Nucleophilic reactivities of sulfur ylides and related carbanions: Comparison with structurally related organophosphorus compounds

Article abstract of DOI:10.1002/chem.201001455

(Figure Presented) The nucleophilicity parameters of stabilized sulfur ylides, methylsulfonyl-, and methylsulfinyl stabilized carbanions have been determined from the rates of their reactions with benzhy-drylium ions and quinone methides. Direct compariso

Full text of DOI:10.1002/chem.201001455

DOI: 10.1002/chem.201001455
Nucleophilic Reactivities of Sulfur Ylides and Related Carbanions:
Comparison with Structurally Related Organophosphorus Compounds
Roland Appel and Herbert Mayr*[a]
Dedicated to Professor Helmut Vorbrꢀggen on the occasion of his 80th birthday
Phosphorus and sulfur ylides are two important classes of
reagents in organic chemistry. While phosphorus ylides and
related phosphoryl stabilized carbanions are used in the
most common olefination reactions, that is, Wittig, Wittig–
Horner, and Horner–Wadsworth–Emmons reactions,[1]
sulfur ylides have been introduced as versatile reagents for
the syntheses of three-membered carbo- and heterocyclic
rings (Corey–Chaykovsky reaction).[2]
By using this methodology, we have developed the most
comprehensive nucleophilicity scale presently available and,
therefore, were able to directly compare many different
classes of nucleophiles.[8,9] With the rule of thumb that elec-
trophile–nucleophile combinations at room temperature
only take place when (E + N> ꢀ5), we have been able to
establish a rough ordering principle of polar organic reacti-
vity.[9c]
In contrast to their phosphorus-stabilized analogues, sulfi-
nyl- and sulfonyl-stabilized carbanions react with aldehydes
to form b-hydroxysulfines and -sulfones,[3] respectively, or
undergo Knoevenagel condensation reactions.[4] Acylation
and subsequent reductive elimination transfers b-hydroxy-
sulfones into olefins (Julia and related olefinations).[5]
Previous investigations on structure–reactivity relation-
ships of sulfur and phosphorus ylides were focused on their
basicities[6] and the different leaving group abilities of R2S
and R3P. [7] Owing to the poor correlation between basicities
and reactivities of carbon-centered nucleophiles,[8] a quanti-
tative comparison of the reactivities of sulfur and phospho-
rus ylides as well as their related carbanions has so far not
been possible.
After determining the nucleophilicities of phosphorus
ylides and phosphoryl-stabilized carbanions,[8c] we have now
studied the kinetics of the reactions of the sulfur ylides 1a
and 1b, the sulfonyl-stabilized carbanion 1c, and the sulfi-
nyl-stabilized carbanion 1d with the benzhydrylium ions 2a–
e and the structurally related quinone methides 2 f–k
(Table 1) in DMSO, to derive the nucleophilicity parameters
N and s for the nucleophiles 1 and to compare them with
those of analogous phosphorus compounds.
In recent years, we have shown that the rates of the reac-
tions of carbocations and Michael acceptors with n-, p-, and
s-nucleophiles can be described by Equation (1), where
k208C is the second-order rate constant in mꢀ1 sꢀ1, s is a nucle-
ophile-specific slope parameter, N is a nucleophilicity pa-
rameter, and E is an electrophilicity parameter.
As shown in Scheme 1, the reference electrophiles 2a and
2h were employed to elucidate the course of these reactions.
Because of the low stability of the addition products 3a,b
obtained from 2a and the sulfur ylides 1a,b, the adducts
3a,b were not isolated but immediately treated with thio-
phenolate to afford the non-charged products 4a,b, which
were fully characterized. For identifying the products
formed from the nucleophiles 1c,d and the quinone methide
2h, solutions of the carbanions 1c,d were generated by de-
protonation of the corresponding CH acids (1c,d)-H with
KOtBu in DMSO, subsequent addition of 2h, and aqueous
acidic workup. The addition products 5a and 5b were ob-
tained as mixtures of two and four diastereomers, respec-
tively (1H and 13C NMR spectroscopy).
log k20 ꢁ ¼ sðN þ EÞ
ð1Þ
C
[a] R. Appel, Prof. Dr. H. Mayr
Department Chemie, Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstrasse 5-13 (Haus F), 81377 Mꢁnchen (Germany)
Fax : (+49)89-2180-77717
E-mail: herbert.mayr@cup.uni-muenchen.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001455.
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Chem. Eur. J. 2010, 16, 8610 – 8614

COMMUNICATION
Table 1. Benzhydrylium ions 2a–e and quinone methides 2 f–k employed
as reference electrophiles in this work.
ments; the carbanions 1c,d were generated by deprotona-
tion of the corresponding CH acids (1c,d)-H with 1.00–
1.05 equivalents of KOtBu in DMSO solution. To prove that
(1c,d)-H were quantitatively deprotonated under these con-
ditions, several kinetic experiments have been repeated by
using only 0.5–0.6 equivalents of KOtBu for the deprotona-
tion of (1c,d)-H. In these experiments, where the concentra-
tions of the carbanions 1c,d correspond to the amount of
KOtBu used, second-order rate constants were obtained,
which agreed within 1–2% with those obtained with a slight
excess of KOtBu (see Table 2). As the presence of
[18]crown-6 did not affect the reactivities of (1c,d)-K, one
can conclude that the reactivities of the free carbanions 1c,d
were observed.
Electrophile
E[a]
2a
2b
X=NMe2
X=N(CH2)4
ꢀ7.02
ꢀ7.69
AHCTUNGTRENNUNG
2c
ꢀ8.76
2d (n=2)
2e (n=1)
ꢀ9.45
ꢀ10.04
From the exponential decays of the UV/Vis absorbances
of the electrophiles, the first-order rate constants kobs were
obtained. Plots of kobs (sꢀ1) against the concentrations of the
nucleophiles 1 were linear with negligible intercepts as re-
quired by Equation (2) (Figure 1).
Electrophile
E[a]
2 f
2g
2h
2i
Y=Ph
Y=Ph
Y=tBu
Y=tBu
Y=tBu
Z=OMe
Z=NMe2
Z=Me
Z=OMe
Z=NMe2
ꢀ12.18
ꢀ13.39
ꢀ15.83
ꢀ16.11
ꢀ17.29
ꢀd½2ꢂ=dt ¼ k2½1ꢂ ½2ꢂ for½1ꢂ ꢃ ½2ꢂ ) kobs ¼ k2 ½1ꢂ
ð2Þ
2j
2k
ꢀ17.90
[a] Electrophilicity parameters E for 2a–e from reference [9b], for 2 f–k
from reference [9c].
Figure 1. Exponential decay of the absorbance at 624 nm during the reac-
tion of 1a (3.14ꢃ10ꢀ4 m) with 2b (2.23ꢃ10ꢀ5 m) at 208C in DMSO. Insert:
Determination of the second-order rate constant k2 =1.33ꢃ105 mꢀ1 sꢀ1
from the dependence of the first-order rate constant kobs on the concen-
tration of 1a.
According to Table 2, the quinone methide 2 f is the only
electrophile for which rate constants with all four nucleo-
philes 1a–d have been determined. The corresponding rate
constants can, therefore, be employed for a direct structure–
reactivity analysis. As shown in Scheme 2, the cyano-substi-
tuted sulfur ylide 1b is marginally more reactive than the
ethoxycarbonyl-substituted analogue 1a. However, the
methylsulfonyl-stabilized carbanion 1c is 45 times and the
methylsulfinyl-stabilized carbanion 1d 990 times more reac-
tive than the ylide 1a. Comparison of the two carbanions
1c,d moreover shows that the methylsulfinyl-stabilized spe-
Scheme 1. Characterization of the reaction products.
All kinetic investigations were monitored photometrically
by following the disappearance of the colored electrophiles
2 in the presence of more than 10 equivalents of the nucleo-
philes 1 (first-order conditions). Solutions of the ylides 1a,b
in DMSO were freshly prepared before the kinetic experi-
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H. Mayr and R. Appel
Table 2. Second-order rate constants for the reactions of the sulfur-stabi-
lized nucleophiles 1 with the reference electrophiles 2 in DMSO at 208C.
Nucleophile
N/s[a]
Electrophile
k2 [mꢀ1 sꢀ1
]
15.85/0.61
2a
2b
2c
2d
2e
2 f
2.70ꢃ105
1.33ꢃ105
1.34ꢃ104
7.30ꢃ103
2.56ꢃ103
2.32ꢃ102
16.23/0.60
18.00/0.66
2a
2b
2c
2d
2e
2 f
3.47ꢃ105
2.08ꢃ105
1.95ꢃ104
9.06ꢃ103
3.07ꢃ103
4.00ꢃ102
2d
2e
2 f
2 f
2g
2h
2i
3.38ꢃ105
1.61ꢃ105
1.04ꢃ104
Figure 2. Plots of log k2 for the reactions of the sulfur ylide 1a and the
sulfur-stabilized carbanions 1c,d with the reference electrophiles 2a–k at
208C in DMSO versus their electrophilicity parameters E. For the sake
of clarity, the correlation line for 1b is not shown (see the Supporting In-
formation).
1.02ꢃ104[b]
1.17ꢃ103
2.72ꢃ101
1.65ꢃ101
2.54
2j
the comparison with the recently investigated phosphoryl-
stabilized carbanions and phosphorus ylides (Figure 3).[8c]
20.61/0.64
2 f
2g
2g
2h
2i
2.29ꢃ105
3.42ꢃ104
3.44ꢃ104[b]
1.34ꢃ103
8.12ꢃ102
1.30ꢃ102[b]
4.43ꢃ101
2j
2k
[a] Nucleophilicity parameters N and s derived by using Equation (1); de-
termination see below. [b] Deprotonation of the conjugate CH acids
(1c,d)-H with 0.5–0.6 equivalents of KOtBu.
Scheme 2. Relative reactivities of the nucleophiles 1a–d toward the qui-
none methide 2 f (DMSO, 208C).
Figure 3. Comparison of the nucleophilicity parameters (N, s) in DMSO
of the sulfur-stabilized nucleophiles 1a,c,d with those of phosphorus ylide
6a and phosphoryl-stabilized carbanions 6b,c. [a] Values (N, s) taken
from reference [8c]. [b] Values (N, s) taken from Table 2.
cies 1d is 22 times more reactive than the analogously sub-
stituted methylsulfonyl compound 1c.
To include compounds 1a–d in our comprehensive nucle-
ophilicity scale, we determined their nucleophilicity parame-
ters N and s. For that purpose, log k2 for the reactions of the
nucleophiles 1 with the electrophiles 2 (Table 2) were plot-
ted against their electrophilicity parameters E as shown in
Figure 2. The linearity of the correlations shows the applica-
bility of Equation (1), which allows one to derive the nucle-
ophile-specific parameters N and s for the nucleophiles 1a–
d, which are listed in Table 2 and Figure 3.
Figure 3 reveals a difference of nucleophilic reactivity of
DN ꢄ 3.6 between the triphenylphosphonium ylide 6a and
the structurally analogous dimethylsulfonium ylide 1a. For
an s value of 0.62, this difference implies that the phospho-
rus ylide 6a is 170 times less reactive than the sulfur ylide
1a. On the other hand, the phosphoryl-stabilized carbanions
6b,c show nucleophilic reactivities, which lie in between
those of the sulfinyl- and sulfonyl-stabilized carbanions 1c,d.
From the nucleophilicities of diethyl malonate anions (N=
20.22), ethyl cyanoacetate anions (N=19.62), and ethyl ace-
toacetate anions (N=18.82),[9c] one can derive that the
Among the many comparisons, which are now possible on
the basis of N, we will restrict the following discussion on
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Nucleophilic Reactivities of Sulfur Ylides and Related Carbanions
COMMUNICATION
ethoxycarbonyl-, cyano-, and acetyl groups have stabilizing
abilities, which are also in between those of a methylsulfinyl
and a methylsulfonyl group.
trophilicity E can be efficiently predicted by Equation (1)
using the N/s parameters reported in Table 2.
As the formation of oxaphosphetanes from phosphorus
ylides and carbonyl compounds generally proceeds via con-
certed [2+2] cycloaddition reactions,[1a–d,12] the N and s pa-
rameters of phosphorus ylides cannot be employed to deter-
mine the E parameters of aldehydes.[8c] On the other hand,
sulfur ylides have been demonstrated to react with alde-
hydes by a stepwise mechanism.[13] It should, therefore, be
possible to use the kinetics of the formation of epoxides via
the Corey–Chaykovsky reaction to derive electrophilicity
parameters of carbonyl compounds.
To examine the applicability of the N and s parameters of
the sulfur-stabilized nucleophiles 1 for reactions with other
electrophiles, we have investigated their reactions with
trans-b-nitrostyrene (7a) and trans-4-methoxy-b-nitrostyrene
(7b), whose electrophilicity parameters E have recently
been determined.[10] Whereas the reactions of the carbanions
1c,d with nitrostyrene 7b yield the Michael addition prod-
ucts 8a and 8b, respectively, the zwitterion 9 initially gener-
ated from the sulfur ylide 1a and 7b, underwent a subse-
quent intramolecular nucleophilic displacement of dimethyl
sulfide to yield the dihydroisoxazole N-oxide 10 (Scheme 3).
The latter compound was not isolated but intercepted by a
1,3-dipolar cycloaddition with dimethyl maleate according
to previous reports[11] and as specified in the Supporting In-
formation.
Acknowledgements
We gratefully acknowledge financial support by the Deutsche For-
schungsgemeinschaft (SFB 749) and the Fonds der Chemischen Industrie
(scholarship to R.A.). We thank Nicolai Hartmann for performing some
of the kinetic experiments and Dr. Sami Lakhdar for helpful discussions.
Keywords: carbanions
· kinetics · linear free energy
relationships · nucleophilicity · ylides
[1] For selected reviews, see: a) B. E. Maryanoff, A. B. Reitz, Phospho-
rus Sulfur Silicon Relat. Elem. 1986, 27, 167–189; b) B. E. Maryan-
off, A. B. Reitz, Chem. Rev. 1989, 89, 863–927; c) E. Vedejs, M. J.
Peterson, Top. Stereochem. 1994, 21, 1–157; d) E. Vedejs, M. J. Pe-
terson in Advances in Carbanion Chemistry, Vol. 2 (Ed.: V.
Snieckus), JAI Press, London, 1996, pp. 1–85; e) K. C. Nicolaou,
M. W. Hꢀrter, J. L. Gunzner, A. Nadin, Liebigs Ann. Chem. 1997,
1283–1301; f) O. I. Kolodiazhnyi, Phosphorus Ylides, 1st ed., Wiley-
VCH, Weinheim, 1999, pp. 258–358.
[2] a) A. W. Johnson, R. B. LaCount, Chem. Ind. (London, U.K.) 1958,
1440–1441; b) A. W. Johnson, R. B. LaCount, J. Am. Chem. Soc.
1961, 83, 417–423; c) E. J. Corey, M. Chaykovsky, J. Am. Chem.
Soc. 1962, 84, 867–868; d) E. J. Corey, M. Chaykovsky, J. Am.
Chem. Soc. 1962, 84, 3782–3783; e) V. Franzen, H.-E. Driessen, Tet-
rahedron Lett. 1962, 3, 661–662; for selected reviews, see: f) B. M.
Trost, L. S. Melvin, Sulfur Ylides. Emerging Synthetic Intermediates,
Academic Press, New York, 1975; g) A.-H. Li, L.-X. Dai, V. K. Ag-
garwal, Chem. Rev. 1997, 97, 2341–2372; h) J. S. Clark in Nitrogen,
Oxygen and Sulfur Ylide Chemistry (Ed.: J. S. Clark), Oxford Uni-
versity Press, New York, 2002, pp. 1–114; i) V. K. Aggarwal, J. Ri-
chardson in Science of Synthesis, Vol. 27, Thieme, Stuttgart, 2004,
pp. 21–104; j) V. K. Aggarwal, C. L. Winn, Acc. Chem. Res. 2004,
37, 611–620; k) V. K. Aggarwal, J. Richardson, C. L. Winn in Sci-
ence of Synthesis, Vol. 22, Thieme, Stuttgart, 2005, pp. 11–73;
l) E. M. McGarrigle, V. K. Aggarwal in Enantioselective Organoca-
talysis (Ed.: P. I. Dalko), Wiley-VCH, Weinheim, 2007, pp. 357–390;
m) E. M. McGarrigle, E. L. Myers, O. Illa, M. A. Shaw, S. L. Riches,
V. K. Aggarwal, Chem. Rev. 2007, 107, 5841–5883; n) V. K. Aggar-
wal, M. Crimmin, S. Riches in Science of Synthesis, Vol. 37, Thieme,
Stuttgart, 2008, pp. 321–406; o) J.-F. Briꢄre, P. Metzner in Organo-
sulfur Chemistry in Asymmetric Synthesis (Eds.: T. Toru, C. Bolm),
Wiley-VCH, Weinheim, 2008, pp. 179–208.
Scheme 3. Reactions of the nucleophiles 1a,c,d with nitroolefin 7b.
In line with these mechanisms, the experimental second-
order rate constants for the reactions of 1a,c,d with the
nitrostyrenes 7a,b agree within a factor of 1.1 to 4.3 with
those calculated by using Equation (1) (Table 3). This re-
markable agreement demonstrates that rates of the reac-
tions of the nucleophiles 1 with electrophiles of known elec-
Table 3. Experimental and calculated second-order rate constants
(mꢀ1 sꢀ1) for the reactions of the nucleophiles 1a,c,d with the nitrostyr-
enes 7 in DMSO at 208C.
exp
calcd[a]
calcd
Nucleophile
Electrophile
k2
k2
k2exp/k2
1a
1c
7b
7a
7b
7a
7b
5.46
5.03
1.1
1.25ꢃ102
3.98ꢃ101
1.21ꢃ104
3.48ꢃ103
5.48ꢃ102
1.51ꢃ102
2.12ꢃ104
6.06ꢃ103
0.23
0.26
0.57
0.57
[3] a) J. C. Stowell, Carbanions in Organic Synthesis, Wiley, New York,
1979; b) H. J. Gais, G. Hellmann, J. Am. Chem. Soc. 1992, 114,
4439–4440; c) A. Solladiꢅ-Cavallo, D. Roche, J. Fischer, A.
De Cian, J. Org. Chem. 1996, 61, 2690–2694; d) H.-J. Gais, M. v.
Gumpel, G. Raabe, J. Mꢁller, S. Braun, H. J. Lindner, S. Rohs, J.
Runsink, Eur. J. Org. Chem. 1999, 1627–1651; e) A. Volonterio, M.
Zanda in Organosulfur Chemistry in Asymmetric Synthesis (Eds.: T.
1d
[a] Calculated by Equation (1) using the electrophilicity parameters
E
N
U
N and s values for 1a,c,d (from Table 2).
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H. Mayr and R. Appel
Toru, C. Bolm), Wiley-VCH, Weinheim, 2008, pp. 351–374; f) H.-J.
Gais in Organosulfur Chemistry in Asymmetric Synthesis (Eds.: T.
Toru, C. Bolm), Wiley-VCH, Weinheim, 2008, pp. 375–398.
[9] a) H. Mayr, M. Patz, Angew. Chem. 1994, 106, 990–1010; Angew.
Chem. Int. Ed. Engl. 1994, 33, 938–957; b) H. Mayr, T. Bug, M. F.
Gotta, N. Hering, B. Irrgang, B. Janker, B. Kempf, R. Loos, A. R.
Ofial, G. Remennikov, H. Schimmel, J. Am. Chem. Soc. 2001, 123,
9500–9512; c) R. Lucius, R. Loos, H. Mayr, Angew. Chem. 2002,
114, 97–102; Angew. Chem. Int. Ed. 2002, 41, 91–95; d) H. Mayr, B.
Kempf, A. R. Ofial, Acc. Chem. Res. 2003, 36, 66–77; e) H. Mayr,
A. R. Ofial, Pure Appl. Chem. 2005, 77, 1807–1821; f) H. Mayr,
A. R. Ofial, J. Phys. Org. Chem. 2008, 21, 584–595.
[4] a) D. A. R. Happer, B. E. Steenson, Synthesis 1980, 806–807; b) R.
Tanikaga, T. Tamura, Y. Nozaki, A. Kaji, J. Chem. Soc. Chem.
Commun. 1984, 87–88; c) R. Tanikaga, N. Konya, T. Tamura, A.
Kaji, J. Chem. Soc. Perkin Trans. 1 1987, 825–830.
[5] a) M. Julia, J.-M. Paris, Tetrahedron Lett. 1973, 14, 4833–4836;
b) P. J. Kocienski, B. Lythgoe, S. Ruston, J. Chem. Soc. Perkin Trans.
1 1978, 829–834; c) M. Julia, Pure Appl. Chem. 1985, 57, 763–768;
d) P. R. Blakemore, J. Chem. Soc. Perkin Trans. 1 2002, 2563–2585.
[6] a) K. W. Ratts, J. Org. Chem. 1972, 37, 848–851; b) X.-M. Zhang,
F. G. Bordwell, J. Am. Chem. Soc. 1994, 116, 968–972; c) J.-P.
Cheng, B. Liu, X.-M. Zhang, J. Org. Chem. 1998, 63, 7574–7575;
d) J.-P. Cheng, B. Liu, Y. Zhao, Y. Sun, X.-M. Zhang, Y. Lu, J. Org.
Chem. 1999, 64, 604–610; e) Y. Fu, H.-J. Wang, S.-S. Chong, Q.-X.
Guo, L. Liu, J. Org. Chem. 2009, 74, 810–819.
[7] a) F. Volatron, O. Eisenstein, J. Am. Chem. Soc. 1987, 109, 1–14;
b) V. K. Aggarwal, J. N. Harvey, R. Robiette, Angew. Chem. 2005,
117, 5604–5607; Angew. Chem. Int. Ed. 2005, 44, 5468–5471.
[8] a) R. Lucius, H. Mayr, Angew. Chem. 2000, 112, 2086–2089; Angew.
Chem. Int. Ed. 2000, 39, 1995–1997; b) S. T. A. Berger, A. R. Ofial,
H. Mayr, J. Am. Chem. Soc. 2007, 129, 9753–9761; c) R. Appel, R.
Loos, H. Mayr, J. Am. Chem. Soc. 2009, 131, 704–714.
[10] I. Zenz, H. Mayr, unpublished results.
[11] a) L.-Q. Lu, Y.-J. Cao, X.-P. Liu, J. An, C.-J. Yao, Z.-H. Ming, W.-J.
Xiao, J. Am. Chem. Soc. 2008, 130, 6946–6948; b) L.-Q. Lu, F. Li, J.
An, J.-J. Zhang, X.-L. An, Q.-L. Hua, W.-J. Xiao, Angew. Chem.
2009, 121, 9706–9709; Angew. Chem. Int. Ed. 2009, 48, 9542–9545.
[12] R. Robiette, J. Richardson, V. K. Aggarwal, J. N. Harvey, J. Am.
Chem. Soc. 2006, 128, 2394–2409.
[13] a) V. K. Aggarwal, S. Calamai, J. G. Ford, J. Chem. Soc. Perkin
Trans. 1 1997, 593–599; b) V. K. Aggarwal, J. N. Harvey, J. Richard-
son, J. Am. Chem. Soc. 2002, 124, 5747–5756; c) D. R. Edwards, P.
Montoya-Peleaz, C. M. Crudden, Org. Lett. 2007, 9, 5481–5484.
Received: May 26, 2010
Published online: June 30, 2010
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