Catalyzing pyramidal inversion: Configurational lability of P-stereogenic phosphines via single electron oxidation

Article abstract of DOI:10.1021/ja404943x

We report that pyramidal inversion of trivalent phosphines may be catalyzed by single electron oxidation. Specifically, a series of P-stereogenic (aryl)methylphenyl phosphines are shown to undergo rapid racemization at ambient temperature when exposed to catalytic quantities of a single electron oxidant in solution. Under these conditions, transient phosphoniumyl radical cations (R₃P^?+) are formed, and computational models indicate that the pyramidal inversion barriers for these open-shell intermediates are on the order of ～5 kcal/mol. The observed 10²⁰-fold rate enhancement over uncatalyzed pyramidal inversion opens new opportunities for the dynamic stereochemistry of phosphines and may hold additional implications for the configurational stability of P-stereogenic phosphine ligands on high-valent oxidizing transition metals.

Full text of DOI:10.1021/ja404943x

Communication
pubs.acs.org/JACS
Catalyzing Pyramidal Inversion: Configurational Lability of
P‑Stereogenic Phosphines via Single Electron Oxidation
Kyle D. Reichl,† Daniel H. Ess,‡ and Alexander T. Radosevich*,†
†Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, United States
‡Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602, United States
S
* Supporting Information
inversion for trivalent aryl and alkyl phosphorus compounds
is on the order of 30−40 kcal/mol.10 These high barriers impart
differentially substituted trivalent phosphines with persistent
chirality, a feature that makes them valuable chiral ligands in
enantioselective synthesis and coordination polymers11,12 but
otherwise limits their use in stereodynamic processes to
specialized P-substituted derivatives with atypically low
inversion barriers.13−15 The ability to trigger facile dynamic
stereoisomerism of underivatized P-stereogenic aryl and alkyl
phosphines at ambient temperature would open the door to
utilization of this important class of compounds in diverse
dynamic stereochemical applications.16
ABSTRACT: We report that pyramidal inversion of
trivalent phosphines may be catalyzed by single electron
oxidation. Specifically, a series of P-stereogenic (aryl)-
methylphenyl phosphines are shown to undergo rapid
racemization at ambient temperature when exposed to
catalytic quantities of a single electron oxidant in solution.
Under these conditions, transient phosphoniumyl radical
cations (R3P•+) are formed, and computational models
indicate that the pyramidal inversion barriers for these
open-shell intermediates are on the order of ∼5 kcal/mol.
The observed 1020-fold rate enhancement over uncatalyzed
pyramidal inversion opens new opportunities for the
dynamic stereochemistry of phosphines and may hold
additional implications for the configurational stability of
P-stereogenic phosphine ligands on high-valent oxidizing
transition metals.
The inversion barrier of trivalent group 15 compounds is
often described within the context of a second-order Jahn−
Teller effect (Figure 1a).7,8 Deformation of the pyramidal C3v-
symmetric ground state to the planar D3h-symmetric transition
state involves an energetic penalty associated with raising of the
HOMO energy due to loss of HOMO−LUMO orbital mixing.
This energy penalty is significant for phosphorus compared
with nitrogen due to the large ground-state HOMO−LUMO
mixing.5 Congruent with this electronic understanding,
theoretical and experimental results have indicated that open-
shell phosphoniumyl radical cations (R3P•+),17 which may be
accessed by removal of one electron18 from the closed-shell
neutral phosphine, may exhibit a decreased electronic penalty
for planarization (Figure 1b).19−21 Indeed, the racemization of
a P-stereogenic phosphine by TCNQ/HCl has previously been
suggested to involve phosphoniumyl radical cations,22 although
the analysis in this circumstance is made ambiguous by the
possible intervention of closed-shell phosphonium or phos-
phorane intermediates.23,24 We show that under diverse
conditions of outer-sphere single electron transfer, the
pyramidal inversion of P-stereogenic phosphines may be
efficiently catalyzed with barriers of only ∼5 kcal/mol.25 This
demonstration opens new opportunities for the use of dynamic
stereochemistry of underivatized phosphines and may have
further implications for the suitability of P-stereogenic
phosphines as chiral ligands for redox-active transition metals.
As an exemplar of the catalyzed pyramidal inversion of
phosphines, we focused initially on the stereodynamic behavior
of (ferrocenyl)methylphenylphosphine (1). The solution
potential and reversibility of the redox couple 1⇌1•+ was
electrochemically interrogated. A cyclic voltammogram (CV) of
1 (1 mM 1 in MeCN, 0.1 M [nBu4N][PF6], T = 293 K, scan
he stereodynamic behavior of chiral compounds under-
1
Tpins numerous techniques in stereoselective synthesis,
chiral sensing,2 and chiroptical switching.3 Pyramidal inversion
of trivalent group 15 compounds, in which C3v-symmetric
ground states interconvert via a planar D3h-symmetric transition
state (Figure 1), is an archetypal example of dynamic
stereoisomerism.4−8 Whereas pyramidal trivalent nitrogen
compounds commonly undergo inversion with low barriers,
heavier group 15 analogues experience signficant energetic
penalties for inversion.9 Indeed, Mislow demonstrated in a
series of landmark papers that the barrier to pyramidal
Figure 1. (A) Frontier orbital correlation diagram for trisubstituted
phosphine. (B) Energy coordinate diagram for pyramidal inversion of
neutral phosphine (1) and phosphoniumyl radical cation (2).
Received: May 16, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja404943x | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
rate = 100 mV/s, stationary glassy carbon working electrode) is
dominated by an irreversible anodic feature at +0.09 V vs
Cp2Fe0/+ (Figure 2A). In accord with previous reports on the
In order to probe the stereochemical lability of 1 under
catalytic single electron oxidation, a sample of enantioenriched
(RP)-1 was prepared in 96% ee.29 This compound is
configurationally stable in solution at ambient temperature,
with an experimentally determined barrier to thermal inversion
of 31.4 kcal/mol.30 However, exposure of 1 to 25 mol % of
[Cp2Fe][PF6] in acetonitrile solution at ambient temperature
results in rapid and significant erosion of optical activity (Table
1, entry 1). Under these conditions, we suggest that thermal
a
Table 1. ET-Catalyzed Pyramidal Inversion
b
entry
catalytic oxidant
Δee
1
2
3
25 mol % [Cp2Fe][PF6]
25 mol % [(p-MeOC6H4)3N][PF6]
25 mol % Cu(OTf)2
96% → 12%
96% → 8%
96% → 2%
a
b
See Supporting Information for full experimental details. Deter-
mined by HPLC of isolated 1 following protection as the BH3-adduct.
electron transfer (ET) from 1 to [Cp2Fe]+ generates transient
1•+, for which racemization via a low-energy pyramidal
inversion pathway (vide infra) precedes return ET. Consistent
with this proposed outer-sphere ET mechanism, the
racemization of 1 may also by catalyzed by oxidation with
organic aminium oxidant [(p-MeOC6H4)3N][PF6] (entry 2).
Additionally, copper(II) triflate was found to catalyze
racemization of 1 (entry 3). Since oxidizing metal salts
including Cu(II) are frequently employed in conjunction with
P-stereogenic ligands for the preparation of chiral catalysts,31
this latter result suggests that stereochemical fidelity may not
necessarily be assumed across all classes of P-stereogenic
phosphine/metal complexes.32,33
A survey of the racemization of P-stereogenic (aryl)-
methylphenylphosphines (2−10) with diverse steric and
electronic properties further indicates the generality of the
catalyzed pyramidal inversion (Table 2). The anodic peak
potentials for phosphines 2−10 range from 620 to 940 mV vs
Cp2Fe0/+ as determined by CV. At these potentials,
ferrocenium ion is ineffective at promoting electron transfer;
prolonged exposure to acetonitrile solutions of [Cp2Fe][PF6]
did not result in any observable erosion of stereochemistry for
any of the phosphines 2−10. By contrast, the use of 25 mol %
of tri(p-tolyl)aminium hexafluorophosphate ([p-MeC6H4)3N]-
[PF6], E1/2 = +0.37 V vs Cp2Fe0/+), proved effective at
catalyzing the pyramidal inversion in acetonitrile solution on a
1 mmol scale within 30 min. In all cases, good mass recovery of
the racemized phosphines is observed with the only minor
byproduct being ∼10−12% of the corresponding phosphine
oxide. Phosphines substituted with both electron-donating (4−
6) and electron-withdrawing substituents (3) are rendered
configurationally labile under these conditions. In addition, the
dialkylarylphosphine 11 (CAMP) experiences significant
erosion of stereochemistry, indicating that the catalyzed
pyramidal inversion is not limited to diarylalkylphosphines.
We note that highly sterically encumbered phosphines (7−10)
undergo incomplete racemization under these conditions, an
outcome that we attribute primarily to retarded rates of
intermolecular ET for these bulky species.34
Figure 2. (A) CV of 1. (B) Scan rate dependence on observed
electrochemical reversibility for the couple 1⇌1•+.
reactivity of electrogenerated phosphoniumyl radical cations,26
we supposed that the observed electrochemical irreversibility
for 1 was due to a rapid chemical reaction with adventitious
water27 following initial one-electron oxidation. Consistent with
this notion, the anodic current at +0.09 V vs Cp2Fe0/+ is
diminished upon successive scans of 1 (taken without pause in
a quiescent solution) as a new reversible wave grows in at +0.21
V vs Cp2Fe0/+. A voltammogram recorded on independently
synthesized (ferrocenyl)methylphenylphosphine oxide
(FcMePhPO) supports the assignment of the wave at
+0.21 V vs Cp2Fe0/+ as this species. Despite the sensitivity of
the electrogenerated phosphoniumyl radical cation 1•+ to oxide
formation, increasing reversibility for the couple 1⇌1•+ may be
demonstrated at faster scan rates (Figure 2B). A return cathodic
wave becomes apparent upon increasing scan rate from 100 to
1000 mV/s, indicating that the phosphoniumyl radical cation is
persistent at least on the millisecond time-scale.28
B
dx.doi.org/10.1021/ja404943x | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Table 2. Examples of ET-Catalyzed Pyramidal Inversion
Figure 3. Ground and transition states for inversion of 2 and 2•+.
Examination of the change in M06-2X HOMO energies for 2
to 2-TS compared with 2•+ to 2•+-TS shows qualitative,
although not quantitative, agreement with inversion barriers
correlated to second-order Jahn−Teller effects. For example,
the HOMO energy of 2 is destabilized by 1.8 eV (41.2 kcal/
mol) in 2-TS, while the HOMO of 2•+ is destabilized by 0.7 eV
(16.9 kcal/mol) in 2•+-TS. In addition to frontier orbital effects,
the low barrier for 2•+-TS is likely due to less electron repulsion
between the phosphine substituents and the singly occupied
orbital in the planar transition-state geometry. This electron
repulsion effect is in line with the observations of the relaxed
ground-state structures.
Related decreases in computed inversion barriers were found
for the other phosphines surveyed (e.g., ΔH‡ = 31.3 and 4.9
kcal/mol for inversion of 3 and 3•+, respectively). The
calculations also support the speculation that slow intermo-
lecular ET rather than large inversion barriers are the origin of
incomplete racemization for phosphines 7−10. For example,
9•+ has an inversion ΔH‡ of 4.0 kcal/mol, which is similar to
the inversion barriers computed for 2•+ and 3•+.
a
See Supporting Information for full experimental details. Enantio-
meric excess of isolated phosphines was determined by HPLC
b
following protection as BH3-adduct. Ferrocenium hexafluorophos-
phate ([Cp2Fe][PF6], 25 mol %) was used as oxidant. CH2Cl2 was
used as solvent.
c
In summary, we have shown that the pyramidal inversion of
trisubstituted (aryl)alkyl phosphines may be catalyzed by single
electron transfer, permitting dynamic stereochemical behavior
of P-stereogenic phosphines at ambient temperatures. We
anticipate that the ability to deliberately control the configura-
tional lability of P-stereogenic phosphines will open new
opportunities for stereodynamic applications of underivatized
phosphines, for instance in stereoselective synthesis and
chiroptical switching. Additionally, our results also bear on
the suitability of certain P-stereogenic phosphines as chiral
ligands for certain high-valent transition metals; the stereo-
chemical fidelity of metal-bound P-stereogenic phosphines, and
by consequence their ability to influence the stereochemical
outcome of a metal-catalyzed process, may not necessarily be
assumed when ligating oxidizing metal centers.
A preliminary attempt to experimentally determine the rate
of ET-catalyzed phosphine inversion evidences a low barrier.
When monitored in situ by circular dichroism spectroscopy,
ET-catalyzed racemization of 1 with [Cp2Fe][PF6] is complete
within the lag time of mixing and acquisition (∼20 s).35
(U)M06-2X/6-31G(d,p) density functional theory (DFT)
calculations36 in SMD37 acetonitrile solvent provide a more
quantitative estimate of the ET-catalyzed pyramidal inversion
barrier.32,38 Optimized ground states and transition structures
for phosphine inversion of 2 and 2•+ are depicted in Figure 3.39
In accord with previous studies,19 the removal of one electron
from 2 leads to a flattening of the ground-state structure for
open-shell 2•+, which adopts a relaxed pyramidal geometry with
a ∼17° reduction in the PR3 internal dihedral angle that
decreases intramolecular R group repulsion. The relaxation
energy associated with this change in structure upon oxidation
for 2/2•+ is estimated to be >15 kcal/mol. With respect to the
inversion transition states, both 2-TS and 2•+-TS are found to
have nearly identical geometries, with PR3 dihedral angles <1°
and similar P-R group bond lengths. However, while neutral 2
inverts via Y-shaped 2-TS with a computed barrier of ΔH‡ =
31.9 kcal/mol, the ΔH‡ for 2•+ via 2•+-TS is found to be only
4.3 kcal/mol. Since the ΔH‡ for 2•+ inversion is significantly
less than the relaxation energy after electron transfer, it is
possible that inversion is coupled mechanistically with geo-
metric relaxation from ET.
ASSOCIATED CONTENT
* Supporting Information
■
S
Synthetic procedures, spectral characterization, HPLC chroma-
tograms, Cartesian coordinates and computational details. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
radosevich@psu.edu
■
C
dx.doi.org/10.1021/ja404943x | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Gronchi, G. Electrochim. Acta 1997, 42, 2445. (c) Pan, X.; Chen, X.; Li,
T.; Li, Y.; Wang, X. J. Am. Chem. Soc. 2013, 135, 3414.
(21) For additional instances of potential energy surface flattening
upon one electron oxidation, see: Saettel, N. J.; Oxgaard, J.; Wiest, O.
Eur. J. Org. Chem. 2001, 1429.
(22) Powell, R. L.; Hall, C. D. J. Am. Chem. Soc. 1969, 91, 5403.
(23) Muetterties, E. L. Inorg. Chem. 1967, 6, 635.
(24) The configurational lability of phosphoranes is featured in a
dynamic asymmetric oxidation of phosphines: Bergin, E.; O’Connor,
C. T.; Robinson, S. B.; McGarrigle, E. M.; O’Mahony, C. P.; Gilheany,
D. G. J. Am. Chem. Soc. 2007, 129, 9566.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
A.T.R. thanks the Pennsylvania State University for generous
financial support, Prof. P. Bevilacqua (PSU) for access to
circular dichroism instrumentation, and Dr. Yogesh Sure-
ndranath for valuable discussions. D.H.E thanks Brigham
Young University and the Fulton Supercomputing Lab.
(25) For a related approach with sulfoxides, see: Aurisicchio, C.;
Baciocchi, E.; Gerini, M. F.; Lanzalunga, O. Org. Lett. 2007, 9, 1939.
(26) (a) Yasui, S.; Tsujimoto, M.; Itoh, K.; Ohno, A. J. Org. Chem.
2000, 65, 4715. (b) Yasui, S.; Tsujimoto, M. J. Phys. Org. Chem. 2008,
21, 7. (c) Yasui, S.; Tojo, S.; Majima, T. Org. Biomol. Chem. 2006, 4,
2969.
REFERENCES
■
(1) Ebbers, E. J.; Ariaans, G. J. A.; Houbiers, J. P. M.; Bruggink, A.;
Zwanenburg, B. Tetrahedron 1997, 53, 9417.
(2) Wolf, C.; Bentley, K. W. Chem. Soc. Rev. 2013, 42, 5408.
(3) (a) Feringa, B. L.; van Delden, R. A.; Koumura, N.; Geertsema, E.
M. Chem. Rev. 2000, 100, 1789. (b) Canary, J. W. Chem. Soc. Rev.
2009, 38, 747.
(27) Trace water is generally present in acetonitrile despite
conventional drying techniques, see: Burfield, D. R.; Lee, K. H.;
Smithers, R. H. J. Org. Chem. 1977, 42, 3060.
(4) Rauk, A.; Allen, L. C.; Mislow, K. Angew. Chem., Int. Ed. 1970, 9,
400.
̌
̆ ̌ ̌ ́
(28) (a) Podlaha, J.; Stepnicka, P.; Ludvík, J.; Císarova, I.
Organometallics 1996, 15, 543. (b) Pilloni, G.; Longato, B.; Corain,
B. J. Organomet. Chem. 1991, 420, 57.
(5) Albright, T. A.; Burdett, J. K.; Whangbo, M.-H. Orbital
Interactions in Chemistry; Wiley-Interscience: New York, 1985.
(6) An alternative mechanism prevails for highly electronegative
ligands: Dixon, D. A.; Arduengo, A. J.; Fukunaga, T. J. Am. Chem. Soc.
1986, 108, 2461.
(7) Pearson, R. G. J. Mol. Struct. THEOCHEM 1983, 103, 25.
(8) (a) Burdett, J. K. Molecular Shapes; Wiley-Interscience: New
York, 1980. (b) Levin, C. C. J. Am. Chem. Soc. 1975, 97, 5649.
(c) Cherry, W.; Epiotis, N. J. Am. Chem. Soc. 1976, 98, 1135.
(d) Gilheany, D. G. Chem. Rev. 1994, 94, 1339.
(9) Mislow, K. Trans. New York Acad. Sci. 1973, 35, 227.
(10) (a) Baechler, R. D.; Mislow, K. J. Am. Chem. Soc. 1970, 92, 3090.
(b) Baechler, R. D.; Mislow, K. J. Am. Chem. Soc. 1970, 92, 4758.
(c) Mislow, K.; Baechler, R. D. J. Am. Chem. Soc. 1971, 93, 773.
(d) Mislow, K.; Egan, W. J. Am. Chem. Soc. 1971, 93, 1805.
(11) Grabulosa, A. P-Stereogenic Ligands in Enantioselective Synthesis;
RSC Publishing: Cambridge, 2011.
(12) Morisaki, Y.; Chujo, Y. In Polymeric Chiral Catalyst Design and
Chiral Polymer Synthesis; Itsuno, S., Ed.; Wiley: Hoboken, NJ, 2011.
(13) (a) Vedejs, E.; Donde, Y. J. Am. Chem. Soc. 1997, 119, 9293.
(b) Vedejs, E.; Donde, Y. J. Org. Chem. 2000, 65, 2337.
(14) (a) Wolfe, B.; Livinghouse, T. J. Am. Chem. Soc. 1998, 120,
5116. (b) Heath, H.; Wolfe, B.; Livinghouse, T.; Bae, S. K. Synthesis
2001, 2341.
́ ́
(29) Zijlstra, H.; Leon, T.; de Cozar, A.; Guerra, C. F.; Byrom, D.;
Riera, A.; Verdaguer, X.; Bickelhaupt, F. M. J. Am .Chem. Soc. 2013,
135, 4483.
(30) See Supporting Information for full details.
(31) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346.
(32) In general, chiral monodentate arylphosphines are poor ligands
for enantioselective Cu-catalyzed conjugate addition. See: Alexakis, A.;
Backvall, J. E.; Krause, N.; Pam
108, 2796.
̀
ies, O.; Dieg
́
uez, M. Chem. Rev. 2008,
̈
(33) For the successful use of phosphine 1 in reductive catalysis, see:
Colby, E. A.; Jamison, T. F. J. Org. Chem. 2003, 68, 156.
(34) Sterically demanding phosphines resist air oxidation. For
example, see: Barder, T. E.; Buchwald, S. L. J. Am. Chem. Soc. 2007,
129, 5096.
(35) Assuming reversible diffusion controlled electron transfer, these
data place an experimental ceiling of ∼17 kcal/mol on the barrier for
pyramidal inversion in this case.
(36) (a) All calculations were carried out in Gaussian 09. Frisch, M.
J.; et al. Gaussian 09, revision B.01; Gaussian, Inc.: Wallingford, CT,
2009. (b) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215.
(c) Zhao, Y.; Truhlar, D. G. Acc. Chem. Res. 2008, 41, 157.
(37) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B
2009, 113, 6378.
(15) (a) Kovacik, I.; Wicht, D. K.; Grewal, N. S.; Glueck, D. S.;
Incarvito, C. D.; Guzei, I. A.; Rheingold, A. L. Organometallics 2000,
19, 950. (b) Moncarz, J. R.; Laritcheva, N. F.; Glueck, D. S. J. Am.
Chem. Soc. 2002, 124, 13356. (c) Blank, N. F.; Moncarz, J. R.; Brunker,
T. J.; Scriban, C.; Anderson, B. J.; Amir, O.; Glueck, D. S.; Zakharov, L.
V.; Golen, J. A.; Incarvito, C. D.; Rheingold, A. L. J. Am. Chem. Soc.
2007, 129, 6847. (d) Scriban, C.; Glueck, D. S. J. Am. Chem. Soc. 2006,
128, 2788. (e) Chan, V. S.; Stewart, I. C.; Bergman, R. G.; Toste, F. D.
J. Am. Chem. Soc. 2006, 128, 2786. (f) Chan, V. S.; Chiu, M.; Bergman,
R. G.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 6021.
(16) Wolf, C. Dynamic Stereochemistry of Chiral Compounds; RSC
Publishing: Cambridge, 2008.
(38) This level of theory was selected since the inversion barriers for
PH3 and H3P•+ ΔH‡ = 31.8 and 2.6 kcal/mol correspond closely to
ΔH‡ = 32.8 and 1.7 kcal/mol computed with the highly accurate G3B3
method. See, Baboul, A. G.; Curtiss, L. A.; Redfern, P. C.;
Raghavachari, K. J. Chem. Phys. 1999, 110, 7650.
(39) While both Y- and T-shape transition structures have been
found for PH3/H3P•+ (ref 19), our calculations show that only a Y-
shape transition structure is possible with large aryl and alkyl
phosphine substituents.
(17) Marque, S.; Tordo, P. Top. Curr. Chem. 2005, 250, 43.
(18) (a) Kochi, J. K. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 7, p 959.
(b) Bauld, N. L. In Electron Transfer in Chemistry; Balzani, V., Ed.;
Wiley-VCH: Weinheim, 2001; Vol. 2, p 133. (c) Tondres, Z. V. Ion-
Radical Organic Chemistry: Principles and Applications; CRC Press:
Boca Raton, FL, 2009. (d) Eberson, L. E. Electron Transfer in Organic
Chemistry; Springer: New York, 1988. (e) Bauld, N. L. Tetrahedron
1989, 45, 5307.
(19) Creve, S.; Nguyen, M. T. J. Phys. Chem. A. 1998, 102, 6549.
(20) (a) Culcasi, M.; Berchadsky, Y.; Gronchi, G.; Tordo, P. J. Org.
Chem. 1991, 56, 3537. (b) Merzougui, B.; Berchadsky, Y.; Tordo, P.;
D
dx.doi.org/10.1021/ja404943x | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX