Rotaxane formation under thermodynamic control

Article abstract of DOI:10.1021/ol990966j

Thermodynamic control operates in the synthesis of a [2]rotaxane based upon the dibenzylammonium ion/crown ether recognition motif. When dibenzo[24]crown-8 is added to an acetonitrile solution containing a diimine dumbbell-like component, the dynamic natu

Full text of DOI:10.1021/ol990966j

ORGANIC
LETTERS
1
999
Vol. 1, No. 9
363-1366
Rotaxane Formation under
Thermodynamic Control
1
Stuart J. Cantrill, Stuart J. Rowan, and J. Fraser Stoddart*
Department of Chemistry and Biochemistry, UniVersity of California, Los Angeles,
405 Hilgard AVenue, Los Angeles, California 90095-1569
stoddart@chem.ucla.edu
Received August 20, 1999
ABSTRACT
Thermodynamic control operates in the synthesis of a [2]rotaxane based upon the dibenzylammonium ion/crown ether recognition motif.
When dibenzo[24]crown-8 is added to an acetonitrile solution containing a diimine dumbbell-like component, the dynamic nature of the system
+
(
i.e., imine hydrolysis/reformation) offers the ring component access to the NH
2
center, allowing the self-assembly of the corresponding
“dynamic” [2]rotaxane to occur. The “fixing” of this [2]rotaxane can be achieved upon reduction of the imine bonds, affording a kinetically
inert [2]rotaxane.
Whereas the noncovalent syntheses1 of supermolecules
interactions and ring-opening/ring-closing metathesis pro-
4
5
(discrete complexes) and supramolecular arrays (polymeric
tocols, have been exploited in the self-assembly of catenanes
aggregates) generally occur under thermodynamic control,
the covalent syntheses of organic compounds are usually
kinetically controlled. However, covalent syntheses can also
be carried out within a thermodynamically controlled regime.
Such reversible covalent bond-forming protocols enjoy the
attributes of supramolecular processes but within a much
more robust bonding framework than their noncovalent
counterparts. Synthetic chemists are already exploring the
opportunities presented by utilizing reversible covalent
modifications, in conjunction with supramolecular assistance,
under thermodynamically controlled conditions. However,
6
7
a wide range of functionalities, including acetals, esters,
8
and disulfides, have also been employed in reversible
processes involving wholly organic compounds. Here, we
report the use of the well-known reversible imine bond-
(
4) (a) Fujita, M.; Ibukuro, F.; Hagihara, H.; Ogura, K. Nature 1994,
67, 720-723. (b) Try, A. C.; Harding, M. M.; Hamilton, D. G.; Sanders,
J. K. M. Chem. Commun. 1998, 723-724.
5) For an example of a [2]catenane synthesissemploying ring opening
3
(
and ring closing metathesis (RORCM)soperating under thermodynamic
control, see: Kidd, T. J.; Leigh, D. A.; Wilson, A. J. J. Am. Chem. Soc.
1999, 121, 1599-1600. For an example of [2]catenane synthesis utilizing
ring-closing metathesis (RCM), see: Mohr, B.; Weck, M.; Sauvage, J.-P.;
Grubbs, R. H. Angew. Chem., Int. Ed. Engl. 1997, 36, 1308-1310.
(6) For an example used in the synthesis of natural products, see: Nadin,
A.; Nicolaou, K. C. Angew. Chem., Int. Ed. Engl. 1996, 35, 1622-1656.
For comments on how ketalization under thermodynamic control can be
exploited in the resolution of racemates, see: Davis, A. P. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 591-594.
2
to make molecular receptors and interlocked molecular
3
compounds, such as catenanes and rotaxanes. To date, labile
coordinative bonds, associated with certain metal-ligand
(
(
(
1) Fyfe, M. C. T.; Stoddart, J. F. Acc. Chem. Res. 1997, 30, 393-401.
2) Sanders, J. K. M. Chem. Eur. J. 1998, 4, 1378-1383.
3) (a) Amabilino, D. B.; Stoddart, J. F. Chem. ReV. 1995, 95, 2725-
(7) Rowan, S. J.; Sanders, J. K. M. J. Org. Chem. 1998, 63, 1536-
1546.
2
828. (b) Breault, G. A.; Hunter, C. A.; Mayers, P. C. Tetrahedron 1999,
5
5, 5265-5293. (c) Hubin, T. J.; Kolchinski, A. G.; Vance, A. L.; Busch,
(8) (a) Hioki, H.; Still W. C. J. Org. Chem. 1998, 63, 904-905. (b)
Tam-Chang, S.-W.; Stehouwer, J. S.; Hao J. J. Org. Chem. 1999, 64, 334-
335.
D. H. In AdVances in Supramolecular Chemistry; Gokel, G. W., Ed.; JAI
Press: Stamford, CT, 1999; Vol. 10, pp 237-357.
1
0.1021/ol990966j CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/13/1999

9
forming reaction to construct a so-called dynamic [2]-
6
1:1 mixture of DB24C8 and 3-H‚PF corresponds to the [2]-
rotaxane, starting from a threadlike component terminated
by aldehyde functionssspecifically, the bis(4-formylbenzyl)-
ammonium ions3,5-di-tert-butylaniline, and a complemen-
pseudorotaxane.
In the knowledge that the aromatic dialdehyde 3-H‚PF
complexes strongly in CD CN with DB24C8, we examined
its ability to form diimine 5-H‚PF , via the intermediacy of
the monoimine 4-H‚PF , on addition of 2 equiv of 3,5-di-
tert-butylaniline. The choice of this amine relates to the fact
that (1) the 3,5-di-tert-butylphenyl group has been shown14
to be sufficiently large to act as a stopper toward DB24C8
and (2) the less basic aromatic amino group of the aniline
will offer little competition for the proton attached to the
much more basic aliphatic nitrogen atom present in
6
3
10
tary ring component, namely dibenzo[24]crown-8 (DB24C8).
The synthesis (Scheme 1) of the threadlike component
6
6
1
1
4
begins with the reduction (LiAlH /THF) of diester 1,
Scheme 1. Synthesis of the Dialdehyde 3-H‚PF
6
3
-H‚PF
6
6
. The reaction of 3-H‚PF with 3,5-di-tert-butyl-
1
aniline was monitored (Figure 1) by H NMR spectroscopy.
affording diol 2 which is oxidized (PCC/CH
hyde 3. Protonation (HCl/MeOH) of 3, followed by coun-
terion exchange (NH PF /H O), produces 3-H‚PF in an
overall yield of 37%. As expected, 3-H‚PF forms a strong
:1 complex with DB24C8, both in solution and the “gas
2 2
Cl ) to dialde-
4
6
2
6
12
6
1
1
phase”, as evidenced by H NMR spectroscopy and FAB
mass spectrometry, respectively. Inspection of the H NMR
1
3
spectrum (400 MHz, CD CN, 20 mM, 300 K) of an
equimolar mixture of these two components revealed the
presence of three sets of signals, corresponding to (1) the
[2]pseudorotaxane [3-H‚DB24C8]‚PF
6
, (2) uncomplexed
3
-H‚PF , and (3) free DB24C8, indicating that these species
6
1
are equilibrating slowly on the H NMR time scale. As a
consequence of this slow exchange, we were able to calculate
1
Figure 1. Top: partial H NMR spectra (400 MHz, CD
3
CN, 300
K), recorded over time, of an initial mixture of 3-H‚PF
6
(20 mM)
-
1
-1
a K
single-point method”.13 Additionally, the base peak which
was observed at m/z ) 702 in the FAB mass spectrum of a
a
value of 1600 M (-∆G° ) 4.4 kcal mol ) using the
and 3,5-di-tert-butylaniline (40 mM). Bottom: schematic repre-
sentation of the dynamic equilibrium established in solution. The
probe protons of, and the associated resonances for, the dialdehyde
“
3
(
-H‚PF
monoimine) 4-H‚PF
dumbbell 5-H‚PF as magenta dots.
6
are represented as purple dots, those of the monoaldehyde
(9) Dayagi, S.; Degani, Y. In The Chemistry of the Carbon-Nitrogen
6
as orange dots, and those of the diimine
Double Bond; Patai, S., Ed.; Interscience: New York, 1970; pp 64-83.
For an example of how the reversible nature of imine bond formation can
be exploited in conjunction with molecular recognition to alter the product
selectivity in a “virtual” combinatorial library, see: Huc, I.; Lehn J.-M.
Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 2106-2110.
6
6 3
A 20 mM solution of 3-H‚PF in CD CN was prepared and,
1
(
10) (a) Kolchinski, A. G.; Busch, D. H.; Alcock, N. W. J. Chem. Soc.,
after recording its H NMR spectrum (t ) 0 min), 2 equiv
Chem. Commun. 1995, 1289-1291. (b) Rowan, S. J.; Cantrill, S. J.;
1
of the aniline was added and the H NMR spectrum was
Stoddart, J. F. Org. Lett. 1999, 1, 129-132.
recorded at appropriate time intervals.
(11) Ashton, P. R.; Glink, P. T.; Stoddart, J. F.; Tasker, P. A.; White,
A. J. P.; Williams, D. J. Chem. Eur. J. 1996, 2, 729-736.
After 10 min, two singlets are observed for the CHO
protons: the more intense singlet corresponds to unreacted
(
12) Ashton, P. R.; Campbell, P. J.; Chrystal, E. J. T.; Glink, P. T.;
Menzer, S.; Philp, D.; Spencer, N.; Stoddart, J. F.; Tasker, P. A.; Williams,
D. J. Angew. Chem., Int. Ed. Engl. 1995, 34, 1865-1869.
(
13) Adrian, J. C.; Wilcox, C. S. J. Am. Chem. Soc. 1991, 113, 678-
(14) Mart ´ı nez-D ´ı az, M.-V.; Spencer, N.; Stoddart, J. F. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 1904-1907.
6
80.
1364
Org. Lett., Vol. 1, No. 9, 1999

3
-H‚PF
6
, while the smaller resonance arises from 4-H‚PF
6
.
observed in the spectra is the decrease in intensity of the
peak at δ ) 8.62 ppm (diimine dumbbell 5-H‚PF ) and the
corresponding growth of a new resonance at δ ) 8.37 ppm
(diimine [2]rotaxane [5-H‚DB24C8]‚PF ). It is apparent,
therefore, that since the diimine dumbbell 5-H‚PF cannot
thread through the cavity of DB24C8, the [2]rotaxane is
being generated via a process in which consumption of 5-H‚
Two singlets, one each for 4-H‚PF
6
and 5-H‚PF , are also
6
6
observed in the CHN region of the spectrum. During the
course of the reaction, both CHO signals decrease in their
intensities, concomitant with the increasing intensities ob-
served for the CHN peaks. Moreover, comparison of the
spectra shows that, although initially intermediate mono-
6
6
aldehyde/monoimine 4-H‚PF
ally, after 60 min, diimine 5-H‚PF
6
is the major product, eventu-
starts to predominate.
PF
6
results in the formation of either a monoaldehyde/
6
monoimine (4-H‚PF
6
) or dialdehyde (3-H‚PF ) thread which,
6
At equilibrium (1440 min ) 1 day), integration of the CHO/
CHN signals allows the product distribution, dialdehyde 3-H‚
in turn, can pass through the cavity of the macrocyclic
polyether and subsequently react to form the diimine [2]-
PF
6
(4%), monoaldehyde/monoimine 4-H‚PF
6
(23%), and
rotaxane [5-H‚DB24C8]‚PF
6
. At equilibrium (t ) 6200 min
1
5
diimine dumbbell 5-H‚PF
6
(73%), to be calculated.
) ca. 4.5 days), the product distribution is [5-H‚DB24C8]‚
The implication of this equilibrium composition is that,
on addition of 1 equiv of DB24C8 to the equilibrated
mixture, no more than 27% of it can be rotaxanated unless
thermodynamic control is operating. The results are recorded
in Figure 2. At t ) 0 min, with no crown ether present, the
PF
4-H‚PF
6
(47%), 5-H‚PF
6
(16%); [4-H‚DB24C8]‚PF
6
(26%),
6
(1%).
6
(6%); [3-H‚DB24C8]‚PF
6
(4%), 3-H‚PF
The same equilibrium proportions of these six species can
be reachedsbut much more quicklysin 2125 min (Figure
3) when DB24C8 is present in the reaction mixture from
1
Figure 3. Partial H NMR spectra (400 MHz, CD
3
CN, 300 K),
(20 mM), 3,5-
di-tert-butylaniline (40 mM), and DB24C8 (20 mM). Peaks
1
Figure 2. Partial H NMR spectra (400 MHz, CD
3
CN, 300 K),
(20 mM) and
,5-di-tert-butylaniline (40 mM), which was allowed to reach
equilibrium (spectrum at t ) 0 min) prior to the addition of DB24C8
recorded over time, of an initial mixture of 3-H‚PF
6
recorded over time, of an initial mixture of 3-H‚PF
6
3
+
corresponding to species containing an NH
2
center not bound/
occupied by a DB24C8 ring are represented in black while those
which are bound/occupied are represented in red. The resonances
associated with the dialdehyde, monoaldehyde, and diimine probe
protons are highlighted as described in Figure 1.
+
(
2
20 mM). Peaks corresponding to species containing an NH center
not bound/occupied by a DB24C8 ring are represented in black
while those which are bound/occupied are represented in red. The
resonances associated with the dialdehyde, monoaldehyde, and
diimine probe protons are highlighted as described in Figure 1.
the outset. This observation is yet another indication that
thermodynamic control is operating in this system, as the
same equilibrium composition is being reached, irrespective
of the starting point of the reaction. By utilizing the
secondary dialkylammonium ion/crown ether recognition
motif to bring about the noncovalent synthesis of a [2]-
pseudorotaxane, in conjunction with reversible imine bond
formation to stopper covalently the [2]pseudorotaxane and
produce a dynamic [2]rotaxane, we have demonstrated that
thermodynamic control can be used in the construction of
interlocked molecular compounds that are wholly organic
in nature. A high degree of control of superstructure and
structure can be envisaged in such “slowly” equilibrating
systems. For example, in Scheme 2, by judiciously altering
spectrum is identical with the one recorded in Figure 1 at
equilibrium (t ) 1440 min). Upon addition of DB24C8, any
species with an aldehyde group at either of its termini (i.e.,
3
-H‚PF
crown ether’s macrocyclic cavity, generating the correspond-
ing [2]pseudorotaxanesi.e., [3-H‚DB24C8]‚PF and [4-H‚
DB24C8]‚PF , respectively. This effect is seen immediately
t ) 10 min) and, subsequently, resonances corresponding
to 3-H‚PF , 4-H‚PF , [3-H‚DB24C8]‚PF , and [4-H‚DB24C8]‚
PF remain substantially unchanged throughout the course
of the experiment. By far the most predominant change
6
and 4-H‚PF
6
) is capable of threading through the
6
6
(
6
6
6
6
(15) Although by no means quantitative, the positive-ion FAB mass
1
6
spectrum of this equilibrium mixture tallies approximately with the ratios
solvent polarities, the equilibria in the “vertical” direction
1
of the components observed by H NMR spectroscopy in solution. The
intensities of the signals in the mass spectrum, corresponding to [5-H‚
+
+
+
+
DB24C8] :5-H :[4-H‚DB24C8] :4-H , occur in the ratio 100:32:11:5.
Signals are not observed for the minor solution components, namely [3-H‚
(16) Ashton, P. R.; Chrystal, E. J. T.; Glink, P. T.; Menzer, S.; Schiavo,
C.; Spencer, N.; Stoddart, J. F.; Tasker, P. A.; White, A. J. P.; Williams,
D. J. Chem. Eur. J. 1996, 2, 709-728.
+
+
DB24C8] and 3-H , respectively.
Org. Lett., Vol. 1, No. 9, 1999
1365

Scheme 2 Dynamic Equilibrium Established upon Dissolution of a 1:2:1 Ratio (20:40:20 mM) of 3-H‚PF
and DB24C8 in CD CN
6
, 3,5-Di-tert-butylaniline,
3
could be controlled, while removal of water from the reaction
mixture should shift the equilibria in the “horizontal”
direction toward diimine formation. Thereafter, a “fast”
reduction of the imine bonds would give kinetically stable
products and, in so doing, “fix” the [2]rotaxane. Indeed,
initial investigations on the “fixing” of this systemsinvolving
reduction of the imine functionssare encouraging. Treatment
of an equilibrated mixture of 3-H‚PF
aniline, and DB24C8 in a CH Cl
solution with PhSeH17
affords the “fixed” [2]rotaxane 6-H‚PF
6
, 3,5-di-tert-butyl-
2
2
(
17) Fujimori, K.; Yoshimoto, H.; Oae, S. Tetrahedron Lett. 1980, 21,
385-3388.
18) An excess of PhSeH (1.0 g, 6.4 mmol) was added to an equilibrated
ca. 3 d stirring under ambient conditions) mixture of 3-H‚PF6 (0.25 g, 0.6
18
6
.
3
1
9
Although kinetic approaches have so far dominated the
syntheses of interlocked molecular compounds with wholly
organic constitutions, strategies involving thermodynamic
(
(
mmol), DB24C8 (0.56 g, 1.3 mmol) and 3,5-di-tert-butylaniline in dry CH2-
Cl2 (10 mL). The reaction mixture was stirred for 4 d under ambient
conditions, before being poured into Et2O (500 mL). A white solid was
recovered upon filtration and subjected to column chromatography (SiO2:
CH2Cl2, then CH2Cl2/MeOH, 99:1). Although fractions containing the
2
0
control are now set to challenge that domination. Such a
seed change in synthetic strategy is one that could lead to
much more efficient routes, not only to rotaxanes and
catenanes but also to their macromolecular counterparts.21
“
fixed” [2]rotaxane as the major product were collected, DB24C8 coelutes
from the column with this compound, accounting for ∼10% (by mass) of
1
the isolated white solid, as determined by H NMR spectroscopy. On the
1
basis of the H NMR spectrum, the yield for the conversion of 3-H‚PF6
into 6-H‚PF6 was calculated to be 18%.
Acknowledgment. We thank UCLA for generous finan-
cial support.
Supporting Information Available: Experimental pro-
1
13
cedures for 2 and 3-H‚PF
scopic and FAB mass spectrometric data for 2, 3-H‚PF
-H‚PF . This material is available free of charge via the
6
and H and C NMR spectro-
6
, and
6
6
Internet at http://pubs.acs.org.
OL990966J
1
Selected data for 6-H‚PF6: H NMR (400 MHz, CD2Cl2, 300 K) δ ) 1.25
(19) Amabilino, D. B.; Ashton, P. R.; P e´ rez-Garc ´ı a, L.; Stoddart, J. F.
Angew. Chem., Int. Ed. Engl. 1995, 34, 2378-2380.
(
s, 36H), 3.48 (s, 8H), 3.73-3.77 (m, 8H), 4.04-4.09 (m, 8H), 4.25 (s,
4
H), 4.60-4, 65 (m, 4H), 6.45 (d, J ) 1.6 Hz, 4H), 6.75-6.80 (m, 6H),
.88-6.94 (m, 4H), 7.22 (AA′ of AA′BB′ system, J ) 8.0 Hz, 4H), 7.29
(20) Thermodynamic control of rotaxane syntheses in a “statistical”
context by reversible covalent bond formation has been reported in some
earlier investigations. See: (a) Harrison, I. T. J. Chem. Soc., Perkin Trans.
1 1974, 301-304. (b) Schill, G.; Beckmann, W.; Schweickert, N.; Fritz,
H. Chem. Ber. 1986, 119, 2647-2655.
6
(
1
3
BB′ of AA′BB′ system, J ) 8.0 Hz, 4H), 7.57 (br s, 2H); C NMR (100
MHz, CD2Cl2, 300 K) δ ) 31.7, 35.2, 48.3, 52.9, 68.6, 70.8, 71.3, 108.1,
1
(
12.7, 113.2, 118.1, 122.1, 128.2, 129.9, 131.0, 142.1, 148.1, 152.3; MS
+
FAB) m/z ) 1081 [M - PF6] .
(21) Raymo, F. M.; Stoddart, J. F. Chem. ReV. 1999, 99, 1643-1663.
1366
Org. Lett., Vol. 1, No. 9, 1999