Mechanisms of stereomutation and thermolysis of spiro-1,2-oxaphosphetanes: New insights into the second step of the wittig reaction

Article abstract of DOI:10.1021/ja307330c

The experimentally observed stereomutation of spiro-1,2-oxaphosphetanes is shown by DFT calculations to proceed through successive M_B2 or M _B4 and M_B3 mechanisms involving two, four, and three Berry pseudorotations at phosphorus, respectively. Oxaphosphetane decomposition takes place in a single step via a polar transition state. The calculated activation parameters for this reaction are in good agreement with those determined experimentally.

Full text of DOI:10.1021/ja307330c

Communication
pubs.acs.org/JACS
Mechanisms of Stereomutation and Thermolysis of Spiro-1,2-
oxaphosphetanes: New Insights into the Second Step of the Wittig
Reaction
Jesus García Lopez,† Antonio Moran Ramallal,‡ Javier Gonzalez,*,‡ Laura Roces,§
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Santiago García-Granda,§ María Jose Iglesias,† Pascual Ona-Burgos,† and Fernando Lopez Ortiz*,†
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†
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Area de Química Organ
‡Departamento de Química Organ
§Departamento de Química Física y Analítica, Universidad de Oviedo-CINN, C/Julian
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ica, Universidad de Almería, 04120 Almería, Spain
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ica e Inorganica, Universidad de Oviedo, C/Julian
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Clavería 8, 33006 Oviedo, Spain
Clavería 8, 33006 Oviedo, Spain
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S
* Supporting Information
The positional interchange of apical (ap) and equatorial (eq)
ligands in the trigonal bipyramid (TBP) geometry of OPAs has
been described as a Berry pseudorotation7 (BPR) or turnstile
rotation8 (TR).1,9 Very recently,10 it has been shown that
isomerization of TBPs may occur in three ways: BPR, threefold
cyclic permutation, and half-twist ap−eq interchange (MB1,
MB2, and MB3, respectively). These are one-step processes, and
the subscript indicates the number of BPRs involved (Scheme
1).11 TR has been proved to be equivalent to BPR. The
comments above indicate that the role and mechanism of
stereomutation in the Wittig reaction remain unclear.
Addressing this issue is hampered by the instability of the
substrates. The rate of ap−eq exchange can be decreased using
bidentate ligands.5b,c,9,12 Herein we describe a study of the
isomerization and thermal decomposition of isolable spiro-1,2-
oxaphosphetanes. Key features of this study are (1) the
synthesis of enantiopure derivatives, (2) the identification of
three mechanisms of OPA stereomutation (MB2, MB3, and a
new one labeled as MB4), and (3) the description of olefination
as a single-step reaction.
ABSTRACT: The experimentally observed stereomuta-
tion of spiro-1,2-oxaphosphetanes is shown by DFT
calculations to proceed through successive MB2 or MB4
and MB3 mechanisms involving two, four, and three Berry
pseudorotations at phosphorus, respectively. Oxaphosphe-
tane decomposition takes place in a single step via a polar
transition state. The calculated activation parameters for
this reaction are in good agreement with those determined
experimentally.
he Wittig reaction is the most popular method for
T
introducing double bonds at specific positions of organic
molecules.1a,c The generally accepted mechanism involves three
stages:1b asynchronous [2 + 2] cycloaddition to give an
oxaphosphetane (OPA, I), pseudorotation at phosphorus to
form an anti-apicophilic P−Oeq isomer (III),2 and asynchro-
nous [2 + 2] cycloreversion to yield the olefin and phosphine
oxide (Scheme 1). Although some anti-apicophilic OPAs have
Spiro-oxaphosphetanes 2−6, which are stabilized by the
presence of the o-benzamide (oBA) moiety, were synthesized
using previously reported procedures (Table 1).13 The
reactions with the hindered ketone L-(−)-camphor (technical
grade, ca. ∼70% ee) gave products 5 and 6 (90% conversion,
45:55 ratio; entries 4 and 5) arising from endo attack at the CO
group of L-camphor. They were separated through semi-
preparative HPLC. Recrystallization of 6 (72% ee) from
toluene furnished crystals of ( )-6 suitable for X-ray diffraction
(XRD) [Figure S27 in the Supporting Information (SI)] and
(+)-6 (>97% ee). The corresponding reactions with D-
(+)-camphor (>97% ee) gave rise to enantiopure ent-5 and
ent-6 (Figures S7 and S8).
Thermal decomposition of OPAs 2−6 afforded alkenes 7−
11 and heterocycle 12 quantitatively (Table 1). In the
thermolysis of 3−6, partial isomerization to 3′−6′ having the
configuration of the P atom inverted was observed (Table 1,
Tables S4 and S5 in the SI, and Figure S14). The new products
were characterized in situ by NMR spectroscopy (Figure S14).
Scheme 1. Possible Stereomutation Mechanisms in the
Wittig Reaction
been isolated,3 they convert into the P−Oap isomer during
decomposition.3b Recent ab initio calculations on realistic
Wittig reactions suggested that III is not an intermediate in the
reaction pathway.4 Isomerization of P−Oap OPAs (I ⇄ II) is
also known. In typical OPAs, this stereomutation is much faster
than fragmentation.5 The activation free energy (ΔG⧧) for
OPA interconversion in spirodibenzophosphole (spiro-DBP)
derivatives (13.1−14.6 kcal mol−1) is ca. 10 kcal mol−1 lower
than the ΔG⧧ for decomposition.5a,b In special cases, OPA
decomposition may be faster than stereomutation.6
Received: July 26, 2012
Published: November 20, 2012
© 2012 American Chemical Society
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Communication
recombination). As far as we know, this is the first time that the
stereochemical course of the P stereocenter has been
ascertained in the decomposition of an enantiopure OPA.
McEwen et al.6a reported that the Wittig reaction of
(+)-EtMePhPCHPh with benzaldehyde proceeds stereo-
specifically with retention of configuration of the P atom (i.e.,
decomposition is faster than stereomutation). The results were
explained in terms of the participation of three possible OPAs
of TBP and square pyramid (SP) geometry.
Table 1. OPAs 2−6, Decomposition Products 7−11, and
PO Byproduct 12
Since decomposition and stereomutation are concurrent
processes, we determined the activation parameters for the
thermolysis of 2, where only the latter is observed. The kinetics
of olefin formation in toluene was investigated by 31P NMR
spectroscopy. The reaction was first order in the oxaphosphe-
tane. The temperature dependence of k led to an estimation of
the activation parameters as ΔH⧧ = 30.4 0.6 kcal mol−1 and
ΔS⧧ = −1.3 1.4 cal mol−1 K−1 (see the SI), which gave ΔG⧧
= 30.9 1.1 kcal mol−1 at T = 403.15 K. This activation barrier
is >10 kcal mol−1 higher than those for typical OPAs1,5,9 and
slightly lower than those for disubstituted spiro-oxaphosphe-
tanes stabilized by the Martin ligand.15
The mechanism of olefination of oxaphosphetanes 2, 5, and
6 was studied using density functional theory at the B3LYP/6-
31G* level. The validation of the method is described in the SI.
The potential energy surface (PES) of 2 consists of seven
stationary points: energy minima for OPAs 2 and 2″, alkene 7,
and benzoazaphosphol 12 and the respective transition states
(TSs) for fragmentation ([2·A]⧧ and [2″·A]⧧) and stereo-
mutation ([2·B]⧧) (Figure 1 and Table S6). 2 and 2″ are
a
Conversion of permutational isomers 3′−6′ was observed by 31P
b
c
NMR spectroscopy. Characterized in ref 13. ent-5/6 and ent-10/11
were prepared from D-(+)-camphor (>97% ee).
In the decomposition of enantiopure 6 (THF, 7 days!), this
stereomutation led to partially racemized 12 (80% ee; Scheme
2).14 The collapse of 5 (84% ee)/ent-5 (>97% ee) to the final
products was achieved in only 15 h. Recrystallization of the P
O byproduct from toluene furnished optically pure (SP)-12.
The configuration was assigned by XRD analysis (Figure S28).
The stereospecific formation of alkenes 10 and 11 ruled out the
existence of stereochemical drift (reversible OPA opening/
Figure 1. Energy profile of the decomposition of 2 and stereomutation
via the MB2 mechanism.
Scheme 2. Decomposition of Spiro-OPAs 5 and 6
permutational isomers showing distorted TBP geometries. 2 is
6 kcal mol−1 more stable than 2″, which supports the exclusive
detection of 2 in solution. Isomerization of 2 into 2″ proceeds
through [2·B]⧧ (barrier of 24.4 kcal mol−1), which has a TBP-
like geometry with the O1, N, and C8 atoms in the equatorial
plane and C3 and C13 in apical positions (Figure S17). The
negative ΔS⧧ of −6.9 cal mol−1 K−1 is assigned to steric strain
induced by ligand interchange.5c The calculated ΔG⧧ of
stereomutation is ca. 10 kcal mol−1 higher than that
experimentally obtained for DBP-stabilized spiro-OPAs.5a,b
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Communication
This difference in ΔG⧧ can be assigned to the larger
stabilization provided by the oBA ligand compared with the
DBP moiety. The process 2 ⇄ 2″ can be described as a 120°
cyclic rotation of one apical and two equatorial ligands (i.e., an
MB2 mechanism; Figure 1).10,11 The imaginary vibrational
mode of [2·B]⧧ supports this conclusion. To the best of our
knowledge, this is the first report of the interconversion of
OPAs by the MB2 mechanism.
166.63(15)°/165.4°]. The motion of the P substituents of 6
may follow two courses. Two consecutive 60° clockwise
rotations of the N, C8, and C13 ligands (MB2 mechanism)
convert 6 into 6″ via TS [6·B]⧧ having a TBP geometry
(barrier of 24.2 kcal mol−1; Figure 3 and Figures S21−S23).
The decomposition of 2 is a single-step, highly exothermic,
irreversible reaction (Figure 2) with a barrier of 31.2 kcal mol−1
○
Figure 2. Graph of relative energy ΔE (blue ) and TP (red line)
along the IRC for the decomposition of 2.
and a small negative entropy of −2.7 cal mol−1 K−1 (Table S6),
in excellent agreement with the activation parameters obtained
in toluene. 2 decomposes in an asynchronous concerted
process via [2·A]⧧. The normal mode of the imaginary
frequency of this TS corresponds to dissociation of the P−
C3 and C4−O1 bonds (with the former being more advanced
than the latter) and formation of the C3−C4 and P−O1 double
bonds. [2·A]⧧ shows a TBP geometry with C3 and C8 in apical
positions, indicating that ring opening involves P pseudor-
otation (the O1−P−N angle decreases from 170.7 to 129° and
the C3−P−C8 angle increases from 124.8 to 167.7°).
In contrast to the generally accepted mechanism of the
second step of the Wittig reaction,1b,c,2 at the level of
computation used, positional exchange of the ligands is
predicted to take place along the reaction coordinate leading
to [2·A]⧧ without the participation of an anti-apicophilic P−
Oeq intermediate. This finding is supported by recent ab initio
calculations.4 A TBP structure containing a P−Oeq bond was
found at an internal reaction coordinate (IRC) of 90% in the
cycloreversion reaction (Figure 2). The V-shaped pattern of the
topology parameter (TP)16 connecting this point with 2 is
characteristic of a Berry stereomutation. Analogously, the
decomposition of 2″ proceeds through [2″·A]⧧ to give 7 and
12 and is disfavored by 7.1 kcal mol−1 relative to that of 2.
The computational study was extended to 5 and 6 to explain
why 6, with the R configuration at the P atom, decomposes
with partial racemization of 12 at a rate that is ca. 20 times
lower than for 5. The PES for the decomposition of 6 includes
OPAs 6, 6′, and 6″ and products 11 and 12 (Table S9). Solvent
effects were estimated by using the polarized continuum model
(PCM). The geometrical parameters calculated for 6 are in
excellent agreement with those experimentally determined for
( )-6 [e.g., the bond distances in the OPA ring for the
isolated/calculated structures are P−O1 1.724(3)/1.773, P−C3
1.821(4)/1.870, C3−C4 1.535(5)/1.555, and C4−O1
1.453(5)/1.446 Å, and the N−P−O1 bond angles are
Figure 3. (A) Energy profile for the 6 ⇄ 6″ ⇄ 6′ interconversion. (B)
Minimum-energy pathway involving the MB2 and MB3 mechanisms.
Most importantly, two successive 120° anticlockwise rotations
produce the same isomerization through the new TS [6·C]⧧
having a TBP configuration with O1 and C13 in apical
positions. This process involves four BPRs and represents a
new mechanism of stereomutation identified as MB4. The
barrier is only 1 kcal mol−1 higher than that of the MB2
mechanism, which makes MB4 a reasonable alternative for the 6
⇄ 6″ interconversion.
The validity of the MB4 mechanism is supported by the
analysis of the TP for this stereomutation.10 A plot of the TP
along the IRC shows the expected quadruple-V-shaped pattern
(Figure 4). The discontinuity observed is due to differences
between bond angles arising from the lack of symmetry of the
system. The four local vertexes correspond to structures having
SP geometry (TP = 0.0) and the three local cusps are TBP
structures characterized by TP values in the range 0.45−0.75
(Figure S25). This analysis shows that the new MB4 mechanism
complements the description of stereomutation in TBP
structures proposed by Lammertsma and co-workers10 as
single-step processes involving a number of BPRs.
Interchange of the C8 and N ligands in 6″ through a 180°
rotation leads to 6′, the isomer of 6 experimentally observed via
P stereomutation. The TSs for this process, [6″·B]⧧ and
[6″·C]⧧, arise from clockwise and anticlockwise rotations,
respectively (Figure S24). Both TSs have SP geometry and are
located halfway through three consecutive Berry pseudorota-
tions, as expected for an MB3 mechanism.10 Stereomutation
through [6″·B]⧧ is highly favored because its barrier (30 kcal
mol−1)17 is 7.1 kcal mol−1 lower than that of [6″·C]⧧. A Levi−
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Communication
ACKNOWLEDGMENTS
Dedicated to Prof. F. J. Palacios on the occasion of his 60th
birthday. This work was supported by the Ministerio de Ciencia
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e Innovacion
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and the FEDER Program (Projects CTQ2008-
117BQU, CTQ2011-27705, MAT2010-15094, PTA-2009-
2346-I, and CSD2006-015, Consolider Ingenio 2010, “Factoria
de Crystalizacion”).
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REFERENCES
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Figure 4. Graph of relative energy ΔE (blue) and TP (red) along the
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atom assignments are shown.
Desargues18 graphical representation of the 6 ⇄ 6″ ⇄ 6′
isomerization is shown in Figure S26.
The barrier for olefination of 6 (29.9 kcal mol−1) is 0.5 and
6.8 kcal mol−1 lower than those for decomposition of 6′ and
the 6 ⇄ 6′ interconversion, respectively. The unfavorable
formation of 6′ may be accelerated by the presence of acidic
species in the reaction medium (e.g., 12).3b,19 The detection of
6′ only after 57.5 h of heating supports this assumption.
Importantly, 5 is destabilized by 5.1 kcal mol−1 with respect to
6, and the barrier for cycloreversion (27.3 kcal mol−1) is 1.7
kcal mol−1 lower than for 6. The destabilization of 5 arises from
the interaction of the C3-Me protons with the camphor moiety
(Figure S15).
(6) (a) McEwen, W. E.; Kumli, K. F.; Blade-Font, A.; Zanger, M.;
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Nakamoto, M.; Akiba, K.-y. Eur. J. Org. Chem. 2008, 1715. (c) Akiba,
K.-y. Organo Main Group Chemistry; Wiley: New York, 2011.
In summary, this study of the decomposition of isolable
spiro-1,2-oxaphosphetane intermediates in a Wittig-type
reaction allowed us to determine the activation parameters
for the process; to characterize the cycloreversion as a single-
step concerted asynchronous reaction that irreversibly affords
the corresponding alkene and P byproduct via a polar TS; and
to describe for the first time the stereomutation through three
possible mechanisms MB2, MB3, and MB4 involving two,
three, and four Berry pseudorotations, respectively. The MB4
mechanism is unprecedented and contributes to completing the
description of the motion of substituents in the interconversion
of pentacoordinated species having TBP geometry.10,11
(13) García-Lop
́ ́ ́
ez, J.; Peralta-Perez, E.; Forcen-Acebal, A.; García-
Granda, S.; Lopez-Ortiz, F. Chem. Commun. 2003, 856.
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ASSOCIATED CONTENT
* Supporting Information
■
(14) Thermolysis of enantiopure ent-5 and ent-6 furnished (SP)-12
(>97% ee) and (RP)-12 (80% ee), respectively, together with the
corresponding enantiopure olefins ent-10 and ent-11 (Figure S13).
(15) (a) Kawashima, T.; Kato, K.; Okazaki, R. J. Am. Chem. Soc. 1992,
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S
Experimental and computational details, characterization data,
rate constants measured, Cartesian coordinates and energies of
the stationary points located, and crystallographic data for
( )-6 and (SP)-12 (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
(16) The TP defined in ref 10 represents the distortion along a Berry
process. The limiting values are 0 (ideal SP) and 1 (ideal TBP).
(17) Similar barriers were found in the stereomutation of 10-P-5
spirophosphoranes. See: Jiang, X.-D.; Matsukawa, S.; Yamamich, H.;
Kakuda, K.-I.; Kojima, S.; Yamamoto, Y. Eur. J. Org. Chem. 2008, 1392.
(18) Mislow, K. Acc. Chem. Res. 1970, 3, 321.
AUTHOR INFORMATION
Corresponding Author
flortiz@ual.es; fjgf@uniovi.es
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(19) Ramirez, F.; Loewengart, G. V.; Tsolis, E. A.; Tasaka, K. J. Am.
Chem. Soc. 1972, 94, 3531.
Notes
The authors declare no competing financial interest.
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