboronic acid to 1,2dibromo-4,5-difluorobenzene. The 19F NMR spectrum of 2 contains a broad resonance at −140.6 ppm, and the 1H NMR spectrum contains seven aromatic resonances between 7.11 and 8.81 ppm. Treating 2 with {Rh(COE)2(μ-TFA)}2 (COE = cyclooctene) in THF affords (Q2FB)Rh(TFA) (COE) (3). The 19F NMR spectrum of 3 contains two Ar−F multiplets at −139.2 and −139.9 ppm that support the proposed C1-symmetric structure. A second set of Q2FB resonances corresponding to a minor isomer (30%) appear at −139.1 and −140.4 ppm. Previously, we reported the oxidation of RhI to form (Q2X)RhIII(TFA)3 (Q2X = 8,8′-(4,5-o-xylene)diquinoline) using Cu(TFA)2 in HTFA.10b To our surprise, CuII reagents do not oxidize complex 3 to produce the corresponding RhIII complex, but employing the stronger oxidant AgTFA readily provides the desired complex 1. This result highlights an interesting inductive effect of the axial-capping arene ring on the Rh oxidation potential that suggests a possible arene interaction similar to the η6-arene structure proposed during SNAr. The 1H NMR spectrum of 1 contains seven aromatic peaks consistent with Cs symmetry with the furthest downfield peak (α-C−H) appearing at 9.24 ppm. The 19F NMR spectrum contains axial and equatorial TFA signals at −73.4 and −73.6 ppm, respectively. Additionally, the Ar−F resonance appears as a virtual triplet (3JFH = 9 Hz) at −121.9 ppm.11 The proton
Scheme 3. Defluorination of 1 by an SNAr Pathway via Intermediate 4 To Yield 2 CF3C(O)F and 5a
a
B
DFT calculated energies are shown below each complex. DOI: 10.1021/acs.organomet.6b00285 Organometallics XXXX, XXX, XXX−XXX
Communication
Organometallics Scheme 4. Calculated Energetics for the Defluorination of 1 by E-SNAr (Pathway A) and I-SNAr (Pathway B)
spectroscopy (see the Supporting Information), which displays the arene 13C−F and 13C−OH resonances at 159.2 and 145.8 ppm, respectively, consistent with their expected chemical shifts. Continued heating of the sample at 90 °C consumes the remaining Ar−F peaks of 4, and at least two different products emerge in the 1H NMR spectrum. Tentative assignments for complexes 5a,b are presented in the Supporting Information. The strongest support for 5b is from gHMBC experiments, where two resonances (13C NMR) at 170.8 and 55.3 ppm are consistent with CO and Rh−C moieties. Attempts to isolate complexes 5a,b were unsuccessful due to decomposition. DFT calculations provide further elucidation of the mechanism of C−F/C−OH bond metathesis (see the Supporting Information for full details). Calculated free energies for proposed intermediates and products are shown in Scheme 3. The overall reaction is calculated to be exergonic, with intermediate 4 having a ΔG = −2.4 kcal/mol and the final products of the reaction, complex 5 and 2 equiv of CF3C(O)F, having an overall free energy change of −8.2 kcal/mol. Multiple tautomeric structures are possible for the defluorinated products 5a,b, but 5b is most preferred thermodynamically. It is quite remarkable that two strong bonds, C−F and C−OH, are easily metathesized by heating at 90 °C in neat HTFA.12 As a point of comparison, we examined the previously reported catalyst Cp*Rh(C6H6)2+,7f which mediates SNAr of fluorobenzene with MeOH in CH3NO2 at 90 °C. The corresponding reaction of fluorobenzene in HTFA yields only marginal turnover (TON = 0.7) at 180 °C for 18 h (eq 1). In addition, we also examined RuCl2(C6H6)/AgTFA,7e which yielded an improved TON value of 1.7 under identical conditions. We suspect that the lower activation energy barrier for 1 stems from the designed I-SNAr mechanism that is relatively unaffected by the acid medium.
Scheme 5. Two Proposed Mechanisms for CF3C(O)F Formation from 1d
Pathway A features an intermolecular attack by HTFA (E-SNAr) on the arene ring (TS1) that is consistent with other transitionmetal-mediated SNAr mechanisms. The nucleophilic attack produces the dearomatized intermediate 1b, where the fluoride lies below the “Rh(TFA)3” unit. However, the computed activation energy barrier requires two additional explicit HTFA solvent molecules that act as a proton relay to obtain a value of 26.9 kcal/mol. Interestingly, the ΔH⧧298 value is only 10 kcal/ mol of the total barrier, indicating a large entropic penalty (−54 cal/(mol T)) for the E-SNAr mechanism in HTFA that likely results from the cost of the proton relay. Thus, the overall ΔG⧧ value is expected to rise substantially at elevated temperatures. A lower transition state barrier was found for pathway B that involves a migratory insertion by a coordinated TFA−, with a calculated barrier of 20.5 kcal/mol. More importantly, the entropic contribution is relatively small, and ΔH⧧298 = 18.7 kcal/ mol. The lower transition state barrier for pathway B preordains 1d as the intermediate prior to the final C−F/C−OH bond metathesis step. Scheme 5 depicts two possible mechanisms from 1d for the formation of CF3C(O)F. The reaction can occur via fluoride ion dissociation and then nucleophilic attack on −C(O)CF3 (pathway C) or via a concerted metathesis mechanism (pathway D). For the former, a computed intermediate 1e with HF (pathway C) is energetically
catalyst
PhF + HTFA ⎯⎯⎯⎯⎯⎯→ PhTFA + HF 180 ° C
(1)
DFT transition state calculations provide strong support for the I-SNAr mechanism. Schemes 4 and 5 depict the stepwise transformation of 1 and HTFA to 4 and acyl fluoride by focusing on the nucleophilic attack to form dearomatized intermediates 1b−d (Scheme 4) and rearomatization that ultimately produces CF3C(O)F and 4 (Scheme 5). Scheme 4 contains two possible mechanisms of nucleophilic attack on the fluoroarene ring. C
DOI: 10.1021/acs.organomet.6b00285 Organometallics XXXX, XXX, XXX−XXX
Communication
Organometallics Notes
competent. However, its preceding activation barrier from 1d is ∼46 kcal/mol, whereas the computed barrier for the direct transfer pathway D (TS3) is ΔG⧧ = 21.0 kcal/mol when adding an explicit HTFA molecule to stabilize the TS3 transition state. Several isomers, with and without solvent, were calculated in addition to the reported structure to capture the effect of solvation. These higher energy transition states, which can be seen in the Supporting Information, show that the specific orientation of the proton of TFAH toward the bridging fluorine lowers the transition state approximately 5 kcal/mol, making it thermally accessible. The analogous defluorination transition state resulting from 1b is 4 kcal/mol higher than those resulting from 1d, further supporting pathway B as the main pathway. Further support for the DFT calculated mechanism comes from kinetic experiments monitoring the disappearance of 1 by 19 F NMR spectroscopy between 70 and 110 °C. An Arrhenius plot yields an activation energy (Ea) barrier of 18.1(±0.9) kcal/ mol (Figure S33), which is in good agreement with pathways B and D. In summary, this report contributes two advancements in the field of transition-metal-mediated SNAr. (1) Establishing circumstances under which nucleophilic attack by an acid on fluoroarenes is unprecedented. These results highlight the potential of metal ions such as Rh3+ to enhance the electrophilicity of electron-rich fluoroarenes to allow even weak nucleophiles, such as HTFA, to initiate SNAr. (2) The combined mechanistic and DFT studies of 1 establish a new mechanism of SNAr in which the nucleophile is coordinated to the metal prior to nucleophilic attack. This I-SNAr strategy (reminiscent of CMD) allows nucleophilic substitution in an acidic medium at moderate temperatures (
