The synthesis and solubilization of amide macrocycles via rotaxane formation

Full text of DOI:10.1021/ja962046r

10662
J. Am. Chem. Soc. 1996, 118, 10662-10663
Scheme 1
The Synthesis and Solubilization of Amide
Macrocycles Wia Rotaxane Formation
Andrew G. Johnston,† David A. Leigh,*,† Aden Murphy,†
John P. Smart,† and Michael D. Deegan‡
Department of Chemistry, UniVersity of Manchester
Institute of Science and Technology
P.O. Box 88, Manchester M60 1QD, U.K.
British Gas PLC, Gas Research Centre
Ashby Road, Loughborough
Leicestershire LE11 3QU, U.K.
ReceiVed June 17, 1996
The application of supramolecular chemistry and noncovalent
bond assembly processes to the preparation of difficult (or
otherwise impossible) to obtain target molecules is an exciting
emerging area of synthetic strategy and design.1 Here we
describe how the templated assembly of a macrocycle around
a thread to form a [2]rotaxane,2 followed by its quantitative
disassembly into topologically simple components,3 allows the
facile preparation and chromatography-free purification of 1, a
molecule that had eluded isolation by conventional methodolo-
gies because of its inherent poor solubility characteristics. The
mechanically interlocked intermediate circumvents the lack of
solubility of the macrocycle by tying up its amide groups in
intramolecular hydrogen bonding resulting in the [2]rotaxane
being a remarkable 105 times more soluble in chloroform than
its cyclic component. Disassembly of the rotaxane by trans-
esterifcation of the bulky “stoppers” gives the target macrocycle
in quantitative yield. Films of the liberated macrocycle bind
rapidly and reversibly to CO2.
macrocycle 1, intractable from a mixture of other precipitated
cyclic oligomers and polymers. Molecules containing a high
proportion of amide groups are frequently insoluble (e.g., nylons,
kevlar, etc.)5 because of the high enthalpy of formation of
intermolecular hydrogen bond networks formed in the solid state.
Such problems can, however, be overcome through satisfying
hydrogen-bonding requirements intramolecularly (e.g., through
protein folding),6 and we therefore sought a synthetic route to
1 that involved an intermediate which could solubilize the
macrocycle through internal hydrogen bonding thereby allowing
its isolation and purification Via standard laboratory techniques.
Equimolar quantities of isophthaloyl dichloride and p-
xylylenediamine were slowly added to a chloroform solution
of 3,7 an auxiliary designed to act as both a hydrogen-bonding
template for the macrocycle and a “trap” by way of [2]rotaxane
formation (Scheme 1b). After 5 equiv was added,8 the reaction
was filtered and washed with acid and base to leave only three
components in the organic layer. These were separated by flash
chromatography and identified as the unrotaxanated thread 3,
the [2]rotaxane 4 (28% yield), and the [2]catenane 2. The
isolated [2]rotaxane could then be disassembled Via trans-
esterification of the ester groups (NaOMe in MeOH/THF) to
give the desired macrocycle 1, which precipitated quantitatively
and analytically pure from the reaction mixture. The practical
utility of this synthetic strategy is further demonstrated by the
fact that the purification of the [2]rotaxane is actually unneces-
sary for large-scale preparation of 1 or other benzylic amide
macrocycles since the disassembly step works equally well on
an unchromatographed mixture of the thread, [2]rotaxane, and
[2]catenane.
We recently reported4 that the [2]catenane 2 is the only
product isolable from the condensation of p-xylylenediamine
with isophthaloyl dichloride (Scheme 1a) with the tetraamido
† UMIST.
‡ British Gas PLC.
(1) A classic example is Cram’s isolation of cyclobutadiene where a
problematic property of the hydrocarbon (its high chemical reactivity) is
overcome by insulating it from other reactive species inside a carcerand
[Cram, D. J.; Tanner, M. E.; Thomas, R. Angew. Chem., Int. Ed. Engl.
1991, 30, 1024-1027]. Examples involving topologically nontrivial com-
pounds include the Stoddart synthesis of a [3]catenane which is more
efficient than that of its central ring component on its own because stabilizing
interactions during catenation overcome the kinetic barrier to macrocy-
clization [Amabilino, D. B.; Ashton, P. R.; Brown, C. L.; Co´rdova, E.;
Godinez, L. A.; Goodnow, T. T.; Kaifer, A. E.; Newton, S. P.; Pietraszk-
iewicz, M.; Philp, D.; Raymo, F. M.; Reder, A. S.; Rutland, M. T.; Slawin,
A. M. Z.; Spencer, N.; Stoddart, J. F.; Williams, D. J. J. Am. Chem. Soc.
1995, 117, 1271-1293]. Catenanes are also intermediates in some DNA
replication processes [Bates, A. D.; Maxwell, A. DNA Topology; Oxford
University Press: New York, 1993].
(2) The only other examples of rotaxane syntheses where the macrocycle
is cyclized around the thread are based upon the π-electron rich/π-electron
deficient system developed by Stoddart [Amabilino, D. B.; Stoddart, J. F.
Chem. ReV. 1995, 95, 2725-2828], although Sauvage has applied similar
“clipping” strategies extensively in catenane synthesis [Dietrich-Buchecker,
C. O.; Sauvage, J. P. Chem. ReV. 1987, 87, 795-810 and Sauvage, J. P.
Acc. Chem. Res. 1990, 23, 319-327]. Vo¨gtle has recently reported the
synthesis of amide-based rotaxanes Via a “threading” strategy. See: Vo¨gtle,
F.; Ha¨ndel, M.; Meier, S.; Ottens-Hildebrandt, S.; Ott, F.; Schmidt, T.
Liebigs Ann. Chem. 1995, 739-743. Vo¨gtle, F.; Ja¨ger, R.; Ha¨ndel, M.;
Ottens-Hildebrandt, S.; Schmidt, W. Synthesis 1996, 353-356. Vo¨gtle, F.;
Ja¨ger, R.; Ha¨ndel, M.; Ottens-Hildebrandt, S. Pure Appl. Chem. 1996, 68,
225-232. Vo¨gtle, F.; Ha¨ndel, M.; Ja¨ger, R.; Meier, S.; Harder, G. Chem.
Eur. J. 1996, 2, 640-643. Ja¨ger, R.; Ha¨ndel, M.; Harren, J.; Rissanen, K.;
Vo¨gtle, F. Liebigs Ann. Chem. 1996, 1201-1207.
1
The H NMR spectra for 1-4 in [D6]DMSO are shown in
Figure 1. In the [2]rotaxane spectrum (Figure 1b) the resonances
(5) Yang, H. H. Aromatic High-Strength Fibers; John Wiley & Sons:
New York, 1989.
(3) Degradable catenanes and rotaxanes date back to some of the earliest
examples of catenane and rotaxane synthesis [Wasserman, E. J. Am. Chem.
Soc. 1960, 82, 4433-4434 and Harrison, I. T.; Harrison, S. J. Am. Chem.
Soc. 1967, 89, 5723-5724]. The Birmingham group has recently described
their utility in the templated synthesis of a “molecular square”, see: Raymo,
F. M.; Stoddart, J. F. Pure Appl. Chem. 1996, 68, 313-322. Asakawa, M.;
Ashton, P. R.; Menzer, S.; Raymo, F. M.; Stoddart, J. F.; White, A. J. P.;
Williams, D. J. Chem. Eur. J. 1996, 2, 877-893.
(6) Protein Folding; Creighton, T. E., Ed.; Freeman: New York, 1992.
(7) The thread (3) was synthesised in three chromatography-free steps
from 4-hydroxybenzonitrile: (i) Raney Ni, NH3, MeOH; (ii) isophthaloyl
dichloride, Et3N, THF; (iii) Ph2CHCOCl, Et3N, THF; 56% overall yield.
(8) The reaction reaches a virtual end point after several equivalents of
acid chloride and bisamine are added, probably because of the buildup of
the concentration of amide, amine, and ammonium species which can
compete for and disrupt the hydrogen bonding necessary for the rotaxane
assembly mechanism. Filtration and washing of the reaction mixture can
be used to increase the yield of [2]rotaxane if necessary.
(4) Johnston, A. G.; Leigh, D. A.; Pritchard, R. J.; Deegan, M. D. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1209-1212.
S0002-7863(96)02046-X CCC: $12.00 © 1996 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 118, No. 43, 1996 10663
the conventional methods of covalent derivatization. The bis-
((2-ethylhexyl)oxy) derivative 5 has the highest chloroform
solubility (8 g L-1) we have determined to date for any
noninterlocked derivative of 1.
Changing the bisacid chloride from isophthaloyl to 5-meth-
ylisophthaloyl also produces a chloroform-soluble (2 + 2)
macrocycle (6)11 and was used to assess the templating effect
in the rotaxanation reaction by considering the “overall yield”
of the (2 + 2) macrocycle through summation of the yields of
the macrocycle on its own together with those species where it
is also a component, namely the (2 + 2) + (2 + 2) [2]catenane
7 and (2 + 2) + 1 [2]rotaxane 8. In the absence of the thread
the yields of 6 and 7 are 22% and 20%, respectively,11 an
“overall macrocycle yield” of 42%. In the presence of the thread
3, 2 equiv of acid chloride and 2 equiv of xylylenediamine give
the [2]rotaxane 8 (13%), the macrocycle 6 (20%), and the
catenane 7 (19%), an overall macrocycle yield of 52% indicating
that the thread does actively direct the formation of the
macrocycle rather than simply trap it.
Macrocycle 1 was designed as a potential receptor for CO2.4,12
Although 1 is insufficiently soluble in nonpolar solvents to
assess any hydrogen bond-mediated complexation properties in
solution, solid thin films could be assessed for their CO2 binding
affinity by measuring the change in frequency of oscillation
between two 5 MHz 60 mm2 piezoelectric crystals (one coated
with 10 µg of 1 deposited from evaporation of a saturated
solution of the macrocycle in DMF) that occurs when they are
exposed to the analyte gas.13 Exposure of the two crystals to
an atmosphere of CO2 resulted in a rapid frequency change
greater than 300 Hz. A control experiment using a similar
crystal coated with the [2]rotaxane 2, gave a response of <5
Hz upon changing gases.14 A detailed investigation of the
binding properties of films of 1 and related macrocycles is
ongoing.
Figure 1. 1H NMR spectra (300 MHz) in [D6]DMSO of (a) the thread
(3), (b) the [2]rotaxane (4), (c) the macrocycle (1), and (d) the [2]-
catenane (2).4 The key to the assignments of the resonances of 1-4
are shown on the individual components in Scheme 1.
for the benzylic region of the thread (He-h) are shifted
significantly upfield with respect to the analogous protons in
the unrotaxanated thread (3, Figure 1a) by the xylylene rings
of the macrocyclic sheath. In contrast, the protons (Ha-c) of
the isophthaloyl unit of the thread appear at virtually the same
chemical shifts in both rotaxane and unrotaxanated thread,
indicating that the preferred relative positions of the two
components of the rotaxane in DMSO has the macrocycle
located around the polarphobic ends of the thread. The proton
resonances in the free macrocycle (1, Figure 1c) are shifted
downfield with respect to the analogous protons in the [2]-
rotaxane (4, Figure 1b) and the [2]catenane4 (2, Figure 1d). The
broadening of several of the resonances in both interlocked
compounds is caused by dynamic processes (e.g., spinning of
rings) that are not fully resolved at room temperature.
The use of noncovalent bond assembly processes such as
rotaxanation15 and catenation10a to alter molecular properties,
or to select and/or isolate target structures and intermediates,
promises to be a powerful tool with potential for exploitation
in many areas. The simple route to 1 employed here demon-
strates again the practicality of utilizing these strategies in the
laboratory.
Acknowledgment. This work was supported in part by the EPSRC
IPS managed program (GR/J88579).
Supporting Information Available: Experimental details (5 pages).
See any current masthead page for ordering and Internet access
instructions.
Comparison of the 1H NMR spectra of the thread and rotaxane
in CDCl3 (Supporting Information) shows that in this solvent
the macrocycle is hydrogen bonded to the central unit of the
thread (one such hydrogen-bonding network is shown in Scheme
1).9,10 The involvement of five or all six amide groups of the
rotaxane in intramolecular hydrogen bonds is doubtless respon-
sible for the high solubility (100 g L-1) of 4 in chloroform
compared to that of its component macrocycle (<1 mg L-1).
The use of rotaxanation to enhance the solubility of benzylic
amide macrocycles in nonpolar solvents compares favorably to
JA962046R
(11) Johnston, A. G.; Leigh, D. A.; Nezhat, L.; Smart, J. P.; Deegan, M.
D. Angew. Chem., Int. Ed. Engl. 1995, 34, 1212-1216. The (n + n) notation
indicates the number of reactant molecules used to form each interlocked
component of the product.
(12) The convergent amide hydrogen bonding groups at either end of 1
are not required to be orthogonal to each other to bind to the lone pairs of
the CO2 oxygen atoms, as one might assume by analogy to the orientation
of CdCdC allene substituents. The D∞h symmetry of CO2 confers a
symmetrical electron density around the OdCdO axis.
(13) The gas sensing system used was similar to that described by Lu et
al. [Lu, C.-J.; Shih, J. S. Anal. Chim. Acta 1995, 306, 129-137].
Chloroform-soluble analogues of 1, such as 5 and 6, bind weakly and
reversibly to CO2 in nonpolar solvents as well as thin films.
(9) Low-temperature 1H NMR spectra of 4 in CDCl3 show that
pirouetting of the macrocycle occurs more quickly (890 s-1 at 298 K) than
shuttling of the macrocycle along the thread (560 s-1 at 298 K) reflecting
an increased degree of molecular rearrangement that must happen in order
for shuttling to occur.
(10) Solvent-dependent translational isomerism has been observed in (a)
amphiphilic benzylic amide catenanes [Leigh, D. A.; Moody, K.; Smart, J.
P.; Watson, K. J.; Slawin, A. M. Z. Angew. Chem., Int. Ed. Engl. 1996, 35,
306-310] and (b) some of the Stoddart catenanes [Ashton, P. R.; Blower,
M.; Philp, D.; Spencer, N.; Stoddart, J. F.; Tolley, M. S.; Ballardini, R.;
Ciano, M.; Balzani, V.; Gandolfi, M. T.; Prodi, L.; McLean, C. H. New J.
Chem. 1993, 17, 689-695].
(14) This does not prove that the mode of CO2 binding is primarily within
the cavity of 1, however, since “nondesigned” exocyclic binding which is
not normally a significant process in solution can play an important role in
gas-solid interface host-guest systems [Grate, J. W.; Patrash, S. J.;
Abraham, M. H.; Du, C. M. Anal. Chem. 1996, 68, 913-917].
(15) Gibson, H. W.; Liu, S.; Lecavalier, P.; Wu, C.; Shen, Y. X. J. Am.
Chem. Soc. 1995, 117, 852-874 and references therein.