Round-Trip Oxidative Addition, Ligand Metathesis, and Reductive Elimination in a PIII/PVSynthetic Cycle

Article abstract of DOI:10.1021/jacs.0c07580

A synthetic cycle for aryl C-F substitution comprising oxidative addition, ligand metathesis, and reductive elimination at a Cs-symmetric phosphorus triamide (1, P{N[o-NMe-C6H4]2}) is reported. Reaction of 1 with perfluoroarenes (ArF-F) results in C-F oxidative addition, yielding fluorophosphoranes 1·[F][ArF]. The P-fluoro substituent is exchanged for hydride by treatment with DIBAL-H, generating hydridophosphoranes 1·[H][ArF]. Heating of 1·[H][ArF] regenerates 1 by C-H reductive elimination of ArF-H, where experimental and computational studies establish a concerted but highly asynchronous mechanism. The results provide well-characterized examples of the full triad of elementary mechanistic aryl C-X substitution steps at a single main-group site.

Full text of DOI:10.1021/jacs.0c07580

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Communication
Round-Trip Oxidative Addition, Ligand Metathesis,
and Reductive Elimination in a PIII/PV Synthetic Cycle
Soohyun Lim, and Alexander T. Radosevich
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c07580 • Publication Date (Web): 10 Sep 2020
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Round-Trip Oxidative Addition, Ligand Metathesis, and Re-
ductive Elimination in a PIII/PV Synthetic Cycle
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Soohyun Lim and Alexander T. Radosevich*
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139,
United States
Supporting Information Placeholder
known within the PIII/PV couple, no single system exhibits the
full suite of elementary steps in the aryl C–X substitution mech-
anism. Here, we report well-defined stoichiometric reactions
atop a single phosphorus platform that trace a closed PIII/PV
ABSTRACT: A synthetic cycle for aryl C–F substitution
comprising oxidative addition, ligand metathesis, and re-
ductive elimination at a Cs-symmetric phosphorus triamide
(1, P{N[o-NMe–C6H4]2}) is reported. Reaction of 1 with per-
synthetic loop comprising aryl C–F OA and aryl C–H RE inter-
fluoroarenes (ArF–F) results in C–F oxidative addition yield-
posed with F→H ligand metathesis (Figure 1B).26 These results
ing fluorophosphoranes 1•[F][ArF]. The P-fluoro substitu-
establish the redox equipoise of the PIII/PV couple as required
ent is exchanged for hydride by treatment with DIBAL-H,
for OA/RE round-tripping, providing a further basis for for-
ward-going development of group 15 promoted aryl C–X sub-
stitution chemistry.
generating hydridophosphoranes 1•[H][ArF]. Heating of
1•[H][ArF] regenerates 1 by C–H reductive elimination of
ArF–H, where experimental and computational studies es-
tablish a concerted but highly asynchronous mechanism.
The results provide well-characterized examples of the full
triad of elementary mechanistic aryl C–X substitution steps
at a single main-group site.
Oxidative addition, ligand metathesis (transmetalation), and
reductive elimination are the elementary mechanistic steps by
which numerous aryl C–X substitution reactions are enabled.
Round-trip sequencing of these steps is well-known for the late
transition metals, enabled by the kinetically and thermody-
namically favorable two-electron redox reactivity of the d-
block elements.1 Despite significant recent advances in oxida-
tive addition (OA) and reductive elimination (RE) at main-
group element centers,2,3 the realization of an analogous mech-
anistic triad with p-block elements is beset by poor energetic
parity among oxidation states En/n+2 that favors unidirectional
OA or RE. For instance, low-valent group 13/14 compounds
cleave aryl C–X bonds by OA (Figure 1A, left),4-9 but RE from
high-valent compounds of these electropositive elements is
rare. 10 , 11 Complementarily, aryl C–H RE from high-valent
Group 16/17 compounds have been described (Figure 1B,
right), 12-15 but OA to the low-valent state of such electronega-
tive elements is challenging.
Figure 1. (A) Selected examples of main-group oxidative addition
and reductive elimination reactions. (left) C–F oxidative addition
to Group 13/14 compounds; (right) C–H reductive elimination
from Group 16/17 compounds. (B) Phosphorus-centered two-
electron redox cycle for aryl C–F substitution.
The central position of the group 15 elements within the p-
block results in moderate electronegativities and accessible
EIII/V redox couples16-19 useful for aryl functionalization. Recent
excellent examples by McNally20 (for heteroaryl functionaliza-
tion via a PV→PIII RE step) and Cornella21 (for functionalization
of aryl boron compounds via a BiV→BiIII RE step) are paradig-
matic; nonetheless the high-valent arylpnictogen(V) interme-
diates are accessed via the use of an exogenous oxidant (SVI re-
agent in the former, ‘F+’ reagent in the latter), not aryl C–X OA.
Indeed, while both OA 22 - 24 and RE12, 25 are independently
On the basis of prior research showing that Cs-symmetric σ3-
phosphorus triamide 1 undergoes reversible OA/RE of amine
N–H substrates,23 we considered whether this compound
would be energetically poised to support the targeted elemen-
tary aryl substitution reactions. As depicted in Figure 2, reac-
tion of 1 with the perfluoroarenes—aryl C–X compounds oth-
erwise known as nucleophilic aromatic substitution (SNAr)
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Figure 2. PIII/PV synthetic cycle on 1 comprising aryl C–F oxidative addition, F→H ligand metathesis, and C–H reductive elimination. Ther-
mal ellipsoid plots of intermediates 1•[F][C5F4N] (left) and 1•[H][C5F4N] (right) are rendered at the 50% probability level. Hydrogen atoms
except H(1) in 1•[H][C5F4N] are omitted for clarity. a Isolated yield. b Internal standard yield by NMR.
substrates—was selected for investigation.27 Treatment of 1
with pentafluoropyridine (2a, >2 equiv) in tetrahydrofuran
above 50 °C leads to the clean consumption of 1 and formation
of a new species with spectral features consistent with C–F OA
product 1•[F][C5F4N]. The large upfield shift of the 31P NMR
resonance for 1•[F][C5F4N] (δ –61.0 ppm) compared to 1 (δ
+159.8 ppm) conforms with expectations for an increase in P-
coordination number, and the further presence of a large cou-
pling constant (1JP–F = 768.8 Hz) confirms the formation of a P–
F bond.19F NMR spectra show complementary coupling to a flu-
orine-19 nucleus (δ –34.67 ppm; 1JF–P = 765.7 Hz). Related C–F
OA reactivity is observed upon reaction of 1 with other per-
fluoroarenes (viz. perfluorotoluene 2b gives 1•[F][C5F4CF3]
and perfluorobenzonitrile gives 1•[F][C5F4CN]),28 although not
for simple arylfluorides.29 σ3-P Compounds are known to un-
dergo addition to electron-deficient haloarenes by SNAr, but
stable σ5-P adducts by C–F OA are not formed.30,31 The unique
reactivity of 1 is attributable to its unusual biphilicity;32 analo-
gous OA was not observed with common phosphorus tri-
amides.33
Table 1. Tabulated bond distances (Å), angles (°), and δ (ppm) val-
ues for selected compounds.a
Metric
1b
1•[F][C5F4N] 1•[H][C5F4N]
d(P1–N1)
1.7610(12) 1.7616(8)
1.7014(14) 1.6841(9)
1.7190(13) 1.6753(9)
1.778(2)
1.698(2)
1.695(2)
1.347(19)
1.884(2)
172.7(10)
94.31(9)
139.41(10)
–62.7
d(P1–N2)
d(P1–N3)
d(P1–F1/H1)
d(P1–C1)
—
1.6282(6)
1.8456(10)
174.28(4)
95.62(4)
139.66(5)
–61.0
—
∠N1–P1–F1/H1
∠N1–P1–C1
∠N2–P1–N3
—
—
115.21(7)
159.8
δ 31
P
a See SI for full details. b Data from Ref. 23.
Consistent with the short P–F distance, fluoride abstraction
from 1•[F][C5F4N] was not accessible by treatment with
B(C6F5)3 (FIA = 107.1 kcal/mol)39; however, the addition of the
more potent fluoride acceptor Al(C6F5)3 (FIA = 130.0 kcal/mol)
did result in fluoride transfer and formation of
1•[C5F4N]+[AlF(C6F5)3]– as observed by 31P NMR spectroscopy
(δ +54.3 ppm). Likewise, 1•[F][C5F4N] is unreactive to common
borane reagents (9-BBN, HBcat) but undergoes smooth reac-
tion instead with diisobutylaluminum hydride (DIBAL-H, 1.5
equiv) in toluene at room temperature. In this latter reaction,
31P NMR spectra are consistent with an exchange of fluoride for
hydride at the pentacoordinate phosphorus (δ –62.7 ppm), for-
mulated as hydridophosphorane 1•[H][C5F4N] (Figure 2); a
doublet resonance with large coupling constant (1JP–H = 541.7
Hz) collapses to a singlet upon proton decoupling, corroborat-
ing the presence of the P–H bond. 1•[F][C5F4CF3] also trans-
forms to 1•[H][C5F4CF3] in the same conditions. The require-
ment for a strongly fluorophilic metathesis reagent would
seem to imply a significant stepwise character to the exchange
reaction.
The fluorophosphoranes obtained by C–F OA to 1 are indefi-
nitely stable in solution at ambient temperature; diffraction
quality single crystals deposit from concentrated solutions in
diethyl ether upon cooling. By X-ray diffraction analysis, the
solid-state structure of 1•[F][C5F4N] adopts a pentacoordinate
geometry intermediate between trigonal bipyramidal and
square pyramidal extrema along the Berry coordinate, biased
somewhat toward the former (τ = 0.6034). Indeed, as repre-
sented in the thermal ellipsoid plot in Figure 2 (left), the P-
fluoro substituent of 1•[F][C5F4N] is distal, but not rigorously
apical, with respect to the diarylamino N1; the fluoroheteroaryl
group similarly deviates from an idealized equatorial position
(Table 1). By structural comparison to known fluorophospho-
rane compounds, the P1–F1 bond length of 1•[F][C5F4N]
(1.6282(6) Å) is short relative to the average apical P–F dis-
tance (1.650 Å).35 For reference, 1•[F][C5F4N] shows a P–Fax
distance and IR stretching frequency (687 cm–1) intermediate
of the polyfluorophosphoranes MePF4 (1.612 Å, 720 cm–1) and
Me2PF3 (1.643 Å, 648 cm–1).36 Given the known correlation of
P–Fax bond energy and electronegativity of the ancillary lig-
ands,37 we infer a high affinity of the phosphorus center for the
fluoride substituent in 1•[F][C5F4N]38 (vide infra).
Structural determination of 1•[H][C5F4N] was undertaken by
X-ray diffraction on a single-crystalline sample, wherein the
phosphorus-bound hydrogen atom (H1) was located in the dif-
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ference Fourier map and refined isotropically. Modest distinc-
the foregoing lines of evidence inform the conclusion that the
C–H RE from 1•[H][C5F4E] proceeds via a unimolecular ligand
coupling event.
tions are noted when comparing 1•[F][C5F4N] and
1•[H][C5F4N]; as depicted in Figure 2 (right), the intermediate
trigonal bipyramidal/square pyramidal geometry of
1•[F][C5F4N] is largely retained in 1•[H][C5F4N] (τ = 0.56).
With the less electronegative H substituent in place of F, a slight
lengthening of the remaining four bonds to P is observed (Table
1). Overall, the geometry of 1•[H][C5F4N] is comparable to the
reported structures of the other hydridophosphorane mole-
cules derived from 1,23 where the P-hydrido substituent occu-
pies a distal position from N1 (viz. ∠N1–P1–H1 = 167-176°).
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A solution of 1•[H][C5F4E] (E = N or C–CF3, 5-100 mM in
C6D6) sealed in an NMR tube is stable at ambient temperature,
but heating above 140 °C results in the consumption of the
starting material. Time-stacked 31P NMR spectra (Figure 3a) in-
dicate that 1•[H][C5F4N] (δ –62.5 ppm) is reverted to 1 (δ
+160.4 ppm) through an apparent C–H RE from phospho-
rus(V). Simultaneous monitoring within the 19F NMR channel
(Figure 3b) confirms the concomitant formation of RE product
2,3,5,6-tetrafluoropyridine 3a. Quantitative 1H NMR analysis of
the reaction under these conditions establish that the reaction
proceeds cleanly (ca. 95% mass recovery).
Figure 4. Experimental studies to probe into the mechanism of the
H–C5F4E reductive elimination from 1•[H][C5F4E]. (a) The first-or-
der reaction kinetics with respect to [1•[H][C5F4N]]. (b) Crossover
experiment with 1•[D][C5F4N] and 1•[H][C6F4CF3] producing only
non-crossover products.
Although a direct apical-equatorial ligand coupling is forbid-
den on orbital symmetry grounds, 41 DFT modelling (ωB97X-
D3/def2-TZVP) identifies two candidate pathways describing
concerted (albeit highly asynchronous) C–H RE mechanisms
from 1•[H][C5F4N]. In the first pathway, the incipient C–H bond
is substantially developed prior to P–C bond cleavage in the
transition structure (TS1, Figure 5, top). In effect, the RE has
substantial character of a hydride migration from phosphorus
to the carbon in the fluoroaryl group via an addition to the ar-
omatic π*-orbital reminiscent of concerted SNAr42 (see SI for
details). Despite an apparent increase in P1–C1 bond order near
the saddle point, no stationary point corresponding to a stable
phosphonium intermediate is obtained along the reaction co-
ordinate. Although analogous mechanisms have been sug-
gested for other phosphorus-based ligand coupling reac-
tions,12,20 the high energy of this transition state (ΔG‡TS1 = 49.2
kcal/mol) likely renders such a pathway inaccessible in this
case.
Figure 3. Time-stacked (a) 31P{1H} NMR and (b) 19F NMR spectra
of 1•[H][C5F4N] in C6D6 at t = 0, 52, 108, and 178 h at 160 °C. Units
are ppm relative to 85% H3PO4 (31P) and CFCl3 (19F). See SI for un-
abridged spectra.
To further characterize the nature of this C–H RE, the reac-
tion kinetics were evaluated at 160 °C by quantitative 1H NMR
spectroscopy using durene as an internal standard. As shown
in Figure 4a, the concentration of 1•[H][C5F4N] decays accord-
ing to first-order kinetics, with a rate constant k = 6.38±0.01 ×
10–6 s–1. Isotope labelling studies confirm the intramolecular
provenance of the C-H coupling partners; heating a solution of
1•[D][C5F4N] exclusively generated D–C5F4N. Independentki-
netic profiling of the C-H RE for 1•[H][C5F4N] and 1•[D][C5F4N]
establish a kinetic isotope effect of kH/kD = 1.17±0.11.40 Fur-
thermore, a crossover experiment by heating a mixture of
1•[D][C5F4N] and 1•[H][C6F4CF3] formed only D–C5F4N (3a-d)
and H–C6F4CF3 (3b) with no evidence for crossover products
H–C5F4N (3a) or D–C6F4CF3 (3b-d) (Figure 4b). Taken together,
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F→H ligand metathesis, and C–H reductive elimination at a
nontrigonal phosphorus triamide 1. The sequencing of these el-
ementary reactions at phosphorus is reminiscent of the role
played by transition metals in aryl C–X substitution reactions,44
but is without precedent for p-block compounds. The closed
synthetic loop—beginning and ending with 1—suggests that it-
erative cycling (i.e. catalysis) is in principle possible, but unfor-
tunately the thermal instability of DIBAL-H is not compatible
with the elevated temperature needed to promote C–H reduc-
tive elimination in this system. That said, our mechanistic mod-
els for concerted asynchronous C–H reductive elimination pro-
vide a basis for evaluating the impact of tailored alterations to
1 on the kinetics of reductive elimination with the purpose of
enabling swifter C–H and related reductive elimination pro-
cesses in a catalytic fashion.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures; crystallographic details; compu-
tational details; IR spectra; 1H, 13C, 19F, and 31P NMR spectra
(PDF)
Crystallographic data for C19H14F5N4P (CIF)
Crystallographic data for C19H15F4N4P (CIF)
Crystallographic data for C21H14F8N3P (CIF)
Crystallographic data for C21H14F5N4P (CIF)
AUTHOR INFORMATION
Corresponding Author
*radosevich@mit.edu
Figure 5. DFT pathways for C–H reductive elimination from
1•[H][C5F4N] at the ωB97X-D3/def2-TZVP level of theory (Gibbs
free energies in italics). (top) Model of TS1 and mapping of key
bond orders along the intrinsic reaction coordinates. (bottom)
Model of TS2 and mapping of key bond orders along the intrinsic
reaction coordinates.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Financial support was provided by NSF (CHE-1900060). S.L.
acknowledges the ILJU Academy and Culture Foundation for
academic year fellowship support and Masamune Memorial
Fellowship for summer fellowship support. S.L. appreciates
Soonhyoung Kwon (MIT Chemical Engineering) for assistance
in experimental setup for reaction kinetics. We are grateful to
Dr. Peter Mueller, Dr. Seung Jun Hwang, Gregory T. Cleveland,
and Akira Tanushi for assistance in collecting and processing
crystal structure data. ChemMatCARS Sector 15 is principally
supported by the Divisions of Chemistry (CHE) and Materials
Research (DMR), National Science Foundation, under grant
number NSF/CHE1346572. Use of the PILATUS3 X CdTe 1M de-
tector is supported by the National Science Foundation under
the grant number NSF/DMR-1531283. Use of the Advanced
Photon Source, an Office of Science User Facility operated for
the U.S. Department of Energy (DOE) Office of Science by Ar-
gonne National Laboratory, was supported by the U.S. DOE un-
der Contract No. DE-AC02-06CH11357.
A second transition state (TS2, Figure 5, bottom), also lo-
cated as a stationary point on the potential energy surface but
lower in energy (∆G‡TS2 = +37.7 kcal/mol), is distinguished by
both the sequencing of the asynchronous bond making/break-
ing stages along the reaction coordinate and by the polarity of
reacting P–H moiety. In TS2, P1–C1 bond elongation (d(P1–C1) =
3.16 Å) precedes P1–H1 cleavage; the P1–H1 distance (1.42 Å) is
essentially identical to starting material 1•[H][C5F4N] (d(P1–
H1) = 1.42 Å). According to the natural bond orbital analysis on
TS2, natural population analysis assigns protic character to H1
(+0.080) and a significant second-order perturbation (17.3
kcal/mol) between the C1 lone pair and a P1–H1 σ* orbital is de-
tected. In effect, this RE—although concerted—proceeds with
high asynchronicity and resides near the boundary with a step-
wise polar heterolysis/deprotonation pathway. The ensemble
of experimental observations obtained to date—the tempera-
ture of reaction, kinetic unimolecularity, lack of crossover—are
most consistent with TS2 representing the operative pathway
for this C–H RE.43
REFERENCES
In sum, the foregoing results thus transit a closed PIII/PV syn-
thetic cycle for hydrodefluorination via C–F oxidative addition,
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