Nucleophilicity parameters for phosphoryl-stabilized carbanions and phosphorus ylides: Implications for wittig and related olefination reactions

Article abstract of DOI:10.1021/ja8056216

The kinetics of the reactions of four phosphoryl-stabilized carbanions 1a-d and four phosphorus ylides 1e-h with benzhydrylium ions 2a-h and structurally related quinone methides 2i-m have been determined by UV-vis spectroscopy. The second-order rate constants (k) correlated linearly with the electrophilicity parameters E of 2a-m, as required by the correlation log k= s(N + E) (J. Am. Chem. Soc. 2001, 123, 9500-9521), allowing us to calculate the nucleophile-specific parameters N and s for phosphoryl-substituted carbanions and phosphorus ylides. In this way, a direct comparison of the nucleophilic reactivities of Horner-Wadsworth-Emmons carbanions and Wittig ylides became possible. Ph₂PO- and (EtO)₂PO-substituted carbanions are found to show similar reactivities toward Michael acceptors, which are 10 ⁴-10⁵ times higher than those of analogously substituted phosphorus ylides. The relative reactivities of these nucleophiles toward benzaldehydes differ significantly from those toward carbocations and Michael acceptors, in accordance with a concerted [2 + 2] cycloaddition being the initial step of these olefinations reactions. Effects of the counterion (K ⁺, Na⁺, or Li⁺) on the nucleophilicities of the phosphoryl-stabilized carbanions in DMSO have been studied. Whereas the effects of K⁺ and Na⁺ are almost negligible for all types of carbanions investigated, Li⁺ coordination reduces the reactivities of phosphonate-substituted acetic ester anions (1a) by a factor of 10² while the reactivities of phosphonate-substituted acetonitrile anions (1b) remain almost unaffected.

Full text of DOI:10.1021/ja8056216

Published on Web 12/23/2008
Nucleophilicity Parameters for Phosphoryl-Stabilized
Carbanions and Phosphorus Ylides: Implications for Wittig
and Related Olefination Reactions
Roland Appel, Robert Loos,† and Herbert Mayr*
Department Chemie und Biochemie, Ludwig-Maximilians-UniVersita¨t Mu¨nchen,
Butenandtstrasse 5-13 (Haus F), 81377 Mu¨nchen, Germany
Received July 18, 2008; E-mail: herbert.mayr@cup.uni-muenchen.de
Abstract: The kinetics of the reactions of four phosphoryl-stabilized carbanions 1a-d and four phosphorus
ylides 1e-h with benzhydrylium ions 2a-h and structurally related quinone methides 2i-m have been
determined by UV-vis spectroscopy. The second-order rate constants (k) correlated linearly with the
electrophilicity parameters E of 2a-m, as required by the correlation log k ) s(N + E) (J. Am. Chem. Soc.
2001, 123, 9500-9521), allowing us to calculate the nucleophile-specific parameters N and s for phosphoryl-
substituted carbanions and phosphorus ylides. In this way, a direct comparison of the nucleophilic reactivities
of Horner-Wadsworth-Emmons carbanions and Wittig ylides became possible. Ph2PO- and (EtO)2PO-
substituted carbanions are found to show similar reactivities toward Michael acceptors, which are 104-105
times higher than those of analogously substituted phosphorus ylides. The relative reactivities of these
nucleophiles toward benzaldehydes differ significantly from those toward carbocations and Michael
acceptors, in accordance with a concerted [2 + 2] cycloaddition being the initial step of these olefinations
reactions. Effects of the counterion (K+, Na+, or Li+) on the nucleophilicities of the phosphoryl-stabilized
carbanions in DMSO have been studied. Whereas the effects of K+ and Na+ are almost negligible for all
types of carbanions investigated, Li+ coordination reduces the reactivities of phosphonate-substituted acetic
ester anions (1a) by a factor of 102 while the reactivities of phosphonate-substituted acetonitrile anions
(1b) remain almost unaffected.
and can be carried out with high stereoselectivity.4 Detailed
mechanistic investigations by Vedejs and co-workers4e,5 and
Introduction
The Wittig reaction1 as well as the related Wittig-Horner2
and Horner-Wadsworth-Emmons3 reactions are among the
most important methods for synthesizing CdC double bonds.
These olefinations provide access to a wide structural variety
Maryanoff, Reitz, and co-workers6 as well as quantum-chemical
approaches by Yamataka and co-workers,7a,b Aggarwal, Harvey,
and co-workers,7c,d and other authors8 led to the generally
accepted model of salt-free Wittig reactions (Scheme 1). In the
first step, an oxaphosphetane is formed via a concerted
asynchronous [2 + 2] cycloaddition with a transition state in
which the C-C bond formation is more advanced than the P-O
bond formation. The resulting oxaphosphetane decomposes into
† Current address: BASF SE, Ludwigshafen, Germany.
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Wittig, G.; Geissler, G. Liebigs Ann. Chem. 1953, 580, 44–57. (c)
Wittig, G.; Scho¨llkopf, U. Chem. Ber. 1954, 87, 1318–1330.
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Ber. 1959, 92, 2499–2505.
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J. Am. Chem. Soc. 1988, 110, 3948–3958. (e) Vedejs, E.; Fleck, T. J.
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K. C.; Ha¨rter, M. W.; Gunzner, J. L.; Nadin, A. Liebigs Ann./Recl.
1997, 1283–1301. (g) Kokin, K.; Iitake, K.-I.; Takaguchi, Y.; Aoyama,
H.; Hayashi, S.; Motoyoshiya, J. Phosphorus, Sulfur Silicon Relat.
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(8) Further references on theoretical studies of the Wittig reaction are
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9
704 J. AM. CHEM. SOC. 2009, 131, 704–714
10.1021/ja8056216 CCC: $40.75
2009 American Chemical Society

Nucleophilicity Parameters for Carbanions and Ylides
A R T I C L E S
Scheme 1. Mechanism of the Salt-Free Wittig Reaction
Table 1. Benzhydrylium Ions 2a-h and Quinone Methides 2i-m
Employed in This Work
Scheme 2. Betaine Intermediates in the Presence of Lithium
Halides
the olefin and phosphine oxide. NMR studies showed that the
initial oxaphosphetane formation is in general a nonreversible
step,4a,e,5g,6a,9 although some exceptions have also been
reported.4a,e,5d,g,10
In the presence of lithium halides, the oxaphosphetane inter-
mediates can be transformed into betaine intermediates5b,11 (Scheme
2), which may be isomerized by additional base before they cyclize,
forming the thermodynamically more stable trans-oxaphosphetanes,
which finally yield the trans-olefins selectively.4b,e,5g,12 Recently,
alternative ionic intermediates have been suggested to account for
the stereochemical drift.13
The mechanistic course of the Horner-Wadsworth-Emmons
reactions is closely related to that of the Wittig reaction,4b,i,k,l
although it is still controversial whether the initial attack of the
carbanion at the carbonyl group and the oxaphosphetane ring
closure proceed in a concerted or stepwise manner and which
step is rate-determining in the latter case.14 Systematic kinetic
investigations of this reaction in ethanol solution by Larsen and
Aksnes15 led to the conclusion that the oxaphosphetane inter-
mediate is formed in a concerted manner in the rate-determining
step.
It is well-known that phosphoryl-substituted carbanions are
generally more reactive than phosphorus ylides. A quantitative
comparison of these two classes of compounds has, to our
knowledge, not been performed to date.
In recent years, we have developed the most comprehensive
nucleophilicity scale presently available.16 By defining a series
of structurally related benzhydrylium ions and quinone methides
a E values for 2a-h were taken from ref 16b and those for 2i-m
from ref 16c.
(some of them are depicted in Table 1) having widely varying
reactivities, we have been able to directly compare nucleophiles
that differ largely in reactivity.16b-f In this way, we have
circumvented the problem that a single reference electrophile
does not allow one to compare a large variety of nucleophiles
because (1) second-order rate constants k2 < 10-6 M-1 s-1
cannot easily be determined and (2) the upper limit for the rates
of bimolecular reactions is given by diffusion control (k2 )
109-1010 M-1 s-1 in typical solvents). It has been demonstrated
that the nucleophile-specific parameters N and s (defined by eq
1), which are derived from the second-order rate constants of a
particular nucleophile with a series of benzhydrylium ions and/
or quinone methides, correctly predict the reactivity of this
(9) Ward, W. J.; McEwen, W. E. J. Org. Chem. 1990, 55, 493–500.
(10) Schlosser, M.; Christmann, K. F. Angew. Chem., Int. Ed. Engl. 1965,
4, 689–690.
(11) (a) Schlosser, M.; Christmann, K. F. Synthesis 1969, 38–39. (b)
Schlosser, M.; Tuong, H. B.; Tarchini, C. Chimia 1977, 31, 219–220.
(c) Schlosser, M.; Tuong, H. B. Angew. Chem., Int. Ed. Engl. 1979,
18, 633–634. (d) Neumann, R. A.; Berger, S. Eur. J. Org. Chem. 1998,
1085–1087. (e) Pascariu, A.; Mracec, M.; Berger, S Int. J. Quantum
Chem. 2008, 108, 1052–1058.
(12) (a) Schlosser, M.; Christmann, K. F. Liebigs Ann. Chem. 1967, 708,
1–35. (b) Schlosser, M. Top. Stereochem. 1970, 5, 1–30. (c) Schlosser,
M.; Oi, R.; Schaub, B. Phosphorus, Sulfur Silicon Relat. Elem. 1983,
18, 171–174.
(13) Mracec, M.; Pascariu, A.; Berger, S.; Mracec, M. Int. J. Quantum
Chem. 2007, 107, 1782–1793.
(14) (a) Brandt, P.; Norrby, P. O.; Martin, I.; Rein, T. J. Org. Chem. 1998,
63, 1280–1289. (b) Ando, K. J. Org. Chem. 1999, 64, 6815–6821.
(c) Norrby, P. O.; Brandt, P.; Rein, T. J. Org. Chem. 1999, 64, 5845–
5852. (d) Motoyoshiya, J.; Kusaura, T.; Kokin, K.; Yokoya, S.-i.;
Takaguchi, Y.; Narita, S.; Aoyama, H. Tetrahedron 2001, 57, 1715–
1721.
(16) (a) Mayr, H.; Patz, M. Angew. Chem., Int. Ed. Engl. 1994, 33, 938–
957. (b) Mayr, H.; Bug, T.; Gotta, M. F.; Hering, N.; Irrgang, B.;
Janker, B.; Kempf, B.; Loos, R.; Ofial, A. R.; Remennikov, G.;
Schimmel, H. J. Am. Chem. Soc. 2001, 123, 9500–9512. (c) Lucius,
R.; Loos, R.; Mayr, H. Angew. Chem., Int. Ed. 2002, 41, 91–95. (d)
Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66–77.
(e) Mayr, H.; Ofial, A. R. Pure Appl. Chem. 2005, 77, 1807–1821. (f)
Mayr, H.; Ofial, A. R. J. Phys. Org. Chem. 2008, 21, 584–595.
(15) (a) Larsen, R. O.; Aksnes, G. Phosphorus, Sulfur Silicon Relat. Elem.
1983, 15, 219–228. (b) Larsen, R. O.; Aksnes, G. Phosphorus, Sulfur
Silicon Relat. Elem. 1983, 15, 229–237.
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A R T I C L E S
Appel et al.
Scheme 5. Reactions of the Phosphorus Ylides 1e-h with the
Reference Electrophile 2c
nucleophile toward other types of carbocations and Michael
acceptors of known electrophilicity E.16b-f,17
log k20°C ) s(N + E)
(1)
In this work, we have employed this method for characterizing
the nucleophilicities of four phosphorus ylides and four phos-
phoryl-stabilized carbanions (Scheme 3), and we will discuss
the impact of these results on carbonyl olefinations. In order to
achieve conveniently measurable reactions, the carbanions 1a-d
were predominantly characterized by their reactions with
quinone methides 2i-m and the least electrophilic benzhydry-
lium ion 2h, while the much less nucleophilic phosphorus ylides
1e-h were almost exclusively characterized through their
reactivities toward benzhydrylium ions 2a-h.
Scheme 6. Substituted Benzaldehydes 4 Employed in This Work
Results
Product Studies. As shown in Scheme 4, the phosphoryl-
stabilized carbanions 1a-d react with the reference electrophiles
2 to give the addition products 3 or 3′. Solutions of the
carbanions 1a-d were generated either by deprotonating the
corresponding CH-acids in DMSO with KOtBu or by isolating
Scheme 7. Reactions of the Phosphoryl-Stabilized Carbanions
1a-d and the Phosphorus Ylide 1e with the Benzaldehydes 4a,
4e, and 4g
Scheme 3. Phosphoryl-Stabilized Carbanions 1a-d and
Phosphorus Ylides 1e-h Investigated in This Work
the potassium salts (1a-d)-K and dissolving them in DMSO
or CH3CN. The particular electrophile, in DMSO or CH2Cl2
solution or in a mixture of the two solvents, was then added.
Detailed procedures and characterizations of the isolated
products 3 or 3′ are reported in the Supporting Information.
The bis(p-dimethylamino)benzhydrylium ion 2c was the only
electrophile used for product studies with the phosphorus ylides
1e-h (Scheme 5). One can assume that variation of the remote
aryl substituent of the electrophile does not affect the types of
products. The formation of 3′′ from 1e-h and 2c was studied
in CDCl3 solution by NMR, and the procedure as well as the
characterizations of the addition products are described in the
Supporting Information.
Scheme 4. Reactions of the Phosphoryl-Stabilized Carbanions
1a-d with the Reference Electrophiles 2
The olefination reactions with the nucleophiles 1a-e were
studied with the series of substituted benzaldehydes 4 (Scheme
6). Representative combinations of the nucleophiles 1a-e with
the benzaldehydes 4a, 4e, and 4g in DMSO showed the expected
trans selectivity (Scheme 7). The cis/trans ratio of the olefins 5
was determined by GC/MS. In order to exclude the possibility
that the observed cis/trans ratio was changed during workup or
purification, samples were taken from the reaction mixtures after
different reaction times and analyzed after dilution with acetone.
Details are given in the Supporting Information.
Kinetic Investigations. For the kinetic measurements, solu-
tions of the carbanions 1a-d were generated either by depro-
tonation of the corresponding CH-acids with 1.00-1.05 equiv
of KOtBu in DMSO solution or by isolating the potassium salts
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Nucleophilicity Parameters for Carbanions and Ylides
A R T I C L E S
Figure 2. Determination of the second-order rate constant k2 ) 1.38 ×
101 L mol-1 s-1 for the reaction of the phosphoryl-stabilized carbanion 1a
with the quinone methide 2l in DMSO at 20 °C.
Figure 1. UV-vis spectroscopic monitoring of the reaction of the
phosphoryl-stabilized carbanion 1a (7.57 × 10-4 mol L-1) with the quinone
methide 2l (3.52 × 10-5 mol L-1) at 486 nm in DMSO at 20 °C.
spectroscopy at or close to the absorption maxima of the
electrophiles. In all of the cases examined, complete consump-
tion of the electrophiles 2 was observed when their solutions
were combined with an excess of the carbanions 1a-d, as
shown in Figure 1.
Because the nucleophiles 1a-h were employed in large
excess over the electrophiles 2a-m, their concentrations can
be considered almost constant throughout the reactions, resulting
in first-order kinetics with an exponential decay of the concen-
trations of 2 (eq 2):
(1a-d)-K and then dissolving them in DMSO. The reactions
of the nucleophiles 1a-h with the reference electrophiles 2a-m
in DMSO or CH2Cl2 at 20 °C were monitored by UV-vis
Table 2. Second-Order Rate Constants for the Reactions of the
Phosphoryl-Stabilized Carbanions 1a-d and 0-1.3 equiv of
18-Crown-6 with the Reference Electrophiles 2h-m in DMSO at
20 °C
d[2]
dt
-
) kobs[2]
(2)
The first-order rate constants kobs were obtained by least-squares
fitting of the single-exponential At ) A0 exp(-kobst) + C to the
time-dependent absorbances A of the electrophiles. Second-order
rate constants then were obtained as the slopes of plots of kobs
versus the concentration of the nucleophile (Figure 2).
The rate constants listed in Table 2 refer to the reactivities
of the free carbanions 1a-d. Though most of the reactions of
(1a-d)-K were performed in the presence of 18-crown-6, this
additive was not really necessary. In a control experiment, it
was found that the rate of the reaction of 1b-K with 2k
remained constant in the absence of crown ether even when
large amounts of KBF4 (up to 1.6 × 10-2 mol L-1) were added
(see Table S88 in the Supporting Information). However, as
discussed below, counterion effects were observed when sodium
or lithium salts were employed.
Analogously, the reactions of the phosphorus ylides 1e-h
with the electrophiles 2 generally proceeded with full conversion
of the electrophile. In only a few cases, which are marked in
Table 3, was the consumption of the electrophiles 2 not
complete, indicating equilibrium situations.
The kinetics of the reactions of the nucleophiles 1a-e with
the substituted benzaldehydes 4a-g were investigated in DMSO
at 20 °C using large excesses of the nucleophiles. The first-
order rate constants kobs were usually derived from the single-
exponential increase of the absorbances of the resulting styrenes
5. As shown in Figure 3 for the reaction of p-methoxybenzal-
dehyde 4g with the phosphoryl-stabilized carbanion 1b, the rate
of consumption of p-methoxybenzaldehyde (monitored at 270
nm) was equal to the rate of formation of p-methoxycinna-
monitrile (monitored at 310 nm), excluding the formation of a
long-lived intermediate during the reaction.
Second-order rate constants (Table 4) were again obtained
as the slopes of plots of kobs versus the concentration of the
nucleophile (Figure 4).
a Values of the nucleophilicity parameters N and s were derived using
eq 1, as described in the Discussion. b Reaction occurred in the presence
of the corresponding conjugate CH-acid (1b-d)-H.
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A R T I C L E S
Appel et al.
Table 3. Second-Order Rate Constants for the Reactions of the
Phosphorus Ylides 1e-h with the Reference Electrophiles 2a-i in
CH2Cl2 at 20 °C
Table 4. Second-Order Rate Constants for the Reactions of the
Phosphoryl-Stabilized Carbanions 1a-d (with K+/18-Crown-6 as
the Counterion) and the Phosphorus Ylide 1e with the Aldehydes
4a-g in DMSO at 20 °C
a Values of the nucleophilicity parameters N and s were derived using
eq 1, as described in the Discussion. b Incomplete consumption of the
electrophile was observed, indicating an equilibrium situation.
Counterion Effects. In order to gain more insight into the
role of the counterions in the reactions of the carbanions 1 with
the reference electrophiles 2 as well as with the aldehydes 4,
additional studies in the presence of different alkali cations were
performed. For this purpose, the CH-acids 1a-H and 1b-H
were deprotonated with 1.00-1.05 equiv of NaOtBu or LiOtBu
in DMSO solution to generate the corresponding sodium or
lithium salts 1a-Na and 1b-Na or 1a-Li and 1b-Li,
respectively. Their reactions with the reference electrophiles
2j-m and the aldehydes 4a, 4e, and 4g were then investigated
kinetically using the same method as described above.
All of the reactions, which are listed in Table 5, followed
first-order kinetics regardless of the counterion (K+, Na+, or
Li+) when the carbanions 1a and 1b were used in large excess
over the electrophiles 2 or 4. Except for the reactions of 1a-Li,
second-order rate laws were followed, as derived from the linear
increase of kobs with the concentrations of 1a and 1b (Figures
2 and 4; for details, see Tables S70-S76, S89-S97, and
S99-S103 in the Supporting Information). In contrast, the plots
of kobs versus [1a-Li] were curved (Figure 5 and Tables S78
a From ref 23d.
and S85 in the Supporting Information), and it was not possible
to determine second-order rate constants for the reactions of
1a-Li with the electrophiles.
In order to obtain more information about the effect of Li+
on the reactivity of 1a, further kinetic studies of the reactions
of 1a with different electrophiles were performed at various
concentrations of Li+. For that purpose, the carbanion concen-
tration [1a] (obtained by deprotonation of the corresponding
CH-acid 1a-H with 1.00-1.05 equiv of LiOtBu) was kept
constant while the Li+ concentration was modulated by adding
various amounts of LiBF4. As depicted in Figure 6, the first-
order rate constants kobs for the reactions of the quinone methide
2k with 1a decreased dramatically as the Li+ concentration was
increased.
Li+ effects on kobs, as depicted in Figure 6, were also observed
for the reactions of 1a with the benzhydrylium ion 2h (see
Tables S83 and S84 in the Supporting Information) and the
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Nucleophilicity Parameters for Carbanions and Ylides
A R T I C L E S
Figure 3. Reaction of p-methoxybenzaldehyde 4g (5.58 × 10-5 mol L-1) with the phosphoryl-stabilized carbanion 1b (7.99 × 10-4 mol L-1) in DMSO at
20 °C (the UV absorption of 1b at λmax ) 257 nm is partially superimposed by the aldehyde). The inset shows the time traces along with the corresponding
kobs values for the single-exponential increase of the reaction product p-methoxycinnamonitrile and the single-exponential decrease of the aldehyde 4g.
Figure 4. Determination of the second-order rate constant k2 ) 1.48 ×
102 L mol-1 s-1 for the reaction of the phosphoryl-stabilized carbanion 1b
Figure 5. Nonlinear dependence of kobs on the concentration of the
with m-chlorobenzaldehyde 4c in DMSO at 20 °C.
nucleophile for the reaction of 1a with the reference electrophile 2j in the
presence of Li+ in DMSO at 20 °C.
aldehyde 4a (see Tables S86 and S87 in the Supporting
Information). In contrast, the addition of LiBF4 had only small
effects on the rates of the reactions of the carbanion 1b with
electrophiles. Thus, the reaction of 1b with the quinone methide
2k was only 2.3 times slower than the corresponding reaction
of the free carbanion 1b at a high concentration of Li+ ([Li+]
) 1.19 × 10-2 mol L-1 and [1b] ) 8.02 × 10-4 mol L-1; see
Table S98 in the Supporting Information). The rates of the
reactions of the phosphorus ylide 1e with the benzhydrylium
ion 2h as well as with the aldehyde 4a were not at all affected
by the addition of variable amounts of LiBF4 (see Tables
S104-S106 in the Supporting Information).
carbanion, in which the negative charge is mainly localized on
the nucleophilic carbon center,18 is not affected by the positively
charged alkali ions. Even when a 15-fold excess of Li+ ([Li+]
) 1.19 × 10-2 mol L-1) over the carbanion 1b was employed,
the reactivity of 1b toward 2k decreased by a factor of only
2.3 (see Table S98 in the Supporting Information). The reactions
of 1b with the aldehydes 4a, 4e, and 4g were even 9-34%
faster in the presence of Na+ and Li+ counterions (Table 5,
entries 16-18) than in the presence of K+/18-crown-6. A slight
stabilizing coordination of Na+ and Li+ with the partial negative
(17) (a) Lemek, T.; Mayr, H. J. Org. Chem. 2003, 68, 6880–6886. (b)
Berger, S. T. A.; Seeliger, F. H.; Hofbauer, F.; Mayr, H. Org. Biomol.
Chem. 2007, 5, 3020–3026. (c) Seeliger, F.; Berger, S. T. A.;
Remennikov, G. Y.; Polborn, K.; Mayr, H. J. Org. Chem. 2007, 72,
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2738–2745.
Discussion
Counterion Studies. Variation of the counterion of the cyano-
stabilized phosphonate 1b from K+ via Na+ to Li+ revealed
(within the error limits of our experiments) no change in the
reactivity toward the quinone methides 2j-m (Table 5, entries
12-15). Consequently, the nucleophilic reactivity of this
(18) (a) Fleming, F. F.; Shook, B. C. Tetrahedron 2002, 58, 1–23. (b)
Fleming, F. F.; Zhang, Z.; Wei, G.; Steward, O. W. J. Org. Chem.
2006, 71, 1430–1435.
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A R T I C L E S
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Table 5. Second-Order Rate Constants for the Reactions of the Phosphoryl-Stabilized Carbanions 1a and 1b with the Reference
Electrophiles 2h-m and the Aldehydes 4a, 4e, and 4g in the Presence of Different Counterions in DMSO at 20 °C
a Reactions used 0-1.3 equiv of 18-crown-6; data from Tables 2 and 4. b No second-order kinetics; k ) kobs/[1a] at [1a] ) [Li+] ) 1 × 10-3 mol
L-1 c No second-order kinetics; k ) kobs/[1a] at [1a] ) 1 × 10-3 mol L-1 and [Li+] ) 9 × 10-3 mol L-1
.
.
1.7 times faster with the aldehydes 4e and 4g than the free
carbanion (Table 5, entries 10 and 11). As shown in the
Supporting Information (e.g., Table S51), K+ also has a slight
activating effect (by a factor of 1.1-1.3) on the olefination
reactions of aldehydes when high concentrations of the potas-
sium salts ([(1a-d)-K] > 1.30 × 10-3 mol L-1) were
employed without crown ether. Below this concentration, the
addition of 18-crown-6 did not affect reactivity.
With Li+ as the counterion, the reactions of 1a become
considerably slower and do not follow simple second-order
kinetics (Table 5, entries 1-5, 8, and 9). These findings can be
explained by the high charge delocalization in this carbanion,
with most of the negative charge residing on the oxygen atom
of the carbonyl group (enolate structure). The higher affinity
of the (charged) oxygen for the lithium counterion results in
the formation of less reactive contact ion pairs even in DMSO
(dielectric constant εr ) 46.45). Because the degree of ion-
pairing increases with increasing concentration, the nonlinear
correlation in Figure 5 can be rationalized. The strong decrease
of kobs at constant [1a] with increasing [Li+] (Figure 6) can also
be explained by the increasing degree of ion-pairing.
Figure 6. Dependence of kobs on the absolute concentration of Li+ for the
reaction of 1a (1 × 10-3 mol L-1) with the quinone methide 2k (3 × 10-5
mol L-1) in DMSO at 20 °C. (The second-order rate constant k2 ) 128 L
mol-1 s-1 for the reaction of 1a-K/18-crown-6 with 2k in DMSO at 20
°C (see Table 2) was used to calculate the kobs value for [Li+] ) 0 mol
L-1).
According to Table 5, at [Li+] ) 1 × 10-3 mol L-1, 1a-Li
reacts 3.1-3.7 times more slowly than the free carbanion 1a
with 2h-k and 4a (Table 5, entries 1, 3, 4, and 8). At a higher
concentration of Li+ ([Li+] ) 9 × 10-3 mol L-1), 1a-Li reacts
25-51 times more slowly than the free carbanion with the
benzhydrylium ion 2h, the quinone methide 2k, and the aldehyde
4a (Table 5, entries 2, 5, and 9). Because the magnitude of the
Li+ effect depends only slightly on the nature of the electrophile,
we have to conclude that under these conditions, the activation
charge of the carbonyl oxygen of the aldehyde in the transition
state of the olefination reaction may account for this observation.
The situation is different for the ethoxycarbonyl-stabilized
carbanion 1a. In this case, even the Na+ counterion has a slight
decelerating effect (by a factor of 1.35) on the reactions of 1a
with the quinone methides 2j-m (Table 5, entries 3, 4, 6, and
7). In the olefination reactions, the slight reduction of the
nucleophilicity of 1a by Na+ is overcompensated by the
activation of the aldehydes by Na+, and 1a-Na reacts 1.3 and
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Nucleophilicity Parameters for Carbanions and Ylides
A R T I C L E S
Figure 7. Plots of log k2 for the reactions of the phosphoryl-stabilized carbanions 1a and 1b and the phosphorus ylides 1e-g with the reference electrophiles
2a-m at 20 °C (filled symbols denote reaction in DMSO, open symbols reaction in CH2Cl2) versus the electrophilicity parameters E of 2a-m.
of the electrophiles by Li+ is much less important than the
deactivation of the carbanion 1a by Li+ coordination.
The reactivity of phosphorus ylide 1e is not affected by Li+
ions at all in either the reaction with benzhydrylium ion 2h or
the olefination reaction with p-nitrobenzaldehyde 4a (see Tables
S104-S106 in the Supporting Information).
Nucleophilicity Parameters. As previously shown for many
nucleophile-electrophile combinations,16,17,19 the second-order
rate constants given in Tables 2 and 3 correlate well with the
electrophilicity parameters E of the benzhydrylium ions 2a-h
and quinone methides 2i-m. In Figure 7 these correlations are
shown exemplarily for the nucleophiles 1a, 1b, and 1e-g. The
correlations for the other nucleophiles used in this work (1c,
1d, and 1h) are of similar quality and allow the calculation of
the values of the nucleophile-specific parameters N and s, which
are listed in Tables 2 and 3.
The similarities of the slopes for the correlations of the
nucleophiles 1a-e in DMSO and for the nucleophiles 1e-g in
CH2Cl2 (Figure 7), which are numerically expressed by the s
parameters in Tables 2 and 3, imply that the relative nucleo-
Figure 8. Comparison of the nucleophilicity parameters N (in DMSO or
philicities of 1a-e in DMSO and 1e-g in CH2Cl2 depend only
CH2Cl2) of the phosphorus ylides 1e-h, the phosphonate-stabilized
carbanions 1a and 1b, and the phosphine oxide-stabilized carbanions 1c
and 1d.
slightly on the electrophilicity of the reaction partner. Conse-
quently, the N parameters can be used to compare the relative
reactivities of these compounds (Figure 8).
Figure 8 shows that phosphonate-stabilized (1a, 1b) and
phosphine oxide-stabilized carbanions (1c, 1d) do not differ
much in reactivity. This indicates that ethoxy substituents on
the phosphorus center have a similar effect on the nucleophilicity
of the carbanionic center as phenyl substituents. In analogy to
the behavior of other carbanions bearing CN and CO2R
groups,16c the ethoxycarbonyl-substituted carbanions 1a and 1c
show slightly higher reactivities than the cyano-stabilized
carbanions 1b and 1d.
stabilized ylide 1e is slightly more reactive than the cyano-
stabilized ylide 1g. Substitution of an R-H atom of 1e by a
methyl group has almost no effect on the nucleophilic reactivity
(cf. 1f vs 1e). The benzoyl-substituted ylide 1h is ∼102 times
less reactive than the structurally analogous phosphorus ylides
1e and 1f. Because 1h could only be investigated with two
different reference electrophiles, the atypically high s value of
0.96 is not reliable and shall not be discussed in detail.
It has long been known that the phosphoryl-stabilized
carbanions react faster with carbonyl compounds than the Wittig
ylides.3,20 The N (and s) values for the phosphoryl-stabilized
carbanions 1a-d and the ylides 1e-h in Figure 8 now provide
a quantitative comparison of the reactivities of phosphoryl-
stabilized carbanions and phosphorus ylides. A problem in this
A comparison of the substituent effects on the reactivity
(given by the N parameters for their reactivities in CH2Cl2) of
the phosphorus ylides 1e-h also shows that the ethoxycarbonyl-
(19) (a) Bug, T.; Lemek, T.; Mayr, H. J. Org. Chem. 2004, 69, 7565–
7576. (b) Mayr, H.; Ofial, A. R. In Carbocation Chemistry; Olah,
G. A., Prakash, G. K. S., Eds.; Wiley: Hoboken, NJ, 2004; pp 331-
358. (c) Berger, S. T. A.; Ofial, A. R.; Mayr, H. J. Am. Chem. Soc.
2007, 129, 9753–9761. (d) Brotzel, F.; Chu, Y. C.; Mayr, H. J. Org.
Chem. 2007, 72, 3679–3688. (e) Nigst, T. A.; Westermaier, M.; Ofial,
A. R.; Mayr, H. Eur. J. Org. Chem. 2008, 2369–2374.
(20) (a) Horner, L.; Hoffmann, H.; Klink, W.; Ertel, H.; Toscano, V. G.
Chem. Ber. 1962, 95, 581–601. (b) Boutagy, J.; Thomas, R. Chem.
ReV. 1974, 74, 87–99. (c) Schlosser, M.; Tuong, H. B. Chimia 1976,
30, 197–199.
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A R T I C L E S
Appel et al.
Figure 9. Plot of log k2 for the reactions of the phosphoryl-stabilized carbanions 1a, 1b, and 1d and other classes of carbanions with the benzhydrylium
ion 2h (DMSO, 20 °C) versus the corresponding pKaH values of the carbanions (DMSO, 25 °C). The second-order rate constants k2 (filled symbols) were
taken from refs 16c, 17a, 19a, and 19c. Second-order rate constants k2 for the alkyl nitronates (open symbols) were calculated using eq 1. The pKaH values
were taken from ref 21.
Figure 10. Correlation of the second-order rate constants k2 for the reactions of the phosphoryl-stabilized carbanions 1a-d and the phosphorus ylide 1e
with the benzaldehydes 4 in DMSO at 20 °C versus Hammett’s σp or σm values for the substituents of the benzaldehydes: (b) log k2 ) 3.38σ + 0.734, R2
) 0.9887, n ) 7; (O) log k2 ) 3.64σ + 0.214, R2 ) 0.9894, n ) 7; (9) log k2 ) 2.76σ - 0.268, R2 ) 0.9978, n ) 5; (0) log k2 ) 2.67σ - 0.800, R2 )
0.9953, n ) 3; ([) log k2 ) 2.87σ - 2.84, R2 ) 1, n ) 2. The data point for the reaction of 1e with benzaldehyde (4e) was taken from ref 23d.
comparison is the different solvents used for the two classes of
compounds. While the carbanions 1a-d were investigated in
DMSO solution, the kinetic investigations of the phosphorus
ylides 1e-h were performed in CH2Cl2. However, the ylide 1e
was investigated in both solvents, showing that the reactivity
is less than 1 order of magnitude higher in CH2Cl2 than in
DMSO. Comparison of the nucleophilicities of the Wittig ylide
1e and the two structurally analogous phosphoryl-stabilized
carbanions 1a and 1c reveals a difference of nucleophilic
reactivity of ∆N ≈ 7 (for N in DMSO). For an averaged s value
of 0.65, this difference implies that the ylide 1e is 104-105 times
less reactive than the carbanions 1a and 1c. A similar reactivity
ratio can be derived for the comparison of the cyano-substituted
carbanions 1b and 1d with the cyano-substituted phosphorus
ylide 1g, if one assumes that the change from CH2Cl2 to DMSO
solution has an effect on the reactivity of 1g similar to that on
1e.
Figure 9 shows a rather poor relationship between the rates
ofthereactionsofthebenzhydryliumion2hwithcarbanions16c,17a,19a,c
and the carbanion pKaH values in DMSO.21 One can see that
the phosphoryl-stabilized carbanions 1a, 1b, and 1d are located
in the lower part of this “correlation corridor”. The phosphonate-
substituted carbanions 1a and 1b are even less reactive than
several of the phenyl-substituted nitronates 7-(X) and the
malononitrile anion (NC)2CH-, even though the basicities of
1a and 1b are 4-8 units higher. It is probably the stabilization
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712 J. AM. CHEM. SOC. VOL. 131, NO. 2, 2009

Nucleophilicity Parameters for Carbanions and Ylides
A R T I C L E S
Figure 12. Comparison of the nucleophilicities of different ethoxycarbonyl-
stabilized carbanions in DMSO.
(Table 4) showed that in all cases, electron-withdrawing groups
at the 3- or 4-position of the benzaldehydes 4 increase the
reaction rate whereas electron-donating substituents decelerate
the reaction (Figure 10).
Plots of log k2 versus the Hammett substituent constants σ
are linear (Figure 10) and yield F ) 3.4-3.6 for the olefination
reactions of the phosphonate-stabilized carbanions 1a and 1b,
F ) 2.7-2.8 for the reactions of the phosphine-oxide stabilized
carbanions 1c and 1d, and F ) 2.9 for the reactions of the ylide
1e. Because the correlations with 1c and 1e are based on only
3 and 2 data points, respectively, the resulting F values for these
compounds should be treated with caution. Similar reaction
constants F have been reported for the Wittig reactions of ester-
stabilized triphenylphosphonium ylides with substituted ben-
zaldehydes in benzene at 25 °C (F ) 2.7)23c and in acetonitrile
at 20 °C (F ) 2.9)23d as well as for the Wittig reaction of
benzylidenetriphenylphosphorane with substituted benzalde-
hydes in THF at 0 °C (F ) 2.77).23g The substituent effects are
in line with a concerted [2 + 2] cycloaddition in which the
formation of the C-C bond is more advanced in the transition
state than the formation of the P-O bond.23 In the calculations
by Aggarwal, Harvey, and co-workers,7c,d the bond lengths in
the transition state for the reaction of benzaldehyde with
Ph3PCHCO2Me are reported to be 1.86 Å for the C-C bond
and 2.76 Å for the P-O bond.
Figure 11. Comparison of the second-order rate constants k2 for the
reactions of the nucleophiles 1a-e with the quinone methide 2i (on the
left) and p-nitrobenzaldehyde 4a (on the right) in DMSO at 20 °C.
Scheme 8. Schematic Transition States for the Reactions of
Phosphorus Ylides and Phosphoryl-Substituted Carbanions with
Carbonyl Groups
Whereas the change from ethoxy to phenyl substituents on
the phosphorus center of phosphoryl-stabilized carbanions
revealed no significant change in reactivity toward the reference
electrophiles 2 (Table 2 and Figure 8), the phosphine oxide-
stabilized carbanions 1c and 1d react considerably more slowly
with aldehydes than the corresponding phosphonates 1a and 1b
(Table 4 and Figure 10).
of the phosphoryl-stabilized carbanions 1 through dipole-dipole
interactions in DMSO that is responsible for the unusually high
intrinsic barriers22 of their reactions with electrophiles. Because
of the low quality of this correlation, we refrain from interpreting
the slope.
Olefination Reactions. The kinetic studies on the reactions
of the nucleophiles 1a-e with the benzaldehydes 4 in DMSO
Figure 11 illustrates significant differences in the relative
reactivities toward the Michael acceptor 2i and the benzaldehyde
4a. Whereas the phosphine oxide-substituted carbanions 1c and
1d react with 2i slightly faster (by factors of 1.5 and 1.8,
respectively) than the analogous phosphonate-substituted car-
banions 1a and 1b, 1a and 1b are more reactive toward 4a (by
factors of 47 and 26, respectively) than the corresponding
phosphine oxide-substituted carbanions 1c and 1d. Steric effects
may account for this inversion of reactivity. Because in the
Horner-Wadsworth-Emmons (HWE) reaction, C-C bond
formation is accompanied by the formation of the P-O bond
to yield the oxaphosphetane, the more bulky phenyl groups of
the phosphine oxides 1c and 1d in comparison with the smaller
ethoxy groups of the phosphonates 1a and 1b may explain the
lower reactivities of 1c and 1d in the [2 + 2] cycloaddition
(21) (a) Data taken from http://www.chem.wisc.edu/areas/reich/pkatable/.
(b) Matthews, W. S.; Bares, J. E.; Bartmess, J. E.; Bordwell, F. G.;
Cornforth, F. J.; Drucker, G. E.; Margolin, Z.; McCallum, R. J.;
McCollum, G. J.; Vanier, N. R. J. Am. Chem. Soc. 1975, 97, 7006–
7014. (c) Keeffe, J. R.; Morey, J.; Palmer, C. A.; Lee, J. C. J. Am.
Chem. Soc. 1979, 101, 1295–1297. (d) Olmstead, W. N.; Bordwell,
F. G. J. Org. Chem. 1980, 45, 3299–3305. (e) Arnett, E. M.; Harrelson,
J. A. J. Am. Chem. Soc. 1987, 109, 809–812. (f) Bordwell, F. G. Acc.
Chem. Res. 1988, 21, 456–463. (g) Bordwell, F. G.; Bausch, M. J.;
Branca, J. C.; Harrelson, J. A. J. Phys. Org. Chem. 1988, 1, 225–239.
(h) Bordwell, F. G.; Branca, J. C.; Bares, J. E.; Filler, R. J. Org. Chem.
1988, 53, 780–782. (i) Bordwell, F. G.; Harrelson, J. A.; Satish, A. V.
J. Org. Chem. 1989, 54, 3101–3105. (j) Bordwell, F. G.; Satish, A. V.
J. Am. Chem. Soc. 1994, 116, 8885–8889. (k) Goumont, R.; Kizilian,
E.; Buncel, E.; Terrier, F. Org. Biomol. Chem. 2003, 1, 1741–1748.
(22) (a) Bernasconi, C. F. Acc. Chem. Res. 1987, 20, 301–308. (b)
Bernasconi, C. F. Acc. Chem. Res. 1992, 25, 9–16.
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A R T I C L E S
Appel et al.
tetrafluoroborates16b (2a-h)-BF4 and quinone methides26 2i-m
were prepared as described previously. All of the other chemicals
were purchased from commercial sources and (if necessary) purified
by recrystallization or distillation prior to use.
with 4a. Analogously, the smaller size of CN compared with
CO2Et may account for the finding that the cyano-stabilized
carbanions 1b and 1d are more reactive in the HWE reaction
than the corresponding ethoxycarbonyl-substituted systems 1a
and 1c, even though their relative reactivities toward the Michael
acceptor 2i are the other way around.
A major difference can be seen in the relative reactivities of
the ethoxycarbonyl-substituted carbanions 1a and 1c on one side
and the ethoxycarbonyl-substituted phosphorus ylide 1e on the
other side. Whereas the carbanions 1a and 1c are almost 105
times more reactive than 1e in the Michael additions (Figure
11, left), the reactivity ratio shrinks to a factor of 100-4000 in
the HWE reaction (Figure 11, right). Obviously, the cycload-
dition of the phosphorus ylide 1e profits more from concerted-
ness than the cycloadditions of the carbanions 1a and 1c,
because the energy gain by forming the P-O bond in the
transition state 6 is much higher than in transition state 7
(Scheme 8).
Kinetics. The rates of all of the investigated reactions were
determined photometrically. The temperature of the solutions during
all of the kinetic studies was kept constant (20.0 ( 0.1 °C) using
a circulating bath thermostat. The reactions with the carbanions in
DMSO were carried out either with stock solutions of the potassium
salts of the CH-acids or by deprotonation of the CH-acids with
1.00-1.05 eq of KOtBu, NaOtBu, or LiOtBu in DMSO. The
reactions with the ylides in DMSO or CH2Cl2 were carried out with
solutions of the ylides in the corresponding solvent. The electro-
philes were also prepared in stock solutions of the particular solvent
and were always employed as the minor component in the reactions
with the nucleophiles, resulting in first-order kinetics.
The rates of slow reactions (τ1/2 > 10 s) were determined using
a J&M TIDAS diode array spectrophotometer controlled by
Labcontrol Spectacle software and connected to a Hellma 661.502-
QX quartz Suprasil immersion probe (5 mm light path) via fiber-
optic cables and standard SMA connectors. For the evaluation of
fast kinetics (τ1/2 < 10 s), a Hi-Tech SF-61DX2 stopped-flow
spectrophotometer system or Applied Photophysics SX.18MV-R
stopped-flow reaction analyzer was used.
Conclusions
By using benzhydrylium ions and structurally related quinone
methides as reference electrophiles, we have been able to
directly compare the nucleophilic reactivities of phosphoryl-
stabilized carbanions and stabilized phosphorus ylides. Because
the same reference electrophiles have previously been employed
for quantifying the reactivities of a large variety of π, n, and σ
nucleophiles,16,19 we can now integrate the synthetically im-
portant phosphorus-substituted nucleophiles 1a-h into the
comprehensive nucleophilicity scale based on eq 1.
Figure 12 compares the effects of (EtO)2PO, Ph2PO, and
Ph3P+ groups on the nucleophilicities of ethoxycarbonyl-
substituted carbanions and illustrates that the effect of the
phosphoryl group is comparable to that of an acetyl or cyano
group.16c
Since the pKa values of the conjugate acids of 1a-d are much
higher than those of ethyl acetoacetate and ethyl cyanoacetate,21
we must conclude that the intrinsic barriers for the reactions of
the phosphoryl-substituted carbanions are considerably higher
than those for the reactions of carbanions stabilized by ester,
cyano, and carbonyl groups.
Rate constants kobs (s-1) were obtained by fitting the single-
exponential functions At ) A0 exp(-kobst) + C (exponential
decrease) or At ) A0[1 - exp(-kobst)] + C (exponential increase)
to the observed time-dependent absorbance (averaged from at least
four kinetic runs for each nucleophile concentration in the case of
applying the stopped-flow method).
Acknowledgment. We thank the Deutsche Forschungsgemein-
schaft (SFB 749) and the Fonds der Chemischen Industrie for
financial support. Valuable suggestions by Dr. Armin R. Ofial are
gratefully acknowledged.
Supporting Information Available: Details of syntheses,
product characterization, and kinetic experiments. This material
is available free of charge via the Internet at http://pubs.acs.org.
JA8056216
(23) (a) Goetz, H.; Nerdel, F.; Michaelis, H. Naturwissenschaften 1963,
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Z.-K.; He, C.; Yang, M.; Xia, C.-Q.; Yu, X.-Q. ARKIVOC 2005 (i),
98-104.
Significant differences between the relative reactivities of the
phosphoryl-substituted nucleophiles toward carbocations and
Michael acceptors on one side and benzaldehydes on the other
side are in line with concerted asynchronous oxaphosphetane
formation in the rate-determining step of the olefination
reactions.
Experimental Section
(24) (a) Quin, L. D.; Anderson, H. G. J. Org. Chem. 1964, 29, 1859–
1861. (b) Regitz, M.; Anschu¨tz, W. Chem. Ber. 1969, 102, 2216–
2229.
Materials. Dimethyl sulfoxide (DMSO) with a H2O content of
<50 ppm and dry CH2Cl2 (freshly distilled over CaH2) were used
for the kinetic experiments. The phosphine oxides 1c-H and 1d-H
were synthesized according to a literature procedure,24 as was the
phosphorus ylide 1g.25 The potassium salts of 1a-d were prepared
as described in the Supporting Information. Benzhydrylium
(25) Mauduit, M.; Kouklovsky, C.; Langlois, Y. Tetrahedron Lett. 1998,
39, 6857–6860.
(26) (a) Lucius, R.; Mayr, H. Angew. Chem., Int. Ed. 2000, 39, 1995–
1997. (b) Evans, S.; Nesvadba, P.; Allenbach, S. Ciba-Geigy AG, EP-B
744392, 1996; Chem. Abstr. 1997, 126, 46968v.
9
714 J. AM. CHEM. SOC. VOL. 131, NO. 2, 2009