Encaging the Verkade's superbases: Thermodynamic and kinetic consequences

Article abstract of DOI:10.1021/ja1110333

Proazaphosphatranes, also known as Verkade's superbases, are nonionic species, which exhibit catalytic properties for a wide range of reactions. The properly designed host molecule 3 and its protonated counterpart [3·H]⁺Cl^- were synthesized to study how confinement can modify the stability and the reactivity of a Verkade's superbase. The results show that the encapsulation does not alter the strong basicity of the proazaphosphatrane, but dramatically decreases the rate of proton transfer.

Full text of DOI:10.1021/ja1110333

COMMUNICATION
pubs.acs.org/JACS
Encaging the Verkade’s Superbases: Thermodynamic and Kinetic
Consequences
†
,†
‡
,†
Pascal Dimitrov Raytchev, Alexandre Martinez,* Heinz Gornitzka, and Jean-Pierre Dutasta*
†
ꢀ
Laboratoire de Chimie, Ecole Normale Sup ꢀe rieure de Lyon, CNRS, 46 All ꢀe e d’Italie, F-69364 Lyon, France
‡
Laboratoire de Chimie de Coordination, CNRS, 205, route de Narbonne, F-31077 Toulouse, France
S Supporting Information
b
ABSTRACT: Proazaphosphatranes, also known as Verkade’s
superbases, are nonionic species, which exhibit catalytic
properties for a wide range of reactions. The properly designed
þ
-
host molecule 3 and its protonated counterpart [3 H] Cl
3
were synthesized to study how confinement can modify the
stability and the reactivity of a Verkade’s superbase. The results
show that the encapsulation does not alter the strong basicity
of the proazaphosphatrane, but dramatically decreases the rate
of proton transfer.
Figure 1. Structures of the azaphosphatrane and proazaphosphatrane
derivatives.
Scheme 1. Synthesis of the Hemicryptophane Superbase 3
he use of molecular containers for the design of receptors
containing a reactive site is very attractive, as they can act as
T
supramolecular catalysts and can mimic biological entities such as
1
enzymes. Changes in reactivity in the confines of an enzyme
active site have driven chemists to explain and duplicate these
2
through the formation of supramolecular structures. Synthetic
host molecules have thus been developed to display specifically
tailored functional groups inside their cavity. In particular,
1
to a solution of [(CH ) N] PCl in acetonitrile afforded
3 2 2
12
3
3
þ
-
[
3 H] Cl in 35% yield, which was then deprotonated using
endohedral location of highly reactive species in such artificially
protected and confined spaces has demonstrated the great
potassium t-butoxide in THF followed by extraction with toluene
to give the encaged superbase 3 in 80% yield. The weak acid
4
potential of this approach. Here we report on the synthesis of
þ
-
31
[
3 H] Cl displayed a single P NMR signal at -32 ppm in
3
a proazaphosphatrane included in the cavity of a hemicrypto-
CDCl , which is significantly highfield shifted by about 20 ppm
3
5
10
phane structure, leading to the first encaged Verkade’s super-
compared to other azaphosphatranes. Compound 3 showed a
31
base. Themodynamic and kinetic consequences on the proton
transfer are also discussed.
P NMR signal at 125 ppm in toluene-d as expected for a
8
proazaphosphatrane derivative.
þ
-
Recently, we have described the synthesis of hemicryptophane
containing the tris-(2-aminoethyl)amine (tren) moiety. The
The single-crystal X-ray diffraction analysis of [3 H] Cl
3
6
1
clearly shows the phosphatrane moiety inside the molecular
tren ligand is known to form atrane structures through metal
cavity (Figure 2). The average P-N bond length is 1.62 Å, and
eq
complexation, an interesting class of compounds well represented
the apical P-N bond length is 1.93(2) Å, which are in the range
ap
7
8,9c,12
across the periodic table and widely studied. In particular, the
of typical values determined on phosphatrane derivatives.
proazaphosphatranes 2, first synthesized by Verkade et al., along
The trigonal bipyramidal geometry around the phosphorus atom
is characterized by the sum of the N -P-N angles in the
equatorial plane of 359° and the average N -P-N angle value
of 86°. A dichloromethane molecule is located inside the molecular
cavity and interacts with the aromatic rings of the cyclotriveratylene
(CTV) unit, emphasizing the host properties of the new hemi-
cryptophane.
þ
-
8
with the related azaphosphatranes [2 H] Cl (Figure 1), are
3
eq
eq
nonionic superbases (pK ≈ 32) now broadly used in organic
a
eq
ap
9,10
synthesis as stoichiometric bases and as catalysts. Therefore,
there is a real challenge to combine the properties of Verkade’s
superbases and the confinement upon specific architectures.
Recently, Raymond et al. investigated the host-guest assembly
þ
of azaphosphatrane [2a H] in the hydrophobic pocket of a
metal-organic framework, but the effect of encapsulation could
not be evaluated as experiments were run in water.
The synthesis of hemicryptophane-phosphatrane [3 H] Cl
was performed using the experimental conditions reported for
other azaphosphatranes (Scheme 1): addition of hemicryptophane
Since the phosphatrane structure was preserved in host
3
þ
[3 H] , it wasinterestingtomeasurethe pK
superbase. The pK
value of the enclosed
value was estimated from competition
3
a
11
a
þ
-
3
Received: December 17, 2010
Published: January 31, 2011
r 2011 American Chemical Society
2157
dx.doi.org/10.1021/ja1110333
|J. Am. Chem. Soc. 2011, 133, 2157–2159

Journal of the American Chemical Society
COMMUNICATION
Scheme 2. Kinetic Acid-Base Equilibriums Involved in the
þ
Proton Transfer [3 H] / 3
3
reaction 2 can be neglected at short time. Similarly, as the
concentration of CHD CN is negligible compare to that of
2
Figure 2. X-ray molecular structure of the hemicryptophane-phospha-
CD CN, reaction 1 can be considered as nonreversible. This
3
þ
3 Hþ 2a Hþ
3
3
trane cation CH Cl @[3 H] .
allowed us to establish eq 1 and eq 2, where Ka
, K
and
2
2
3
a
þ
K are the acidity constant of [3 H] , the acidity constant of
e
3
þ
[
2a H] , and the autoprotolysis constant of acetonitrile, respec-
13
3
Table 1. pK Values of Conjugate Acids of Proazaphospha-
a
tively, affording the k and k values. Rate constants for model
1 -1
trane Bases in CH CN, and Rate Constants Values for Proton
3
compound 4 were obtained using a similar method (Supporting
Information).
Transfers
1
-1 [mol L-1 s-1
base
pK
a
K
a
k
1
[mol L- s-1
]
k
]
þ
þ
dð½3ꢁ=½3 H ꢁÞ
klKe ½2aꢁð1þ½3ꢁ=½3 H ꢁÞ
3
3
¼Ka
ðeq 1Þ
ðeq 2Þ
þ
a
-33
-33
-6
-5
2a H
þ
3
32.99
32.14
1.03 ꢀ 10
7.25 ꢀ 10
1.88 ꢀ 10
1.06 ꢀ 10
1.16 ꢀ 10
0.93 ꢀ 10
dt
3
½2a H ꢁ
3
a
-3
-3
4
a
Average values of at least two experiments, T = 298 K.
Ke
k-1 ¼Ka3
kl
þ
H
3
þ
-
experiments: addition of the azaphosphatrane [3 H] Cl to a
solution of the Verkade’s superbase 2a in CD CN led to an
equilibrium mixture that was accurately analyzed by P and H
NMR spectroscopy (Supporting Information). This afforded a
3
The deprotonation rate constant was found to be more than
500-fold lower with the encaged azaphosphatrane [3 H] than
with the model compound [4 H] (Table 1). Despite the higher
basicity of the host superbase 3, the rate constant for its
protonation is nearly 2 orders of magnitude lower than that for
the model superbase 4, where the rate constant turned out to be
unrelated to the thermodynamics of proton transfer. We should
note that previous studies have demonstrated the effect of
encapsulation on the kinetics of proton transfer, in particular
with tertiary amine derivatives. However, to our knowledge, it
has never been reported for such strongly basic species. Thus,
confinement of the proazaphosphatrane in a molecular cavity
dramatically affects the kinetics of proton transfer with CD CN
solvent. The specific environment around the reactive site could
impose a specific orientation of the acetonitrile guest inside the
cavity, involving an entropic cost for proton transfer. Moreover,
orbital overlap between phosphorus and the C-H bond of
acetonitrile could impose the position of the acetonitrile nitrogen
in the vicinity of the electron-rich aromatic rings of the CTV unit.
Therefore, the appearance of a negative charge on this nitrogen
atom, in the transition state, might lead to an unfavorable
interaction and hence increase the enthalpic cost.
In conclusion, a Verkade’s superbase has been covalently
attached inside the host cavity of hemicryptophane 1 , leading
to the host superbase 3 containing a preorganized cavity defined
by the cyclotriveratrylene moiety above the strongly basic
3
þ
31
1
3
þ
3
-
33
reproducible value K = 1.03 ꢀ 10
for 3, slightly lower than
a
-
33
that of the Verkade’s superbase 2a (K = 1.26 ꢀ 10
)
a
9
a
(
Table 1). This highlights that the hemicryptophane caged
structure retains the strong basic character of the proazapho-
sphatrane. It has been shown that the basicity of the proazapho-
sphatranes depends on the nature of the substituents on the
nitrogen atoms. Thus, in order to investigate more accurately
the effect of the cage structure, the K value was compared to that
of the model molecule 4, which lacks a cavity (Figure 1). Com-
pound 4 was synthesized in 3 steps from tris(2-aminoethyl)-
amine and p-anisaldehyde in 24% overall yield (Supporting
14
9
a
3
Information). The K value for 4 was found to be 7 times that of
a
3
, making the encaged superbase 3 7 times more basic than the
-
33
-33
model molecule 4 (K ’s = 1.03 ꢀ 10
and 7.25 ꢀ 10 , res-
a
-
1
pectively), corresponding to a variation of ΔG° of 1.2 kcal mol .
Since the substitents in the vicinity of the phosphorus atom
in 3 and 4 are identical, this enhancement can be uniquely
attributed to the encapsulation of the superbase inside the host
structure.
During the pK measurements we observed that proton
transfer occurred on dramatically different time scales for the
model superbase 4 and the encaged superbase 3. When
3 H] Cl is added to a solution of 2a in CD CN, after more
than 5 h no [3 D] was observed in the P NMR spectra,
whereas under the same experimental conditions, when using
4 H] Cl , [4 D] appeared immediately. As proton transfer
a
þ
-
[
proazaphosphatrane. The pK value showed a 7-fold increase
3
3
a
þ
31
in the basicity of the encaged superbase when compared to
that of the model molecule, which lacks a cavity. This enhance-
ment was attributed to the incorporation of the highly basic
species in a confined medium. The encapsulation of the phos-
phorus moiety was also found to strongly affect the rate for
proton transfer. These thermodynamic and kinetic modifications
by molecular encapsulation may provide valuable information for
a better understanding of enzymes or other complex biological
systems.
3
þ
-
þ
[
3
3
between 3 and acetonitrile occurred on a time scale of hours,
þ
-
addition of the azaphosphatrane [3 H] Cl to a solution of 2a
3
in CD CN allowed the direct monitoring of the transfer kinetics
by recording P and H NMR spectra as a function of time.
Two acid-base reactions are involved (Scheme 2); since, after
more than 5 h, no [3 D] was observed in the P NMR spectra,
3
3
1
1
þ
31
3
2
158
dx.doi.org/10.1021/ja1110333 |J. Am. Chem. Soc. 2011, 133, 2157–2159

Journal of the American Chemical Society
COMMUNICATION
’
ASSOCIATED CONTENT
(11) Pluth, M. D.; Bergman, R. G.; Raymond, K. N. J. Am. Chem. Soc.
007, 129, 11459–11467.
(12) Liu, X.; Ilankumaran, P.; Guzei, I. A.; Verkade, J. G. J. Org.
2
S
Supporting Information. Additional NMR spectra, de-
b
tailed experimental procedures and crystallographic analysis.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Chem. 2000, 65, 701–706.
13) (a) Kolthoff, I. M.; Chantooni, M. K. J. Phys. Chem. 1968, 72,
270–2272. (b) Rondinini, S.; Longhi, P.; Mussini, P. R.; Mussini, T.
Pure Appl. Chem. 1987, 59, 1693–1702.
14) (a) Smith, P. B.; Dye, J. L.; Cheney, J.; Lehn, J.-M. J. Am. Chem.
(
2
(
’
AUTHOR INFORMATION
Soc. 1981, 103, 6044–6048. (b) Ciampolini, M.; Nardi, N.; Valtancoli,
B.; Micheloni, M. Coord. Chem. Rev. 1992, 120, 223–236. (c) Chambron,
J.-C.; Meyer, M. Chem. Soc. Rev. 2009, 38, 1663–1673.
Corresponding Author
alexandre.martinez@ens-lyon.fr; jean-pierre.dutasta@ens-lyon.fr
’
ACKNOWLEDGMENT
Support from the French Ministry of Research (Project ANR-
2
010 JCJC 711 1 [(Sup) Base]) is acknowledged.
3
’
REFERENCES
(1) (a) Kirby, A. J. Angew. Chem., Int. Ed. Engl. 1996, 35, 707–724.
(b) Sanders, J. K. M. Chem.—Eur. J. 1998, 4, 1378–1383. (c) Lehn, J.-M.
Rep. Prog. Phys. 2004, 67, 245–249. (d) Yoshizawa, M.; Klosterman, J. K.;
Fujita, M. Angew. Chem., Int. Ed. 2009, 48, 3418–3438. (e) Rebek, J., Jr.
Acc. Chem. Res. 2009, 42, 1660–1668.
(2) (a) Murakami, Y.; Kikuchi, J.; Hisaeda, Y.; Hayashida, O. Chem.
Rev. 1996, 96, 721–758. (b) Feiters, M. C.; Rowan, A. E.; Nolte, R. J. M.
Chem. Soc. Rev. 2000, 29, 375–384. (c) Breslow, R. Acc. Chem. Res. 1995,
28, 146–153. (d) Engeldinger, E.; Armspach, D.; Matt, D. Chem. Rev.
2003, 103, 4147–4173. (e) Homden, D. M.; Redshaw, C. Chem. Rev.
2008, 108, 5086–5130.
(
3) (a) Tominaga, M.; Suzuki, K.; Murase, T.; Fujita, M. J. Am. Chem.
Soc. 2005, 127, 11950–11951. (b) Koblenz, T. S.; Wassenaar, J.; Reek,
J. N. H. Chem. Soc. Rev. 2008, 37, 247–262.
(4) (a) Darbost, U.; Rager, M-.N.; Petit, S.; Jabin, I.; Reinaud, O.
J. Am. Chem. Soc. 2005, 127, 8517–8525. (b) Deutman, A. B. C.;
Monnereau, C.; Elemans, J. A. A. W.; Ercolani, G.; Nolte, R. J. M.;
Rowan, A. E. Science 2008, 322, 1668–1671.
(5) (a) Gautier, A.; Mulatier, J.-C.; Crassous, J.; Dutasta, J.-P. Org.
lett. 2005, 7, 1207–1210. (b) Martinez, A.; Robert, V.; Gornitzka, H.;
Dutasta, J.-P. Chem.—Eur. J. 2010, 16, 520–527. (c) Martinez, A.; Guy,
L.; Dutasta, J.-P. J. Am. Chem. Soc. 2010, 132, 16733–16734. (d)
Martinez, A.; Dutasta, J.-P J. Catal. 2009, 267, 188–192.
(
6) Dimitrov-Raytchev, P.; Perraud, O.; Aronica, C.; Martinez, A.;
Dutasta, J.-P. J. Org. Chem. 2010, 75, 2099–2102.
7) (a) Verkade, J. G. Acc. Chem. Res. 1993, 26, 483–489. (b)
(
Verkade, J. G. Coord. Chem. Rev. 1994, 137, 233–295. (c) Hammes,
B. S.; Ramos-Maldonado, D.; Yap, G. P. A.; Liable-Sands, L.; Rheingold,
A. L.; Young, V. G., Jr.; Borovik, A. S. Inorg. Chem. 1997, 36, 3210–3211.
(d) Darbost, U.; Zeng, X.; Rager, M.-N.; Giorgi, M.; Jabin, I.; Reinaud,
O. Eur. J. Inorg. Chem. 2004, 22, 4371–4374. (e) Makita, Y.; Sugimoto,
K.; Furuyoshi, K; Ikeda, K.; Fujiwara, S.; Shin-ike, T.; Ogawa, A. Inorg.
Chem. 2010, 49, 7220–7222.
(
8) Lensink, S. K. X.; Verkade, J. G. J. Am. Chem. Soc. 1989, 111,
478–3479.
9) (a) Kisanga, P. B.; Verkade, J. G.; Schwesinger, R. J. Org. Chem.
3
(
2000, 65, 5431–5432. (b) Raders, M. R.; Verkade, J. G. J. Org. Chem.
2010, 75, 5308–5311. (c) Kisanga, P. B.; Verkade, J. G. Tetrahedron
2001, 57, 467–475.
(
10) For a review see: Verkade, J. G.; Kisanga, P. Tetrahedron 2003,
59, 7819–7858 and references therein. For more recent examples see:
(a) Chintareddy, V. R.; Wadhwa, K.; Verkade, J. G. J. Org. Chem. 2009,
74, 8118–8132. (b) Wadhwa, K.; Chintareddy, V. R.; Verkade, J. G.
J. Org. Chem. 2009, 74, 6681–6690. (c) Wadhwa, K.; Verkade, J. G.
J. Org. Chem. 2009, 74, 5683–5686. (d) Wadhwa, K.; Verkade, J. G.
J. Org. Chem. 2009, 74, 4368–4371. (e) Urgaonkar, S.; Verkade, J. G. Org.
Lett. 2005, 7, 3319–3322. (f) Su, W.; McLeod, D.; Verkade, J. G. J. Org.
Chem. 2003, 68, 9499–9501.
2
159
dx.doi.org/10.1021/ja1110333 |J. Am. Chem. Soc. 2011, 133, 2157–2159