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Cyclodextrins Off-the-Shelf Components for the Construction of Mechanically Interlocked Molecular Systems.

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Cyclodextrins, Off-the-shelf Components
for the Construction of Mechanically
Interlocked Molecular Systems
By X Fraser Stoddart*
If any one theme is beginning to dominate the development of synthetic chemistry these days, it must surely be
self-assembly.['] The spread of this concept, though somewhat belated, into all branches of chemistry is mainly due to
the rapidly accelerating growth and acceptance of supramolecular chemistry.['] Long before chemists were thinking
and practicing their own brands of chemistry beyond the
molecule with wholly synthetic systems, nature had been
extolling the virtues of molecular recognition in the production of sophisticated molecular and supramolecular arrays
with linked form and function.
If one class of compound has provided the bridge between
the worlds of natural und unnatural hosts, it has been the
cyclodextrins-or CDs as insiders call them. Yet, even as
they enter their second
of cultivation by chemists,
they continue to fascinate the chemical community.[3b1The
reasons are quite simple: They are aesthetic molecules, and
they lend themselves to novel experiments. The recent reportsL4-71 from four research laboratories in four different
countries of the self-assembly of CDs into [2]rotaxanes and
polyrotaxanes (Fig. 1) serve to remind us all that there is still
a lot of innovation to be forged in and around CDs in the
coming one-hundred years.
stoppers, solid Na,[Fe(CN),NH,]
an aqueous reaction mixture. Indeed, the
[2]rotaxane is formed even when a-CD is added to the dumbbell-shaped component,
[(NC),Fe{bpy(CH,),bpy}Fe(CN),I4-. This infers a slow dissociation of one of the
[Fe(CN),I3- stoppers, formation of a semirotaxane,
[{bpy(CH,),bpy . a-CD}Fe(CN),]-, and its subsequent
rapid recomplexation by [Fe(CN),(0H,)l3- to give the
[2]rotaxane. Evidence for the formation of a [2]rotaxane is
provided by the 'H NMR spectra, in which the signals of the
symmetry-related protons of the [bpy(CHJnbpyI2+unit are
split by the end-to-end asymmetry of the trapped a-CD ring.
It is very likely that a family of such [2]rotaxanes will now
emerge, since the 4,4'-bipyridine thread can be replaced by
pyrazine and other stoppers such as [M(CN),]"- and
[M(NHJ5Im+ ions with redox-active d6 metal (M) centers
like Co, Ru, Os, and Fe are con~eivab1e.l'~~
a - CD
(n= 6)
p-CD ( n = 7)
Fig. 1. Schematic representation of a-cyclodextrin (cr-CD) and 8-cyclodextrin
(P-CD) (top), a [2]rotaxane (bottom left), and a polyrotaxane (bottom right).
The self-assembly of the [2]rotaxane-metal complexes
with a-CD, described by Wylie and MacartneyL4I from
Queen's University, Kingston, Ontario (Canada), happens
(Scheme 1) irrespective of the order of the addition of the
components-the a-cyclodextrin, the 1,l"-(a,o-alkanediy1)bis(4,4'-bipyridinium) bromide, and the precursor for the
[*] Prof. J. E Stoddart
School of Chemistry, The University of Birmingham
Edgbaston, Birmingham B15 2TT (UK)
VCH Verlagsgesellscl?ufl m h H , W-6940 Weinheim. 1992
Scheme 1. The [2]rotaxane-metal complex of Wylie and Macartney [4]
The self-assembly of the asymmetric zwitterionic
[2]rotaxanes incorporating a-cyclodextrin announced towards the end of last year by lsnin and Kaifer['I from the
University of Miami in Florida (USA), demonstrates a
beautifully simple and logical step-by-step approach to what
are really quite complicated compounds (Scheme 2). Because alkyldimethyl(ferrocenylmethy1)ammonium cations
are known to interact with a-CD and p-CD through their
alkyl groups and ferrocene subunits, respectively, the alkyl
chain was terminated with carboxyl groups: 1, n =7; 2,
n = 11. Although their binding to a-CD is now pH dependent (for 1 . a-CD K, = 425 M-' at pH 2.6; K, =71 M - * at
pH KO), both are bound in water. The subsequent capping of
the carboxyl groups is achieved with potassium 5-amino-2naphthalenesulphonate with the water-soluble catalyst 1-[3(dimethylamino)propy1]-3-ethylcarbodiimidehydrochloride
(EDC) to promote amide bond formation. In both cases, the
isomeric zwitterionic [2]rotaxanes 3a, b and 4a, b can be
isolated from the reaction mixtures in 15% yield. The iso-
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Angew. Chem. hi.Ed. Engl. 1992, 31, No. 7
Scheme 2 . The zwitterionic [2]rotaxanes of lsnin and Kaifer [5]
mers have since been separated,[*] and the relative orientations of the x-CD ring on the asymmetric dumbbell-shaped
component have been established: One isomer is stable but
the other one unthreads slowly! Again, the authors recognize
the generality of their self-assembly procedure and anticipate
the production of "a diversity of rotaxane structures having
threaded cyclodextrins."
The isomer phenomenon literally takes on a further dimension in polyrotaxanes, for which the view is growing[']
that CDs might thread under conditions of equilibrium control with alternating orientations, wherein adjacent rings are
matched head-to-head, tail-to-tail in order to optimize hydrogen bonding between the neighboring CD units.
In the knowledge[g1that chains of poly(ethyleneglyco1)
(PEG) thread or-CD beads like a necklace, Harada, Li, and
Kamachi[61at Osaka University in Japan have now succeeded in capping the chain ends of a poly(ethy1eneglycol)diamine (PEG-DA; M , 3450) with dinitrophenyl stoppers. The reaction was carried out in a solution of the
PEG-BA in dimethylformamide (DMF) saturated with aCD and laced with a gross excess (46mol equiv) of 2,4dinitrofluorobenzene. After an extensive purification procedure, full characterization of the product, which was
obtained in high yield (60 %), indicated average molecular
weights of 23200 (by 'H NMR) and 26400 (by UV) commensurate with the respective threading of 20 and 23 a-CD
rings per polyrotaxane molecule (Fig. 2). This type of molecular structure conjures up the image of a molecular abaC U S [ ' ~ ] in terms of both structure and dynamics.
Fig. 2 . Schematic representation of the polyrotaxane [6] constructed by
Harada et al. by the threading of a poly(ethyleneg1ycol)diamine (PEG-DA)
chain with r-cyclodextrin "beads" and coupling with dinitrophenyl (DNP)
Quite independently, Wenz and Keller,['] working at the
Max-Planck-Institut fur Polymerforschung in Mainz (Germany), have demonstrated the threading of CD molecules
onto two polymer chains (Scheme 3): poly(iminoundecamethylene) 5a with a P,,= 43 & 5 and poly(iminotrimethy1eneiminodecamethylene) 5b with a Pn= 23 & 2. Both 'H NMR
spectroscopy and viscosity measurements revealed that,
whereas a-CD threads onto 5a within a couple of hours, it
takes over a week for 5b to receive its full complement of
a-CD rings in aqueous solution. Although equilibrium dialysis of 5 a . (a-CD), into its separate components was over
within 15 hours, dissociation of 5b . (a-CD), was far from
complete after two weeks. When 5b . (or-CD), was treated
with nicotinoyl chloride to introduce at least two hydrophilic
Angekr. Chwi. Ini. Ed. Engl. 1992. 31. No. 7
63 VCH
nicotinoyl blocking groups at arbitrary positions along the
poly(iminoo1igomethylene) chain, a polyrotaxane of M,
55 000 _+ 5000 (determined by laser light scattering) was isolated with an average of 37 a-CD rings permanently threaded
on to the chain.
50 k=l=ll
5b k=10. 1=3
Scheme 3. The [2]rotaxanes and the polyrotaxane of Wen2 and Keller [7].
These exciting developments surrounding the CDs*"]
have been going on against a background of activity in other
laboratories on wholly synthetic rotaxanes['2- 15] and polyrotaxanes.['61 Self-assembly is the unifying concept in the
construction of all these mechanically interlocked molecular
systems. As we begin to comprehend the rules of the game
for different systems in a range of media, our fundamental
understanding of molecular recognition benefits by leaps
and bounds. Applications will begin to surface on a somewhat longer time-scale. Suffice it to say at present that there
are high hopes for the advent of new materials with both
novel forms and functions.
German version: Angew. Chem. 1992, fU4, 860
[I] D. Philp, J. F. Stoddart, Synlett, 1991,445.
(21 J.-M. Lehn, Angew. Chem. 1988, 100, 9 1 ; Angew. Chem. I n i . Ed. Engl.
1988,27, 89; &id. 1990, 102. 1347 and 1990.29, 1304.
[3] a) J. E Stoddart, Carhohydr. Res. 1989, 192, xii; b) W. Saenger. Angew.
Chem. 1980, 92,343; Angew. Chem. Int. Ed. Engl. 1980, 19, 344.
[4] R. S. Wylie, D. H. Macartney. J. Am. Chem. SOC.1992, f f 4 ,3136.
[5] R. Isnin, A. E. Kaifer, J. Am. Chem. Soc. 1991. 113, 8188.
[6] A. Harada, J. Li, M. Kamachi, Nature 1992, 356, 325.
[7] G. Wenz, B. Keller, Angew. Chem. 1992, 104,201; Angew. Chem. Ini. Ed.
Engl. 1992, 31, 197.
[a] See the comments in an article by R. Dagam, Chem. Eng. News, 1992. 70
(15) 39.
Verlags~esellsrhafimbH, W-6Y4U Weinheim, 1992
0570-0X33192/07U7-073 3 . 5 0 i ,2510
191 A. Harada, M. Kamachi, J. Chem. Soc. Chem. Comnzun. 1990. 1322; see
also Macromolecules 1990, 23, 2821.
[lo] M. V. Reddington, A. M. Z. Slawin, N. Spencer, J. F. Stoddart, C. Vicent,
D. J. Williams, .
Chem. Soc. Chem. Comrnun. 1991,630.
[l 11 For examples of comb-shaped rotaxane polymers containing noncovalently bound CDs in the side chains, see M. Born, H. Ritter, Makromol. Chem.
Rapid Commun. 1991, 121, 471.
[12] J. F. Stoddart in Host-Guest Molecular Inleraclions-From Chemistry to
Biology (Cihu Found. Symp. No. IS), Wiley, Chichester. 1991, p. 5 .
1131 P. L. Anelli, N. Spencer, J. F. Stoddart, J. Am. Chem. Soc. 1991, 113,
1141 P. R. Ashton, M. Grognuz, A. M.Z. Slawin, J. F. Stoddart, D. J. Williams,
Tetrahedron Lett. 1991, 32, 6235.
[1S] P. L. Anelli, P. R. Ashton, R. Ballardini, V. Balzani, M. Delgado, M. T.
Gandolfi, T. T. Goodnow, A. E. Kaifer, D. Philp, M. Pietraszkiewicz, L.
Prodi, M. V. Reddington, A. M.Z. Slawin, N. Spencer, J. E Stoddart, C.
Vicent, D. J. Williams, J. h i . Chem. Soc. 1992, 114, 193.
[16] Y. X. Shen, H. W Gibson, Macromolecules, 1992, 25, 2058.
[17] After completion ofthis article a lipophilic [2]rotaxane was described (that
reported by Wylie and Macdrtney is hydrophriic);G. Wenz, E . van der Bey,
L. Schmidt, Angew Chem. 1992, 104. 758; Angew. Chem. Int. Ed. Engl.
1992, 31, 783.
Protein Engineering: Modified Hemoglobin as a Blood Substitute
By Tirnm-H. Jessen and Rolf' Hilgenfeld*
A few years ago, the use of gene technology for modifying
and redesigning proteins in order to improve their properties
("protein engineering""]), enjoyed generous support by national and international programs. This enthusiasm appears
to be gradually waning-today's buzzwords are different
ones, such as glycobiology and nanotechnology. And indeed, it seems that some protagonists in the field of protein
engineering promised more than they have been able to deliver, at least in the short term. The design of enzymes tailored to fit the requirements for the catalysis of organic reactions with the desirable high stereoselectivity has up to now
only been successful in exceptional cases. This is not surprising since our understanding of the relationship between the
structure of proteins and their function is still rather limited.
While the rapid and spectacular successes, with the exception
of a few washing powder proteases, were to a large extent not
achieved, protein engineering has now entered a phase of
consolidation, during which realistic questions can be treated in a sound scientific manner-and not surprisingly, the
fruits of the work are slowly beginning to ripen. This is
particularly evident for proteins that are employed as therapeutics, where properties can be adjusted by genetic modification to meet the requirements more effectively. Thus the
period of time after injection before human insulin takes
effect can be significantly shortened by the specific exchange
of certain amino acid residues.['' Other modifications of the
hormone lead to a prolonged activity, thereby reducing the
number of injections necessary per dayc3].This, of course,
should make life easier for diabetics.
For the rational design of such amino acid exchanges, a
precise knowledge of the three-dimensional structure of the
protein is necessary. This can be achieved in some cases (for
small proteins) by NMR techniques, and in general, by
protein crystallography. Thus, the X-ray structure analysis
of hemoglobin determined by M. Perutz et al. (MRC, Cambridge)[4iformed the basis for the modification of this blood
protein by genetic engineering as reported recently in Nature
by K. Nagai et al. (MRC), together with reseachers from
[*] Dr. R. Hilgenfeld, Dr. T.-H. Jessen
Hoechst Aktiengesellschaft
Postfach 800320
D-W-6230 Frankfurt 80 (FRG)
0 VCH Verlagsgesellschafi mbH, W-6940 Weinheim, 1992
Somatogen (Boulder, Colorado).[51 With this modified
hemoglobin an effective, and at the same time safe, blood
substitute seems at last to be within reach after decades of
intensive research.
Hemoglobin is crucial for the transport of oxygen in the
body. Enclosed in the red blood cells, the protein is supplied
with oxygen in the lungs, and delivers it to the respiratory
cycle in the capillaries of the tissue. Hemoglobin consists of
2 a and 2 /Ipolypeptide chains (a2/& tetramer), each including a protoporphyrin IX (the heme) with a Fe2+ ion. Local
variations in the partial pressure of the gas, allosteric effectors, as well as the cooperativity of the tetramer modulate the
oxygen affinity of the hemoglobin in an ideal way.[6]Since
hemoglobin is a vital constituent of the blood, its application
as a blood substitute seemed logical. There has always been
a need for such a substitute in the face of problems associated with blood transfusions (availability, matching of blood
groups, and storage stability); however, in recent years this
need has become urgent as a result of the emergence of
pathogenic viruses.[']
Since, however, the use of hemoglobin as a blood substitute is not free o f problems, other completely different approaches have also been considered. Synthetic oxygen carriers have been developed from perfluorohydrocarbons, which
when applied as an emulsion can bind oxygen in quantities
proportional to its partial pressure. The low viscosity of the
emulsions, as well as the potential to utilize them in cases in
which religion prohibits blood transfusions, increased the
attractiveness of this approach.[8' At present perfluorooctylbromide is undergoing clinical trials and shows fewer of
the potential problems of this class of substitutes-low oxygen capacity, immunogenicity, hepatotoxicity, and insuffcient storage stability.[g]
The majority of the research approaches, however, are
based on the hemoglobin molecule itself. Already in 1916 an
intravenous infusion of a hemoglobin solution was carried
out on humans.[''] Hemoglobin can be obtained from erythrocytes whose expiry date has already passed. During the
purification process the complete removal of the cell membrane (stroma) must be carried out very carefully because it
can induce a strong immune reaction." Even hemoglobin
itself shows this immunogenic behavior if it is present in
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Angew. Chem. Int. Ed. Engl. 1992, 31, No. 7
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molecular, components, construction, shell, system, interlocked, cyclodextrin, mechanically
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