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Cyclodextrins as Building Blocks for Supramolecular Structures and Functional Units.

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Cyclodextrins as Building Blocks for Supramolecular Structures
and Functional Units
Gerhard Wenz*
Cyclodextrins are frequently used as
building blocks, because they can be
linked both covalently and noncovalently
with specificity. Thus one, two, three,
seven, fourteen, eighteen, o r twenty substituents have been linked to one b-cyclodextrin molecule in a regioselective
manner. Furthermore, cyclodextrins may
serve as organic host molecules. Their
internal cavity is able to accommodate
one or two guest molecules. Conversely,
particular properties of cyclodextrins can
also be employed, for example, for the
chromatographic separation of complex
mixtures of substances, even racemates.
by molecular recognition. Cyclodextrins
and their derivatives have been found to
be remarkably active catalysts as well.
Finally, since cyclodextrins can favorably influence the release of drugs, many
new applications will certainly be developed in the near future.
suitable guest molecules can be used to
thread one, two, or many (one hundred
o r more) cyclodextrin rings. The resulting supramolecular structures are often
formed in solution, which allows characterization by high-resolution spectroscopic methods. Chemical conversion of
these structures provides molecular architectures such as catenanes, rotaxanes,
polyrotaxanes, and tubes, which are not
readily prepared by other methods. The
1. Introduction
Cyclic oligomers of amylose are referred to as cyclooligoamyloses, cyclomaltooligosaccharides, or cyclodextrins (a-, fl-, y-,
and 6-cyclodextrin 1 a, 1 b, 1 c, and 1 d, respectively; Scheme 1).
Since their discovery by Villiers[l’ in 1891, interest in these cyclic
carbohydrates has increased steadily. Why?
Cyclodextrins are of interest for synthetic chemists because
they are chemically stable and can be modified in a regioselective
manner. Cyclodextrins are of great importance for supramolecular chemistry, since they form a homologous series of
water-soluble and chiral host molecules which can be used as
models for studying weak interactions. In addition, their low
price provides motivation for the discovery of new applications. Thus cyclodextrins are used for the solubilization and
encapsulation of drugs, perfumes, and flavorings. Their toxicity
is low. and they are biodegradable. Finally, they are of
interest because they are obtained from a renewable resource,
The last review on cyclodextrins in Angewandte Chemie was
written by Wolfram Saenger in 1979 and entitled “Cyclodextrin
Inclusion Compounds in Research and Industry”.[3] Since then
many (about 7000[41)publications have appeared in this field,
some of them very exciting, and it appears worthwhile to survey
this field once more.[51
la n=6
lb n=7
l c n=8
I d n=9
Scheme 1. Structure of the cyclodextrins. Projections a) 90”, h) 45’.and c) 0 to the
C, axis.
2. Synthesis, Structure, and Physical Properties
of the Cyclodextrins
The enzymatic degradation of starch affords a.mixture of cyclic
and linear maltooligosaccharides. The enzymes used are cyclodextrin glucosyl transferases (CGTases) of bacterial origin, for
example from Bacillus macerans and alcaliphilic bacilli.[61They
Prof. Dr. G. Wenz
Polymer-lnstitut der Universitit
Hertrstrasse 16. D-76187 Karlsruhe (FRG)
Telefax- Int. code + (721)608-4421
Angrit,. Clitw. l n t . Ed. Enxi. 1994. 33. 803-822
VCH Vuriu~sgc.sellscha/imbH, D-69451 Weinheirn, 19Y4
0570-0833!94.’0808-0803$ 10.00f .25:0
G. Wen7
are in general unspecific with respect to ring size.[71The isolation
of a particular cyclodextrin is carried out by the addition of selective precipitating agents.[61Since the various cyclodextrins are
interconverted by CGTases, the final product is the one that is
continuously removed from the reaction mixture by selective
precipitation. Thus cyclodextrins can be obtained in remarkable
yields and high homologous purity (ca. 99 %) (Table 1) .I7,OwWble l . Synrhesis of cyclodextrins by enzyinatic degradation of starch
Precipitating agent
1 -decanol
50- 60
40- SO
[8 bl
18 a1
ing to the biological origin of cyclodextrins, only dextrorotatory
enantiomers are formed. The levorotatory enantiomers could
only be obtained by synthetic procedures, but a t present a n
economical total synthesis does not appear feasible. D-1 a and
D-1 c have been obtained from D-makOSe in multistep procedures
with overall yields of < 0.3 %.rgl
Crystalline cyclodextrins bind 6-13 wt % water, depending on
ring size. The structures of l a ~ 6 H , 0 , 1 1 ' 1 la.7.57H20,["]
1 b.12H,0,['21 lc.13.3H,0,['31 and ld.13.75H,0['41 have
been determined by X-ray and neutron diffraction. These structures show that a cyclodextrin molecule resembles a hollow truncated cone (torus) and has approximate C,, symmetry (Scheme 2).
increases with the number of glucose units (1 a: 4.9 A, 1 b : 6.2 A.
l c : 7.9 A). while the height remains constant at 7.9
1 5 ] All
the glucopyranoside building blocks are relatively rigid and exist
in a 4C, chair conformation. The secondary hydroxyl groups
OH(2) and OH(3) are in equatorial positions; OH(2) groups
point in towards the cavity and OH(3) groups point outwards.
Since the torus bears twice as many hydroxyl groups on one side
as on the other, the dipole moment is relatively large (calculated:
10-15 D,["] found: ca. 5 D["]) and directed along the C, axis.
Cyclodextrins are poorly to moderately soluble in water,['81
methanol, and ethanol, and readily soluble in strongly polar
aprotic solvents like dimethyl sulfoxide (DMSO), dimethylformamide (DMF), N,N-dimethylacetamide, and pyridine["] and
mixtures of these.["] The shape of cyclodextrin molecules can be
approximated by means of molecular dynamics simulations.["]
Although the torus is stabilized by intramolecular hydrogen
bonds, it is still flexible enough to permit considerable deviations from regular toroidal shape.["] However, the time-averaged structure has C, symmetry, such that, for example, all the
glucose building blocks are equivalent by 'H and I3CNMR
Complete rotation of a glucose unit about the
C(I)-O-C(4') bonds is not possible for steric reasons. Thus protons H(3) and H(5) are always situated within the torus, whereas
protons H(1). H(2), and H(4) always point outwards.
3. Synthesis of Cyclodextrin Derivatives
Cyclodextrins are derivatized in order to vary their solubility
behavior, to modify their complexation properties, and to introduce groups with certain specific (e.g. catalytic) functions.
Scheme 2 . Schematic representation of the shape of a cyclodextrin molecule Two
halves of two opposite glucose units are shown in cross section.
The primary hydroxyl groups are located on the narrower side
of the torus and the secondary hydroxyl groups on the broader
side. Because of the conical shape of the cyclodextrins and
deviations from ideal C,, symmetry, their dimensions can be
obtained only to within roughly f0.3 A. The internal diameter
3.1. Survey of Possible Reactions
Since cyclodextrins are polyfunctional, they can undergo a
wide variety of reactions;[23]these may involve cleavage of either 0 - H , C - 0 , C-H, or C-C bonds.
The reaction type most frequently studied is electrophilic attack
at the O H groups. Reactions of 1 with alkyl halides,[241epoxacyl derivatives,[z4a, isocyanates,[26b1and inorganic
acid derivatives such as sulfonic acid
acid chlorides,['*] phosphonic acid chlorides,[291silyl chloride~,[~']
and nitric acid[311lead to cyclodextrin ethers and esters.
Gerhard Wen-. ~vasborn in 1953 in Muinz, Germany, andstudied chemistry from 1972 to 1979
at the Universities of M a i m and Freiburg. He received his Ph.D. in 1984for research with G.
Wegner in Freiburg on the polymerization of diacetylenes. He then spent a year as a reseach
assistant at the Hermann-Staudinger-Institut,
Freihurg, and studied discotic polymeric liquid
crystals. During a subsequent one-year postdoctoral stay with D. J. Cram at the University qf
CaliJbrnia, Los Angeles, he worked on the synthesis o f a chymotrypsin model. In 1986 he moved
to the Mux-Planck-Institutf'ur Polynrerforschung in Main-.. In f 993 he completed his habilitation in organic chemistry at the University of Mainz and accepted a position as Projessor of
Macromolecular Chemistry at the University of Karlsruhe. His research focuses on the
supramolecular chemistry of polymers and carhohydrates.
A n g r h Cheni Int Ed Engl 1994. 33, 803-822
The nucleophilic cleavage of a C-OH bond requires activation of the oxygen atom by an electron-withdrawing group. Thus
the reactions of cyclodextrin-6-0-sulfonates with nucleophiles
such as azide ions,[321halide ions,[331t h i ~ l s , ~ thiourea,[34b1
and a m i n e ~ generally
~ ~ ~ ] afford the corresponding 6-deoxy
derivatives.["] 6-Azido-6-deoxycyclodextrins can be reduced to
the preparatively important 6-amino-6-deoxycyclodextrins.~3 71
The attack of imidazole on a fi-cyclodextrin-2-0-sulfonate affords the 2-( 1 -imidazolyl)-deo~y-fi-cyclodextrin.[~~~
This substitution occurs with retention, presumably due to the neighboring
group effect of OH(3). In contrast, the attack of aqueous bases
on cyclodextrin-2-0-sulfonates leads to an intramolecular nucleophilic substitution by OH(3) to give 2.3-anhydrocyclodextrins with niunno configuration (Scheme 3a) .[27b. 391 In analogy.
5 3
possible. The number of
possible positions for a substituent is given by the number of possible positions at a
glucose unit (three: 2, 3, and
6) multiplied by the number
Scheme 4. Labeling of the positions in
of different glucose units A,
the cyclodextrin molecule.
B, c,, , in the cyclodextrin
(Scheme 4). The number of
combinations increases rapidly with each further substituent.
The number of possible positional isomers, Ni, is shown as a
function of the number of substituents, N s , in Figure 1. In the
case of I h, N , reaches a maximum (50 388) for the substitution
the intramolecular substitution of sulfonate groups in position
3 by OH(2) leads to 2,3-anhydrocyclodextrins with d o configuration (Scheme 3b) .[39c,401
The intramolecular nucleophilic attack of OH(3) on 6 - 0 - ~ u l f o n a t e s [ ~and
' ~ 6 - d e o ~ y i o d i d e s [leads
to the relatively stable 3,6-anhydrocyclodextrins (Scheme 3c).
Nucleophilic attack on 2,3-manno-anhydrocyclodextrinsopens
the epoxide ring with formation of an allose unit substituted in
the 3 - p 0 s i t i o n . [ ~ ~ ]
Electrophilic attack at a C-0-C bond leads to decomposition of
the cyclodextrin molecule. Cyclodextrins are, however, remarkably stable towards aqueous acids; for example, the half-life of
1 h in 1.I 5 M HCI at 80 ' C is 1.6 h.[""] On the other hand, electrophilic attack by Lewis acids under aprotic conditions in the presence of a reducing agent (e.g. BF, Et,O/triethylsilane or trimethylsilyl triflatejtriethylsilane) affords smooth cleavage of the C(1)0-C(4) bonds without affecting the glucose units and their substituents. This method is therefore used for the analytical determination of the distribution of substituents in cyclodextrin derivat i v e ~ . ' Alternatively,
the C(1)-O(5) bonds can be cleaved selectively by 9-borabicyclo[3.3.1]nonyltrifluoromethanesulfonate/ethyldib~rane.["~I
The H atoms are exchanged o n Raney nickel for deuterium
atoms (preferably in the 2-position) .[471 Treatment with N,O,
or PtiO, causes oxidation of CH,(6) to a carboxylic acid
All C(2)-C(3) bonds of 1 b are cleaved upon oxidation with
periodate, which leads to the formation of a derivative of
3.2. The Problem of Positional Isomerism
Many of the cyclodextrin derivatives described in the literat ~ r e [ ~are
~ "complex
mixtures of compounds, since a large number of positional isomers within the cyclodextrin framework are
Aizgru. CIiiwi. fnr. Ed. Enx/. 1994, 33, 803-822
Scheme 3 a ) 2.?-iwunno-, b) 2.3-u//o-, c) 3.6-anhydrocyclodextrins
of half of the hydroxyl groups.[24a1Thus the probability of synthesizing and isolating a uniform product decreases with the
increasing number of isomers. A further difficulty is that homologous derivatives with a lower or higher degree of substitution are also formed in addition to the product, and separation
is required. Thus the synthesis of uniform cyclodextrin derivatives is a daunting task. Only since the advent of powerful
such as gas chromatography (after
degradation) ,[451high-pressure liquid chromatography,[501mass
s p e ~ t r o m e t r y'I, ~and
~ high-resolution 3C N M R spectroscopy
has it become possible to obtain unequivocal proof of the uniformity of a reaction product. By using these methods several
reaction products that had long been considered to be uniform
were shown to be m i x t ~ r e s . 512 ,~5 3~1 ~
3.3. General Strategies for Regioselective Substitution
The synthesis of uniform cyclodextrin derivatives requires
regioselective reagents. optimization of the reaction conditions,
and good separability of the products. Bulky reagents react
preferentially at the primary hydroxyl groups OH(6), since these
are the most accessible. The secondary hydroxyl groups OH(2)
have the highest acidity (pK, = 12.2).[22'.541 Under anhydrous
conditions they can be selectively deprotonated and allowed to
react with electrophilic reagents.[551The secondary hydroxyl
groups OH(3) are the least reactive and can be reacted selectively only after OH(2) and OH(6) have been blocked.["]
G. Wenz
The product distribution can be greatly influenced by the reaction conditions. Monosubstitution of a cyclodextrin is achieved
by using less than one equivalent of the reagent, and its slow
addition can also be advantage~us.[”~
The presence of a large
excess of the reagent must be avoided when the uniform monoor disubstitution of all glucose units in a cyclodextrin is required.
since otherwise the reaction may go too far. The optimum reaction time is determined by carefully monitoring the reaction progress, for example by thin-layer chromatography[581or highpressure liquid chromatography. These reaction times are often
not reproducible; this may be due to the undefined water content
of the reaction
The complete substitution of all hydroxyl groups requires drastic reaction conditions such as a large excess of the reagent,
increased reaction temperature. and complete exclusion of
Since mixtures of cyclodextrin derivatives are generally formed,
chromatographic separation is typically required. Homologous
derivatives can be separated only if the polarity of the substituent differs significantly from that of cyclodextrin. Thus the
separation of derivatives with hydrophobic substituents (e.g.
b ~ t y l , [ ~benzoyl,[s21
and tosyl[601)is easier than that of derivatives with less hydrophobic substituents (e.g. hydroxypropyl[25b1
Scheme 5. Specific introduction ofone, two, or three substituents to cyclodextrins.
a) TsCliPy [37,60], b) 3-nitrophenyltosy1ate/DMF/H2O (pH 10) [27a,62], c ) NsCI:
M e C N / H 2 0 (pH 12) [39c,40,69b], d) TritCi/Py [37,64b.70], e ) [67],f) and g) [66b],
Ts = 4-toluenesulfonyl.Ns = 2-naphthalenesulfony1, Trit = triphenylmethyl. Py =
5aL3’]and 5 b, respectively.[641Similarly, 1 b undergoes regioselective reaction with tert-butyldimethylsilyl chloride at low temperatures to give 6-0-tert-butyldimethylsilyl-~-~yclodextrin.~~~~
Disubstituled cyclodextrins are obtained most easily by bridging the cyclodextrin molecule with difunctional reagents. Thus
Tabushi et al. allowed 1 b to react with arenedisulfonic acid
chlorides; depending on the distance between the sulfonyl chloride groups, they obtained A,B-, A,C-, and A,D-disubstituted
3.4. Mono-, Di-, and Trisubstituted Cyclodextrins
cyclodextrin sulfonates 6,7, and 8, respectively, with yields of up
to 40 %.[661 Such derivatives are referred to as capped cyclodexA cyclodextrin bearing one, two, or three substituents gives
trins. The introduction of inethoxy groups on the aryl residue
extremely complex N M R spectra because of its low symmetry;
these can be assigned only by means of multidimensional methcan increase the stability of the disulfonates and thus facilitate
their purification.[671The reaction of cyclodextrins with monoods such as ‘H-‘H or ‘H-I3C
functional acid chlorides leads to mixtures of mono-, di-, and
The most important cyclodextrins with one activating subhigher substituted cyclodextrins, which can be separated by
stituent (Scheme 5 ) are the cyclodextrin tosylates. The reaction
preparative reversed-phase chromatography. Depending on the
of 1 a, b with tosyl chloride in pyridine affords the 6-0-tosylates
reaction conditions, the substituents can be directed to positions
2 a and 2 b in 10-30% yield.[37,601
(The ring sizes 6, 7, and 8 are
and 0(3).[40b1
denoted throughout the text by a, b, and c, respectively.) In
The synthesis and isolation of trisuhstituted cyclodextrins is
contrast, esterification with 3-nitrophenyltosylate in DMF/water at pH 10 leads to the 2-0-tosylates 3 a and 3b.[27d,3yb,621 very difficult because of the large number of positional isomers
and homologues possible. Tosylation of I b leads to 6A,6C,6E-triWhen I a, b is treated with tosyl chloride in aqueous NaOH,[””]
0-tosyl-8-cyclodextrin in only 2.6 O/O yield.[691In contrast, tri3a and 2b[351are
Topochemical reaction control
tylation of l a gives the 6A,6C,6E-tritylderivative 9 in a remight be the case here. In other words, the reagent might be
spectable yield of 23
A remarkable alternative method
included in the cyclodextrin, and esterification would then occur
should also be mentioned here: Cottaz and Driguez obtained
preferentially within the inclusion compound. Therefore the
in 43 % yield from enzyorientation of the reagent in the cyclodextrin ring determines the
matic cyclotrimerization of 6-0-rnethylrnalto~e.[~~~
position to be attacked. The reaction of dibutyltin oxide with 1
gives cyclic 2,3-0-stannates, which can be converted selectively
(30 YOyield) with tosyl chloride into the 2-0-tosylates 3.[631The
3.5. Cyclodextrins with Uniform Mono-, Di-, and
selective deprotonation of OH(2) in 1 b with NaH and subseTrisubstituted Glucose Units
quent reaction with tosyl chloride also leads to 3 b.IS5]The 3-POsition of 1 can be activated by 2-naphthalenesulfonyl chloride in
Since C, symmetry is preserved if all the glucose units in cyacetonitrile/water at pH 12 to furnish 3-0-(2-naphthalenesuIclodextrin are substituted in the same way, these derivatives
fonates) 4a.L40”14 b,[40h1and 4c.[39”1
generally crystallize more easily and show simpler NMR spectra
The etherification of 1 a, b with the sterically demanding trityl
than the unsymmetrical derivatives.
chloride leads to the singly blocked 6-0-tritylcyclodextrins
In the following sections we shall discuss methods for regioselective derivatization, classified according to the degree of substitution; we shall also distinguish between activating and
blocking substituents.
Angehi. Chem In[. Ed Engl. 1994, 33, 803-822
Complete tosylation of all primary hydroxyl groups is difficult;
because of the increasing bulk of the cyclodextrin upon substitution, the first secondary hydroxyl groups may be attacked before
the last primary hydroxyl groups have completed r e a ~ t i o n . [ ~ ”
Reactions that proceed via an intermediate with bulky substituents but lead to a final product with only small substituents
are more favorable. Thus 1 a and 1 b were converted by triphenylphosphaneibromine (or iodine) into the per(6-deoxy-6-halo)cyclodextrins 10a and IOb in 80 and 88% yield, respectively
(Scheme 6) .[‘*I
Selective deprotonation of all the hydroxyl groups OH(2) of
1 b with NaH and etherification with methyl iodide affords heptakis(2-O-methyl)-fl-cyclodextrin1 I b,Issl Heptakis(2-0-tosyl)[hcyclodextrin 12 b was obtained in an analogous manner.[”]All
the hydroxyl groups in position 6 can be blocked by treatment
with tc~rt-butyldimethylsilylchloride (formation of 13).13’. 33,“I
20 R = M ~ ”
22 R=Bu
21 R=Pe \)
23 R=Pe
17 R=Me
18 R=Eu
19 R=Pe
The remaining hydroxyl groups can be either selectively benzylated[721or t o ~ y l a t e d [at
~ ~OH(2).
or completely a l k ~ l a t e d . [741~ ~ .
The 2-U-tosylates 12 and the 2,3-di-O-alkyIethers 14 are obtained after removal of the TBDMS groups.
Lehn et al. synthesized a cyclodextrin (15) blocked at all OH(2)
and OH(3) positions by saponification of the more reactive ester
groups at position 6 from per(2,3.6-tri-O-benzoyl)cyclodextrin.[24”’Methylation of the OH(6) hydroxyl groups with diazomethane and subsequent cleavage of the benzoyl groups furnishes the per(6-0-methyl)cyclodextrins 16.[24”1
Alkylation of all OH(2) and OH(6) groups is carried out by
treating 1 with alkyl halides or alkyl sulfates and a hydroxide.
Thus with dimethyl sulfate, Ba(OH);SH,O,
and BaO in
DMFiDMSO the per(2,6-di-O-methyl)cyclodextrins 17 are
formed;[24,7s1 with diethyl sulfate the analogous ethyl derivatives are ~ b t a i n e d . [ ~ ’The
. ~ ~introduction
of longer alkyl chains
in positions 2 and 6 is possible by treating 1 with primary alkyl
bromides and NaOH in DMSO (18, 19).1s81
Whereas both
methylation and ethylation yield mixtures of isomers and homologous substitution products which are difficult to separate,[50.s31 the longer chain per(2,6-di-O-alkyl) derivatives (in
particular per(2,6-di-O-butyl)cyclodextrins 18) can be obtained
readily in pure form. In contrast to 1 the latter are soluble in
most organic solvents. even in hexane, but are completely insoluble in water.Is8’
Per(2.6-di-0-a1kyl)cyclodextrins can be coinpletely alkylated
in a subsequent step with strict exclusion of water to give per(2.3,6-tri-U-alkyl)cyclodextrins(e.g. permethyl and perpentyl
derivatives 20 and 21).[
”I Benzyl groups serve as protecting groups for OH(2) and OH(6) in the synthesis of per(3-Omethyl)cycl~dextrins.[~~~
Acylation of per(2,6-di-O-alkyl)cyclodextrins leads to per(3-0-acyl-2,6-di-O-alkyl)cyclodextrins
as 22 and 23.[”. 7 8 1
3.6. Cyclodextrin-Containing Oligomers and Polymers
Reactions of monofunctional cyclodextrin derivatives (e.g.
2 a, b) with difunctional nucleophiles (a,w-diamines, x.o-disul-
Scheme 6 . Homogeneous, regioselective derivatization of all the glucose units of a
cyclodextrin. a ) PPh,.’X,iDMF with X = Br. I [42]. b) NaH;DMSO. Me1 [55]. c)
NaH/DMSO. Tssc‘l 1551, d) TBDMSCliPy [30,33,68], e) TsCI,’DMAP/Py [73], f)
NaH:RI/DMF iR = Me, Pe), Bu,NF [33,74], PheCOCl/Py, iPrOK/iPrOH [24a].
h ) CH2N,:CHC1,, KOHlEtOH [24a]. i) BaO;Ba(OH),.8H,O~R,SO,IDMSOi
DMF for R = Me [24a.78] Et [51b,76], Br [56], otherwise NaOH!RBr.’DMSO
(R = Pr. Bu. Pe. Dodec) [%I. j ) RBr or R1:NaHIDMF [24b.77] or THF 1591
(R = Me. Pe). k ) Ac,OIDMAP!Et,N/CH,CI, [78a,c,e] or R’COCI!Py ( R = Ph,
rBui [52,7Xbl. TBDMSCI = rerl-butyldimethylsilyl chloride, Ts = 4-toluenesulfonyl. Br = benzyl. Pr = propyl, Bu = hutyl, Pe = pentyl. Dodec = dodecyl.
Ph = plienyl. Py = pyridine. DMAP = 4-(dimethylamino)pyridine.
fides, r,w-dicarboxylic acids) lead to singly bridged cyclodextrin
Breslow et al. obtained the doubly bridged cyclodextrin dimer 24 from 6A,6B-diiodo-/~-cyclodextrinand a difunctional nucleophile. Dimer 24 exists in two stable conformations:
in the occlusive conformation the two rings are inclined towardseach other, in the aversive conformation they tilt away from
each other.I*’’
For the synthesis of linear cyclodextrin polymers, polyallylamine was treated with 2b to give 25;[”l the radical polymerization of vinyl-substituted cyclodextrins also provided linear cyclodextrin polymers.[821
3.7. Statistically Substituted Monomeric and Polymeric
Cyclodextrins for Technical Applications
There are many reasons for synthesizing uniform cyclodextrin derivatives. The procedures can be reproduced more
consistently, and the products often crystallize better and are
easier to identify than mixtures. However, statistical mixtures of substituted cyclodextrins also have advantages : they
can be prepared much more simply, and the reactions
can often be carried out in water rather than in expensive
inert solvents such as DMSO. Complicated chromatographic
separations are also unnecessary. In addition, statistically
substituted cyclodextrins are often much more soluble
than pure compounds because of their poorer tendency
Thus until now only statistically substituted derivatives have been used industrially (see Section 8) .rSc1
Hydroxypropylcyclodextrins are the statistically substituted
derivatives of greatest technical interest so far. They are obtained in large quantities by adding propylene oxide to 1 in
aqueous sodium hydroxide125d.8 3 1 and are readily soluble in
water. Depending on the reaction conditions, up to two hydroxyl
groups per glucose unit are etherifled. Pitha et al. studied the
product distribution as a function of the reaction conditions in
detail.” ’. *41The substitution pattern at the glucose unit is determined most easily by degradative analysis.l“’”~4sc1 The hydroxypropyl substituents can be directed to certain positions by regulating the P H . [ ” ~ ~
Methylation of cyclodextrins with dimethyl sulfate in aqueous
solution also leads to a statistical mixture of O-methylcyclodextrins with a degree of substitution of 1-2 per glucose unit.[*’]
Enzymatic linkage of maltose oligomers to 1 leads to mixtures
of branched cyclodextrins which, like the hydroxypropyl derivatives, are readily soluble in water.[’ 86i Depending on the reaction conditions, the reaction of difunctional reagents such as
diisocyanates,[8*1and dicarboxylic acid dichlorides[*91with 1 affords either soluble[87h,901 or insoluble[”1
branched products.
4. Supramolecular Structures Derived from
A supramolecular structure results from defined noncovalent interactions between several individual molecules.[921
Host -guest complexes[931 are important examples of
this type of structure. The host molecule offers the guest
molecule a suitable environment, generally a cavity. The driving force for complexation can arise from Coulombic, dipoledipole. van der Waals, solvatophobic, o r hydrogen bonding interactions between host and guest.[941The outer sphere
of the host should be compatible with the required solvent
in order to avoid aggregation or insolubility problems. In
the following sections we shall distinguish between cyclodextrin derivatives, which according to their solvent compatibility are “exohydrophilic”, “exolipophilic”. or “amphiphilic”
hosts. and describe some examples of supramolecular structures.
G. Wenz
4.1. Cyclodextrins as Exohydrophilic Hosts
Since the exterior of cyclodextrin molecules is hydrophilic, they
can form adducts with guest molecules in aqueous
These adducts can consist of one or more cyclodextrin or guest
molecules. If the guest is situated within the cavity (Scheme
7 a-f), these adducts are termed inclusion compounds according
Scheme 7 . Topology of cyclodextrin adducts with a) complete. b) axial, c) partial.
and d) sandwich-type inclusion; e) 1 : 2 and f ) 2 : 2 inclusion compounds; g) hdlike
associatiori compouiid.
to the nomenclature proposed by Cramer et al.[96iOn the other
hand, if the guest molecule lies outside the cavity. the compounds are referred to as ussociation compounds (Scheme 7 g) .
The packing of the cyclodextrin adducts is determined predominantly by the dimensions of the guest relative to those of
the cavity. The guest can be either completely o r partially surrounded by the host molecule. A long, thin guest can form an
axial inclusion compound, whereas a short thick guest forms a
sandwichlike structure.[971In general the stability of cyclodextrin inclusion compounds increases with the extent to which the
cavity is filled by the hydrophobic part of the guest.
In order to cover the plethora of results in the literature in as
brief a manner as possible, we shall first describe methods for
the preparation and characterization of the cyclodextrin adducts and then consider rules for packing behavior.
4.1 . I . Preparation of Cyclodextvin Adducts
Cyclodextrin adducts are usually prepared in water; the partners must only be minimally soluble. Other solvents such as
DMSO are less suitable than water, since the stability of the
adducts in these is much lower.[”*1Even the addition of small
amounts of short-chain alcohols to the aqueous solution lowers
the adduct stability
‘Ool The more hydrophilic
substituents on the guest or cyclodextrin molecule, the more
readily soluble the adducts are in water. Thus the adducts of
paraffins and 1 a are almost insoluble in water,[”. l o l l while
those of the short-chain alcohols,[’021acids,[’031 and a,w-diO I S [ ’ ~ ~are
] readily soluble. Cyclodextrins with hydrophilic substituents such as sulfopropyl-a-cyclodextrin” ”] o r hydroxypropylcyclodextrin[2sh1can solubilize even completely hydrophobic molecules such as paraffins or toluene. In heterogeneous
systems the rate of adduct formation is determined by the rate
of dissolution. In homogeneous solution most adducts form
very quickly, generally within micro- or milliseconds.[1o61
Angrti. Chm?. Int. Ed. EngI. 1994, 33, 803-822
4.1.2. Methods for Determining the Topology of the Adducts
Precise information on the topology of cyclodextrin adducts
can be obtained from X-ray structural analysis of single crystals
(Table 2 ) . [ ' O 7 ] Not only the position of the guest molecule with
respect to the cavity but also its mobility can be determined.
Neutron diffraction also provides information on the positions
and motion of the protons.
Table 2. Topology o f cyclodextrin adducts from X-ray structure analysis.
[Rh(cod)(NH,),]PF, [a]
[lo7 a]
[I07 b]
17 b
1 1
2-(3-phenoxyphenyl)propionicacid 1 : l
4-111t rophenol
[I?]crown-4. NaCl
1 -propano1
1 1 0 7 41
[I07 hl
[107m, n]
decrease with increasing K s . The physical properties that may be
used are listed in order of increasing sensitivity: solubility," l 7 1
vapor pressure,[10sb1chemical shifts of 'H and 13C NMR sign a l ~ , [ ~ "' I~a 1. , circular dichroism,[' 191 optical absorption,[1201
Common to
all these methods is their limited scope of application. A much
more general method, which is also more precise, is the determination of the heat of formation with the help of a micro~alorimeter.[''~~ The evaluation of the concentration dependence of the heat evolution affords not only the binding
constant but also the enthalpy and entropy changes associated
with the formation of the a d d ~ c t . [ " ~ .
The displacement of an included probe molecule by a guest
molecule can also be used for the determination of K,.['17b.1251
Probes used in the case of a-cyclodextrin include methyl orange
(detection by means of optical absorption)[117b1
and 3-nitrophenyl acetate (rate of solvolysis),
and for [j-cyclodextrin
25a1 methyl orange[1271
(optical absorption), naphthalene derivatives (fluorescence),r1281
and 3-nitrophenyl acetate (rate of s o l v o l y ~ i s ) . ~ ' ~ ~ ~
4.1.4. Methods for Studying the Kinetics of Adduct Formation
[a] cod
= 1.5-cyclooctadiene
The topology of cyclodextrin adducts can also be determined
in solution. The interactions between host and guest may lead to
characteristic shifts in the 'H and I3C NMR spectra that might
give information on the packing.['o81 Nuclear Overhauser effects provide more precise information,[1091
since their magnitudes are a measure of the distance between the protons of host
and guest. As the positions of almost all the protons in the
cyclodextrin molecule are well defined. the location of the guest
in the cyclodextrin can be determined.
The circular dichroism induced by the chiral cyclodextrin on
an achiral guest affords information on the topology of the
adducts, if the orientation of the transition dipole moment of the
guest is known.['08b. 'I Positive circular dichroism indicates
that the transition dipole moment in the cavity lies along the C,
axis (axial) .I1 I ' '1 Negative circular dichroism indicates that
the transition dipole moment is either within the cavity and perpendicular to the C, axis or external and parallel to the axis.'"']
The proximity of two chromophores included in one cyclodextrin molecule can favor the formation of ex~imers["~]
or exciplexes.[' l4I which can be detected by fluorescence spectroscopy." "]
4.1.3. Methods for Determining the Thermodynamic Stability
of the Adducts
The formation of the adducts is described by the law of mass
action. The equilibrium constant K s , also known as the stability
constant, is a measure of the thermodynamic stability of the
cyclodextrin adducts. Any physical property of the host or guest
that changes on formation of the adduct can in principle be used
for the determination of Ks.['
The choice of the method to be used depends on the expected
value of K,. The larger the K, value, the more sensitive the
method must be, since the concentrations of the free species
Information on the kinetics of adduct formation can be obtained by the temperature-jump[106d. 301 and stopped-ilowr'311
methods; the adduct yield is detected as the change in optical
absorption or conductivity. In addition, dynamic NMR spectroscopy affords at least qualitative information. Depending on
whether separate[1321or a ~ e r a g e d [ ' ~ ~ " ~
1 3 3 1 signals are observed, the adduct formation is either slow or fast on the NMR
4.1.5. The Inclusion of Monomeric Guest Molecules
Unbranched alkyl chains lit best into a-cyclodextrin 1 a. The
stability constant Ks increases rapidly with increasing chain length
k and reaches values of up to Ks = lo4 M - ' (Fig. 2). This indi-
4 B
8 'lb ' I >
Fig. 2. Stabilityconstants K , of the inclusion compounds of HOOC-(CH,),-COOH
(o), HOOC-(CH,),-COO- [134a] ( o ) , HO-(CH,),-OH [I041 (o), and -0OC(CH,),-COO- [132b] (A) in l a as a function of the spacer length k .
cates that hydrophobic interactions are the main driving force.
Neutral hydrophilic groups at the ends of longer alkyl chains have
little influence on the stability, presumably because they are
situated outside the cavity in the inclusion compound. Charged
G. Wenz
terminal groups lower the stability.['04,'21~'31~'32h,
1341 If substituents are present at both ends of the chain, they can have a
considerable influence on the inclusion kinetics. For example,
inclusion of 1,I 0-decanediol and decamethylenediamine" 351 is
so fast that signal averaging is observed in the NMR spectra. In
contrast, this process is so slow for 1,l'-decamethylenedipyridinium"32"1 and 1 ,lo-decanedicarboxylic
that averaging is not observed. Instead. the methylene groups give rise to
two sets of signals, because of the removal of mirror symmetry
upon inclusion in the asymmetric host.['32a1In the case of deca~nethylenebis(trimethylammonium)
the end groups are so large
that inclusion in 1 a takes several minutes.['351 Thus the ionic
end groups can provide significant steric hindrance to the inclusion and dissociation processes. When the ion passes through the
ring, its hydrate shell must be shed. This also shows quite
clearly that axial inclusion compounds are actually formed
(Scheme 7b). This finding has been confirmed by NOE measurements[' 32b1 and X-ray structure analysis.[107r1
Although benzene is already too large for 1 a, benzene derivatives (e.g. p-dibromobenzene, K, = 91 3 M - ' ) can undergo inclusion,[117h. 1361 The cyclodextrin apparently sticks preferentially
over one of the substituents and is deformed to give an elIipse.r'3714,4'-Bis(aminomethyl)biphenylis already too large for
1 a (K, = 8 M - ' ) , [ ' ~ ~ ] probably because the two benzene rings
are not coplanar. On the other hand, azobenzene derivatives
form stable axial inclusion compounds with 1
(e.g. methyl
orange, K , = 10-5
most likely because they are planar and dumbbell-shaped.
Bulky benzene derivatives d o fit into p-cyclodextrin 1 b (e.g.
4-tert-butylphenol, K, = 36 300 M - I ) ,[1401as do naphthalene
derivative^."^^' However, the cavity in 1 b is filled by molecules
with a cylindrical shape better than by flat arenes. Thus derivatives of perfluoroalkyl chains,['22a1adamantane,r'271and ferr ~ c e n e , [ l ~as~ well
as transition metal complexes of cyclic
d i e n e ~ , ~1441
' ~ fo
~ rm
, stable inclusion compounds with 1 b. Although the relatively thin, linear alkyl derivatives are included
by 1 b just as well as by 1 a, virtually no spectroscopic changes
occur because of the loose packing, and inclusion can be detected only indirectly, for example, by the displacement of a probe
lar structures. Not only can two cyclodextrins o r two guest
molecules be linked together, equally feasible is linking a cyclodextrin and a guest molecule.
Harada et al. and Breslow et al. described the binding potential of
5 3 1 and doubly[s01bridged cyclodextrin dimers
(Schemes 8 a and 8 b). Such molecules are referred to as ditopic
since they are able to include two hydrophobic guests
or a guest with two hydrophobic binding sites (a ditopic guest).
In the latter case the stability constants can be particularly high
( K , 2 10" M-'). As such systems also have a high recognition
potential for guest molecules, they are also referred to as artificial receptor moIecuIes.[sO1
Scheme 8. Topology of inclusion compounds from a) covalently linked hosts and
guests and b) ditopic host plus ditopic guest; c) monomeric, d) dimeric, and e )
polymeric complexes of a host-guest conjugate.
A unique situation arises when a cyclodextrin molecule and a
guest molecule are covalently linked. Such cyclodextrin-guest
conjugates can organize themselves either intramolecularly to
give monomeric inclusion compounds or intermolecularly to
mo~ecu~e,"02. 125al
give dimeric or polymeric inclusion
3 5 * 541
y-Cyclodextrin 1c is large enough to take up polyannelated
(Scheme 8c-e). A covalently bonded guest molecule can be disring systems such as p ~ r e n e , [ ' ~ jbenzpyrene,"
19'] and even
placed from the cyclodextrin cavity by a free guest molecule.
Since this displacement process can be detected spectroscopicalsteroids.['46' [12]Crown-4 and its alkali metal complexes form
sandwichlike inclusion c o m p l e ~ e s . ~ ']'41~ ~ 'Even
c ~ r o n e n e ~ ' ~ *ly~ by either optical absorption,["51 fluorescence,[' 561 or circular
and buckminsterfullerene C60[1491
such cyclodextrin-guest conjugates can be used
form stable inclusion comas sensor molecules, for example, for steroids.['55bs1561
pounds with two molecules of 1 c (Scheme 7d). 1 c is also able to
take up two guest molecules (e.g. anthracene derivatives[" 5, l S o 11
simultaneously (Scheme 7e,f).
4.1.7. The Inclusion of Polymeric Guest Molecules
Amylose, the polymeric analogue of the cyclodextrins, often
also forms similar inclusion compfexes.r'511In contrast to the
A polymer can by complexed by many host molecules if it has
cyclodextrins the internal diameter of the amylose helix is not
a corresponding number of binding sites, in other words, if it
functions as a polytopic guest molecule. The binding sites can lie
defined. The conformation of the amylose molecule can adapt
itself to the size and shape of the guest molecule.[1521The selectivalong the main chain as well as in the side chains. Since such
polymers can form both inclusion and addition comity of amylose is thus much lower than that of the cyclodextrins.
pounds with cyclodextrins, several arrangements are possible
(Scheme 9). The axial inclusion of the main chain of a polymer
4.1.6. Covalently Linked Cyclodextvins and Guest Molecules
(Scheme 9b) leads to a special topology: the rings are "threadThe formation of covalent bonds between building bLocks
ed" onto a chain. This means that a threaded ring is not underprovides additional possibilities for constructing supramolecugoing dynamic exchange with the free rings, unless it occupies
Angew. Chem. f n f . Ed. En:ng/. 1994, 33. 803-822
26A k = l = 6
268 k = 1 = 11
26C k = 10, 1 = 3
Scheme 9. Topology of cyclodextrin inclusion compounds with polymeric guest
molecules. a ) Inclusion of the side chain, b) axial inclusion of the main chain,
e i addition to the main chain.
the position at the end of the chain. The threaded rings can only
migrate along the chain or rotate about it; they are thus confined to one-dimensional space with respect to the polymer
The formation of inclusion compounds with polymers has
been carried out by free radical polymerization,['
polycond e n ~ a t i o n , [ ' ~and
~ I polyaddition[lfiol in the presence of cyclodextrins or hydrophilic cyclodextrin derivatives. Since the resulting polymeric adducts could not be clearly characterized
owing to their poor solubility and structural heterogeneity, their
topology is still unclear.
In the interactions between poly(styrenesu1fonic acid)""] or
poly(N-alkyl-4-vinylpyridinium bromide)^^'^^] and cyclodextrins the side chains probably undergo inclusion (Scheme 9a).
According to Harada et al., polyethylene glycol and la,['621
polypropylene glycol and 1 b,[1631and polyfmethyl vinyl ether)
and l c form scarcely water-soluble adducts above a chain
length of ten monomer units. The formation of these adducts is
highly specific; for example, polyethylene glycol interacts only
with 1 a but not with 1 b or 1 c. These adducts contain two
ethylene oxide units or three ethylene units per cyclodextrin
molecule. The length of these two or three repeat units (7.5 A)
and the height of the cyclodextrin torus are almost identical.
Hence, it seems reasonable to suppose that the polymer chains
pass through stacks of cyclodextrins. This hypothesis was supported by the X-ray powder diffractogram of the adduct of
polyethylene glycol and 1 a, which is comparable to those found
for axial inclusion compounds with long guest molecules like
p ~ l y i o d i d e [ ~ . in
' ~ ~1.
] Final proof of the axial topology
(Scheme 9 b) of these inclusion compounds was provided by the
fact that termination of the polymer chains with bulky 3,5-dinitrobenzoyl groups inhibits their formation completely.
We have used polymers with alternating hydrophobic and
hydrophilic segments to construct water-soluble polymeric inclusion compounds. The hydrophobic segments (oligomethylene
units) are intended to function as binding sites for l a . The hydrophilic segments (secondary or quaternary ammonium groups)
should ensure solubility in water. The protonated poly(iminooligomethy1ene)s 26[1661and the polymeric compounds with
quaternary ammonium groups, 27[16'] and 28,[16*]are SUEciently soluble in water that the interaction with 1 a occurs in a
homogeneous phase. The 'H N M R spectrum shows new signals
due to the included oligomethylene units and the occupied
rings. The induced signal shifts are independent of the concentration and resemble those of monomeric model compounds (e.g. decamethylenediamine[' 3 5 1 and 1,l'-decamethyle n e d i p y r i d i n i ~ m ~in
' ~ ~1 a).
" ~ The observed signal doubling in
the aliphatic range of the 'H N M R spectrum is characteristic of
the axial inclusion of the chain.['32a] In comparison with the
formation of monomeric inclusion compounds the reaction of
Angew. C/imi. I n r . Ed EngI. 1994, 33. 803-822
l a with polymers 26, 27, and 28 is astonishingly slow;
we have measured reaction times between one hour and six
months. The rate of reaction decreases rapidly with the increasing bulk of the cationic groups, thus confirming the axial
chain inclusion.
The polymers 26C and 28 included in l a are released so
slowly that excess free cyclodextrin molecules can be separated
readily by dialysis or gel permeation chromatography (GPC).
Like the slow threading, the slow release of 1 a is attributed to
the slow migration rate of the rings along the polymer chain.
This migration is probably hampered by the bulky hydrate
shells around the cationic groups.
As with monomeric guest molecules, the final extent of inclusion increases dramatically with the increasing length of the
hydrophobic segments. While no inclusion is observed when the
chain is only six methylene units long (polymer 26A), all watersoluble polymers with more than nine methylene groups undergo
I6'l For example, polymer 26B (45 mM solution
in water) undergoes complexation to the extent of 68 YOwhen an
equimolar amount of 1 a is added.['661 Almost complete coverage of the chain can be achieved when an excess of 1 a is used.
The driving force for the threading of 1 a onto the polymer chain
is a gain in enthalpy; for the polymeric inclusion compound
l a . 2 6 B the enthalpy of formation is -20 kJmol-'."691 This
value lies in the range of the enthalpies of formation of analogous
Our observation that the inclusion of a polymer in 1 a requires
the alkyl group to be at least ten methylene groups long appears
to contradict the results of Harada et al., who detected inclusion
of even ethylene segments in 1 a.11621
Probably the two systems
are topologically quite different. In our systems the ammonium
ions form steric barriers that separate the threaded rings from
each other. In contrast the neutral systems studied by Harada
permit a close packing of the rings, which are linked by hydrogen
bonds, along the chain.['701
The threading of the larger host 1b onto polymers 26C and
28 cannot be detected by either N M R spectroscopy or microcalorimetry. In order to prove the inclusion of polymer 28 in
1 b we made use of the fact that threaded rings cannot pass one
another. Polymer 28 was allowed to interact with 1 b and 1 a
successively in aqueous solution; the free rings were removed
afterwards by dialysis. In the product the chain is occupied up
to 60% b y 1 b and 7.5 % by 1 a. Thus the rings 1b are threaded
rapidly onto the polymer chain, and the "slower" rings 1 a prevent them from slipping off.[168.1691
81 1
G. Wenz
4.2. Cyclodextrins as Exolipophilic Hosts
The binding capability of lipophilic cyclodextrins was first
studied by Menger and Dulany.["I They found that a polar
guest molecule such as 4-nitrophenol is complexed by heptakis(3-O-butyl-2,6-di-O-methyl)-~-cyclodextrin
in organic solvents. In contrast to the hydrophilic systems here the stability
constant K, increases with decreasing solvent polarity; in nonpolar solvents such as heptane the stability constant for the
inclusion of 4-nitrophenol is quite high (K, = 2600 M - ' ) . [ ~ ~ ]
The main driving force for the complexation is thought to
be provided by dipole -dipole interactions and hydrogen
bonds.1771Thus the cyclodextrin ether behaves as an exolipophilic host.
Polar substituents directed towards the interior of the cavity
increase the complexation ability of lipophilic cyclodextrins.
The following values for the complexation of 4-nitrophenol in
cyclohexane have been measured: [ ' 7 1 1 per(2,3,6-tri-U-pentyl)P-cyclodextrin 21 b K, = 3560 M - I , per(2,6-di-U-pentyl)-p-cyclodextrin 19b K, = 6000 h.1- ', and per(2,6-di-O-pentyl-3-0acety1)-p-cyclodextrin 23b K, 2 10000 M - ' .
The complexation of cations by the lipophilic cyclodextrins
per(2,3.6-tri-O-acetyl)- and per(2,3,6-tri-O-phenylcarbamoyl)p-cyclodextrin in organic solvents was first proven by Komiyama et a1.[26hlHowever, the quantification of the complexation
ability with the picrate extraction
showed that
per(di-U-alky1)-, per(tri-0-alky1)-, and per(tri-0-acy1)cyclodextrins interact only weakly with cations. In contrast, per(3-Oacyl-2,6-di-O-alkyl)-~-cyclodextrins
give quite stable complexes
with alkali metal ions; they are in fact even superior to the
standard crown ethers," 731 though they are not as specific
(Fig. 3)
Even very large cations such as the tetramethylammonium ion o r 4,4'-bipyridinium d i c a t i o n ~ ~are
" ~ ~complexed
by 22 b. The good complexing ability of 22 b and 23 b can be
VRb: Cs+
/i+ ait:
1 .O
1 .5
Fig 3. Coinplenation ability (picrate extraction coefticient &) as a function of the
cation radius r for 23b in toluene [174] ( 0 ) and for dibenzo[l8]crown-6 in benzene [173] ( A ) .
Scheme 10. Possible location of an alkali
metal ion in a per(3-0-acetyl-2.6-di-O-alkyl)cyclodextrin.
traced back to the ester carbonyl groups, which according to the
t r a m rule[175]
should be directed preferably towards the C , axis
(Scheme 10). Carbonyl oxygen atoms are known to interact
strongly with ~ a t i o n s . [ " ~ J
4.3. Cyclodextrins as Building Blocks for Mono- and
Multilayer Systems
Apart from host-guest complexes, other supramolecular structures such as monolayers and multilayers have been derived from
cyclodextrin building blocks. Kawabata et al. showed for the first
time that the amphiphilic cyclodextrins 29 and 30 undergo selforganization at the air-water interface to give stable monolayers analogous to crystals.['771The area A occupied by a molecule at the water surface increases with increasing ring size (29a:
A = 173, 29b: A = 210. 29c: A = 281 A') but varies little with
changes in the length of the alkyl chain. Consequently, the cyclodextrin rings swim flat on the water surface, and the secondary hydroxyl groups are oriented towards the water
(Scheme 11). In contrast, the amphiphilic cyclodextrin 30 forms
Scheme 11. Arrangement of amphiphilic cyclodextrins at the water:air interface
X = S . NH [177. 3 2 ~ 1 .
monolayers in which the side with the primary functional
groups is directed towards the water.[32c1
Guest molecules such as azo dyes can be incorporated into the
monolayers formed by cyclodextrins. As the area occupied by
each host molecule does not increase on complexation, the guest
molecule is situated inside the host cavity."77b. ' 7 8 ] Such monolayers together with their included guests can be transferred
repeatedly by means of the Langmuir - Blodgett technique to
planar hydrophobic substrates such as glass slides precoated
with cadmium i c o ~ a n a t e . [ ' ~ ' ~
It] is thus possible to produce
multilayers composed of a defined number of monolayers on
such a substrate. The guest molecules incorporated into the
multilayer still have enough space to undergo photochemical
isomerization. For instance, included azobenzene molecules can
be switched photochemically between the trans and cis configur a t i o n ~ . [ " ~Such
systems could in principle serve as information storage media.['801
Monolayers composed of cyclodextrins are also produced by
For example, cyclodextrins containing thiol
groups have been adsorbed on a gold surface."a21 The formation of inclusion compounds at these monolayers can be detected
by surface analysis (e.g. with plasmon spectroscopy)."
Applications of such systems as sensors are conceivable.
Angew. C l w n . Int. Ed. En,$. 1994, 33, 803-822
5. The Construction of Molecular Architectures by
Supramolecular Positioning
The great interest that supramolecular chemistry has found in
the last few years arises from the idea of building up complex
molecular structures from simple building blocks. The classical
stepwise construction of structures by the formation of covalent
bonds is replaced by the planned positioning of large units by
means of secondary valence forces and their subsequent covalent linkage."831 Whereas a large number of reactions are required in classical organic synthesis to generate, link, convert,
protect, and cleave functional groups, supramolecular synthesis
requires predictable forms of self-organization to bring building
blocks into position in a defined manner prior to the necessary
formation of covalent bonds. The tremendous power of the
supramolecular approach has been demonstrated by the efficient syntheses of catenanes,['22a,1841 rotaxanes,(1851polyrotaxanes,1'851and knots['871by Sauvage, Stoddart, and others.1y2e1
In the following sections we shall discuss the conditions necessary for the construction of catenanes, rotaxanes, and tubes
from cyclodextrin inclusion compounds.
0 0 0 NH,
0 0 0 0 NH-C+t-NHO
0 0 0,
.... 0 :<....
5.1. Synthesis of Catenanes
As early as 1957 Liittringhaus, Cramer, Prinzbach, and Henglein attempted to synthesize a [2]catenane by ring closure of a
long guest molecule included in 1a.[1881This attempt was unsuccessful. perhaps because the guest molecule (28 bonds in length)
was not long enough to circle the wall of the cyclodextrin molecule. Thirty-five years later Stoddart et al. synthesized two
[2]catenanes. 32 and 33, and two [3]catenanes, 34 and 35, from
the inclusion compound of the bitolyl derivative 31 in heptdkis(2.6-di-O-methyl)-fl-cyclodextrin
17 b (Scheme 12) . [ l S 9 l The
cyclization of the guest was carried out by acylation of the two
terminal amino groups with terephthaloyl dichloride, a reaction
which also proceeds in good yields in aqueous solution. The
catenanes formed can be readily separated from the reaction
mixture because of their amphiphilic nature. Thus the requirements for supramolecular positioning, for the ring-closing reaction, and for the separation of the target compound were fulfilled; however, the yield of catenane 32 was only a
disappointing 3 % in spite of the stability of 17b.31 ( K , 2
10000 M - ' ) . It is possible that in 17b.31 the reactivity of the
amino groups is diminished even though the guest 31 is 35 bonds
in length. Amazingly, the catenanes 33,34, and 35 with 84-membered rings could also be detected in yields of about 1 YO,even
though their formation requires the formation of four bonds
rather than two.
5.2. Synthesis of I21Rotaxanes
In 1981 Ogino and Ohata reported that x,w-alkanediyldianiines, included in 1 a or 1b, react with bulky cobalt(1ir) complexes at both ends to give [2]rotaxanes 36 (Scheme 13).[1901The
yield increased with decreasing ring size and depended on the
length k of the alkyl chain, reaching a maximum of 1 9 % at
0 0 0 0 NH-C-@&NHO
.... 0 :.:.:<.:
0 0 0,
0 ....
nnnn ?
o o o o NH-C-@~-NH
o o o ,o
Scheme 12. Synthesis of [2]- and [3]catenanes from 17b [189].
k = 12 (Table 3).[190b1If the chain is too short (k = 8), the
amino groups are probably too strongly shielded by the host; if
it is too long, the alkyl chains may associate. The solvent used
was DMSO. Since the stability constants in this solvent are very
it is necessary to use very high concentrations of both
host and guest. In a similar manner Wylie and Macartney obtained [2]rotaxane 37 by treating the inclusion compound of 1,l'nonamethylenebis(4,4'-bipyridinium) and 1 a with a bulky
iron(1I)cyano complex in aqueous solution.[1921Since the iron
complex formed is kinetically unstable (k, =1.5 x 10 - 3s- ') ,
there is a very slow exchange between the rotaxane 37 and the
uncomplexed dumbbell-shaped compound and 1 a,['y21
Stable rotaxanes are formed only when the blocking groups
are covalently linked to a n included guest molecule. Isnin and
Kaifer obtained a mixture of the two isomeric [2]rotaxanes 38A
and 38 A as well as 38 B and 38 B in 15 YOyield by forming an
G. Wenz
368 k=12
36C k=14
398 X=O
38A k-7
40A-Br X=COO
388 k=ll
c 38A' k=7
41B X=O
Scheme 14. Synthesis of lipophilic [2]rotaxanes from rndo complexes of bipyridinium ions blocked at one end [78e. 108eI.
388' k=ll
Scheme 13. Hydrophilic [2]rotaxanes from cyclodextrins [190- 1931
Table 3. Synthesis of [2]rotaxanes according to Ogino and Ohata[190b]
36 A
36 B
36 C
36 D
amide bond. Surprisingly isomer 38 A is stable, in other words
it is a rotaxane, whereas the other isomer 38A' dissociates slowly
into the dumbbell and 1 a.[1941It seems that the steric hindrance
towards unthreading depends on the orientation of the cyclodextrin.
The main difficulty in these rotaxane syntheses is that the
conditions for the bond-forming reaction must be favorable for
the host-guest interaction as well. Although water is the best
solvent for the formation of inclusion compounds. it is not very
well suited as a reaction medium for the attachment of the
blocking groups, as the reagents are generally only poorly soluble and can be consumed by hydrolysis. It thus appeared of
interest to attempt constructing [2]rotaxanes in inert organic
solvents with exolipophilic cyclodextrins. Per(3-O-acyl-2,6-di-Oalky1)cyclodextrins such as 22b are indeed able to complex
guests such as the 4,4'-bipyridinium ions 39, which are blocked
on one side (Scheme 34). Two orientations of the host 22b (the
exo and the endo form) with respect to the guest can be distinguished in the ' H N M R spectrum.['0se1 Attachment of the
blocking group 40A (as the bromide) to the complexed guest
22b.39A furnished the lipophilic [2]rotaxane 41 A in 19%
yield.[78e1The yield of the analogous [2]rotaxane 41 B starting
from the building blocks 3 9 B and 40B was even better
('HNMR: so%, isolated 36%)."0s'1 The 'HNMR spectra of
both rotaxanes 41 show the distinct doubling of signals for the
protons on the dumbbell axis. Together with NOE studies this
signal doubling indicates that the cyclodextrin molecule is not
situated in the middle of the dumbbell but towards one side of
it. The two halves of the dumbbell were differentiated by deuteration of the benzylic methylene group of the blocking group
40B. It could then be shown that in the rotaxane the host is
located only on the side of the original guest molecule 39 B. Thus
only the endo complex reacts with the blocking group 40-Br. In
the case of the exo complex the terminal pyridine group is probably shielded from attack of 40-Br by the host.['08e1This selective reaction of a host-guest compound with one orientation
could be used for the construction of uniform [2]rotaxanes with
an unsymmetrical dumbbell component.
5.3. Synthesis of Polyrotaxanes
Polyrotaxanes can be prepared by reactions between axial
polymeric inclusion compounds with blocking groups or by
Aiigew. Clzern. Ini. Ed. Engl. 1994, 33, 803-822
polymer-analogous reactions of polymers with monomeric inclusion compounds. In the former case the rotaxane axes lie
along the polymer main chain (main-chain polyrotaxanes) ,
while in the latter they branch off from it as side chains (sidechain polyrotaxanes) .
Starting from the inclusion compounds of the polyamines
26B and 26C with 1 a, we obtained the water-soluble main-chain
polyrotaxanes 42 in good yields by partial polymer-analogous
reaction of the amino groups with nicotinoyl chloride
(Scheme IS) .[16h1 The products were readily purified by dialysis.
In the case of 42B about forty rings were held permanently on
the chain. Nicotinoyl groups are too small, however, to block
the larger rings 1 b, and larger substituents such as 2,4-dinitro-5aminophenyl groups had to be used instead.[’691
Harada et al. synthesized the polyrotaxane 43 with about twenty rings on the chain by reacting the terminal amino groups of
a polyethylene oxide included in 1a with Sanger’s reagent.[’”]
This rotaxane is soluble in water at p H > 12 and in DMSO; it
was purified by GPC.
The synthesis of a side-chain polyrotaxane (Scheme 16) was
achieved by Ritter et al. by the reaction between the guest in
44.17b and the side groups of a reactive comb polymer; the
polymeric product 45 was purified by multiple precipitation.[I9‘1
5.4. Synthesis of Tubular Polymers
We have so far discussed only syntheses in which a chemical
reaction was carried out at an included guest molecule. We shall
now turn our attention to the covalent linkage of threaded rings
to give tubular polymers. The polymeric “thread” has the function of arranging stacks of rings. Harada et al. treated a solution
of polyrotaxane 43 in 10 % N a O H with epichlorohydrin.[’”] By
using gel permeation chromatography they were able to show
that cross-linking occurs only along the polymer chain with
formation of hydroxypropylene bridges. The blocking groups
were then cleaved with 25 YON a O H and the threads removed by
GPC. The final product was the tube 46 consisting of about
fifteen multiply bridged cyclodextrin units.“ 9 7 1
6. Host - Guest Catalysis
Scheme 15. Main-chain polyrotaxanes from 1 a [166, 1951
Scheme 16. A side-chain polyrotaxane from 17b [196]. X
Angen Cliwi Inr. Ed Engi. 1994, 33, 803-822
The defined spatial relationship between the building blocks of
a supramolecular structure makes it possible to carry out reactions under t o p o ~ h e m i c a l [ control.
’ ~ ~ ~ The influence of the host
on reactions a t the guest (host-guest catalysis) has been the
subject of many investigations.[’9y1We shall now discuss the
most important catalytic functions of cyclodextrins.
The term covulent catalysis is used when the catalysis involves
a temporary covalent bond between host and guest. Most
studies have focused on the catalytic activity of cyclodextrins in
ester hydrolysis. Cyclodextrins accelerate the alkaline (pH > 11)
saponification of esters of carboxylic acids.[2001 phosphoric
acids,[” ‘1 and sulfuric acid.[Z021A deprotonated secondary hydroxyl group, probably OH(2), serves as the nucleophile, since
it has the highest acidity. This hydroxyl group forms a cyclodextrin ester, which then hydrolyzes to the cyclodextrin and the free
2 0 3 1 The catalytic activity of the cyclodextrin increases
with the stability of the inclusion compound[2041and with decreasing distance between OH(2) and the ester group of the
guest in the inclusion compound.[’401Optimization of the structure of the guest leads to esters that are cleaved very rapidly by
1b. For instance, the cleavage of ferrocene ester 47 (Scheme 17)
81 S
can be accelerated by 1 b
by a factor of 105.[2051
The cyclodextrin is consumed in this process,
since the cleavage of
47 + lb
the cyclodextrin ester
formed is very slow.
Cyclodextrins (pK, =
12.2) are catalysts for
ester cleavage at pH val49
ues above 11. Since it
would be more useful to
have such catalysis at
lower pH values. functional groups that are
deprotonated more easily were attached to
the cyclodextrins. When
the imidazole moiety
Scheme 17. Catalysts based on cyclodextrins[205.211]. R = p-NO,-C,H,.
(pK, = 7.04)[’06’
used, the catalytic activity of the cyclodextrin increased considerably and the optimum p H shifted to
The activity depends on the position of the imidazole moiety on the cyclodextrin: an imidazole group on the side
with the secondary OH groups causes a greater increase in the
reaction rate than one on the side of the primary O H
groups.[38,207c1 The highest activity, an increase in the rate of
hydrolysis of 4-nitrophenyl acetate by a factor of 1100, was observed by Toda et al. for a heptakis(2,6-di-O-methyl)-fi-cyclodextrin with a 4-imidazoylethyl group at O(3).1207c1 Since one
equivalent of this compound effected the saponification of one
hundred equivalents of the ester, it is evident that the covalent
intermediate is also rapidly cleaved.
Transition metal ions such as Z n Z f and C u 2 + can be coordinated to amine-functionalized cyclodextrins in order to mimic
metalloenzymes. Such complexes have been used to catalyze the
cleavage of esters,[2081cyclic phosphates,[2091and the hydration
of carbon dioxide.[2’ Very recently, the ditopic catalyst 48 was
introduced, which increases the rate of hydrolysis of suitable
esters like 49 at pH 7 by a factor of up to 220000.[2”1 Unfortunately, all such advances have so far been limited to the saponification of a few activated esters (e.g. p-nitrophenolates). Therefore application of these catalysts is still not
Cyclodextrins can catalyze other reactions besides the saponification of esters. For example, pyridoxamine-substituted cyclodextrins catalyze the reduction of a-ketocarboxylic acids,[671
while alkenes can be converted to epoxides with porphyrin-substituted cyclodextrins.[’’ 31
Cyclodextrins can also increase the rate of reactions without
the formation of a covalent bond to the included guest; here the
cyclodextrin serves as a “reaction vessel”. Thus electrophilic
substitution of arenes (e.g. chlorination,[’ 14] carboxylation,[2151
and azo
can be catalyzed by cyclodextrins. The CT
complex is apparently stabilized in the inclusion compound by
the donor action of the cyclodextrin. Such stabilization can even
allow spectroscopic characterization of the CT complex.[2171Tnclusion generally leads to a decrease in the amount of ortho and
meta products because of shielding of these positions by the
G. Wenz
host.[214,2181 The r e g i ~ - [ ’ ~and
~ ] enantioselectivity[2201of a
number of other reactions has also been influenced by the inclusion of starting materials in cyclodextrins.
When two guest molecules are included in the same cavity (cf.
Scheme 7ej. they are compressed, which facilitates pericyclic
and intramolecular[2221[4 + 21 DielsAlder reactions and [2 21 p h o t o d i m e r i ~ a t i o n s [ ” ~ ~ ~ ~ ~
are accelerated by 1b and 1c, and the yields are increased. Both
regio- and enantioselectivity are influenced as
7. Physical Functions of Supramolecular Structures
Derived from Cyclodextrins
In addition to the chemical functions of supramolecular structures we must also mention the physical functions such as recogn i t i ~ n [and
~ ~ translocation
(retention or transport) of guest
molecules.[224]The combination of these functions is of great
practical interest, since it can be employed for the separation of
7.1. Molecular Recognition
A host that forms complexes of different stabilities with two
similar guests is said to display molecular recognition. Cyclodextrins detect not only the length and thickness of a guest
but also distinguish between enantiomeric guest molecules
owing to their chirality. Diastereomeric host -guest complexes
are known both for hydrophilic[28s 14‘, 2 2 5 1 and lipophilic
cyclodextrins.[2261 The interactions that determine chiral
recognition have been studied by computer simulations,121. 2 2 6 , 2271
7.2. Selective Retention of Guest Molecules by
Immobilized Cyclodextrins
A guest molecule can be retained in a molecular current oniy
if the host is bound to a solid substrate. The stronger the interaction between the guest and the immobilized host, the slower
the guest proceeds in the current. Armstrong et al. were the first
to immobilize hydrophilic cyclodextrins on silica gel and to use
them for the separation of a variety of guest molecules (in particular racematesj by liquid chromatography.[2281Konig, Wenz,
et al. showed that coatings of lipophilic cyclodextrins (e.g.
21 a,[229121 b,[23012 1 1 2 , ~ ~23a,[2321
and 23b12j3])inside long
capillaries form excellent stationary phases for the gds-chromatographic separation of enantiomers. The more polar permethylated cyclodextrins 20 also show very good separation performance in a lipophilic medium.[2341Immobilized permethyl-acyclodextrin can also be used for supercritical fluid chromatography, a method that also permits the high-resolution
separation of nonvolatile substance^.[^^^^^ Chromatographic
separation on cyclodextrin-containing stationary phases has become a widely applied analytical method for substances of general importance such as flavorings,[2361
pheromones,[237]anaest h e t i c ~ , [ ~ ~ ~ ~ and a g r o c h e m i ~ a l s , [ ’as
~ ~well
~ as for
AnRew. Chem Inl. Ed Engl. 1994, 33, 803-822
7.3. Transport of Guest Molecules by Means of Mobile
8.2. Reducing or Retarding the Availability of Active
The transport of a guest molecule in o r through a liquid phase
relies primarily o n an increase in its solubility by the formation
of a host-guest complex. This transport can be used for phasetransfer catalysis of chemical reactions[26a.2421 and for the separation of different guest molecules.[2431Hydrophilic cyclodextrins were used to transport hydrophobic guest molecules across
an aqueous phase,[242".'. 2431 lipophilic cyclodextrins to transport ionic guest molecules across a lipophilic phase,[26a1and an
amphiphilic derivative to transport cations across a liposome
membrane.[2441Charged cyclodextrins can effect the transport
of included neutral guest molecules in an electrical field.[2451
The formation of poorly soluble cyclodextrin derivatives, in
particular starting from 1b, can be used for removing undesired
substances (e.g. cholesterol from liquid egg,12471aromatic compounds from wastewater,[2571and nicotine and condensate from
cigarette smoke[2581)and for encapsulating active substances.
Encapsulation can be used to slow down the rate of release and
thus increase the duration of effectiveness.[2591
The vapor pressure of guest molecules can also be lowered by inclusion in
cyclodextrins. This is employed for the carefully dosed long-lasting release of pleasant aromatic compounds such as chamomile,
rose, lemon, and peppermint
For this purpose cyclodextrins can also be immobilized on consumer goods such as texAt the other extreme, unpleasant odors such as those of
metabolic by-products and mercaptans in hair care products
can be masked by cyclodextrins.[2621
Even the viscosity of polymeric thickening agents can be adjusted by cyclodextrins. The addition of 1 leads to readily processable solutions of low viscosity of otherwise associating polymers. The inclusion of polymer side chains probably decreases
polymer -polymer interactions; however, as soon as the host is
saturated by a monomeric guest, the polymer side chains are
released and highly viscous solutions
8. Applications
Cyclodextrins and their derivatives are already in use throughout the world for the formulation of drugs[s3a.2461 and cosmeti
c and ~for technical
~ With
~ the exception of
the latter area these applications must generally be approved by
national licensing authorities. Detailed studies on the toxicity,
mutagenicity, teratogenicity, and carcenbgenicity of cyclodextrins, in particular hydroxypropyl-,kyclodextrin, have thus been
So far cyclodextrins have been found to be nonhazardous with the exception that high concentrations of 1a,
1 b, and Ic cause damage to human erythrocytes.[2501However,
even this can be avoided with hydroxypropyl derivatives.['] At
present cyclodextrins have general approval for use as food
additives in Japan and Hungary and approval for specific applications in France and Denmark. Cyclodextrins often have advantages over starch, which might have similar inclusion properties, since they d o not provide a culture medium for
In most of the applications, cyclodextrin inclusion compounds are formed for the modification of physical or chemical
properties of the guest molecules. Analytical applications have
already been mentioned. Cyclodextrins can be used for both
increasing and decreasing the availability of an active substance
and for protecting it from degradation.
8.1. Increasing the Availability of Drugs
The solubility of hydrophobic drugs in water can be increased
by inclusion in cyclodextrins. The increase in solubility facilitates simpler formulation and an improved uptake of the
drug.[2s'I Tensides are also used for this purpose, but cyclodextrins are more compatible with sensitive biological systems such
as erythrocyte cell
Hydroxypropylcyclodextrins are used for solubilizing drugs that are administered
parenterally.[z521Recently there has been great interest in the
solubilization of insulin[2531and steroid
as well
as antiviral
for nasal application.
Even small amounts of lipophilic cyclodextrin derivatives
such as 22 b accelerate the solidification of cyanoacrylate adhesives. The acceleration of this polymerization probably results
from the solubilization of ionic initiators.[2561
8.3. Stabilization of Active Substances
Cyclodextrins protect the included guest molecule from
degradation by autoxidation, photolysis, and hydrolysis, particularly in the crystalline state. For example it is possible to stabilize sensitive flavorings such as those in onions, dill, garlic and
horseradish,[2621and also vitamins[2631over a long period of
time by forming cyclodextrin inclusion compounds.
9. Future Prospects
Developments shall continue at a great pace in the next few
years, particularly if cyclodextrins are licensed for further applications in food and drug production.
F o r the synthesis of cyclodextrins the development of simpler,
more easily reproducible procedures will be important. All
available chromatographic and spectroscopic methods will be
required for characterizing new products. Standard measurement and evaluation protocols should be developed for the determination of the stoichiometry and stability of cyclodextrin
inclusion compounds to ensure the comparability of the data.
Of the methods available at present, 'H N M R spectroscopy and
microcalorimetry are of particular importance, as they are almost universally applicable.
The boundaries drawn here, which indeed still exist, between
preparative, physical, theoretical, macromolecular. biomimetic,
analytic, and physiological chemistry will be fascinating to
cross. For example, catalytically active catenanes and rotaxanes
appear feasible. Rotaxanes and cyclodextrin catalysts could also
be built into larger supramolecular structures such as monolayers and vesicles in order to carry out specific operations. Poly817
G. Wenz
mers of defined length could be synthesized in tube-shaped polymers. The programmed release of several active substances
could be achieved by the slow unthreading from polymer chains.
Because of the common solvent, water, it even appears rewarding to forge a link to biochemistry. The imagination knows no
I thank m.v co-ccorkers and the research group of Pro$ u/: A .
Konig. Universitat Hamburg,f o r discussions and for reading this
manuscr$t. I am also indebted to Wacker Chemie GmbH,
Miinchen, and Henkel KGaA, Diisseldorf, as well as to the Bundesministerium fi?r Forschung und Technologic (Prqekt B E 0 221
031905SA) aizd the Max-Plunck-lnstitut , f i r Polymerforschung
,for the generous support of my work in this ,field.
Received: December 21, 1992 [A9361E]
German version: Angew. Cliem. 1994, 106. 851
Translated by: Dr. T. N. Mitchell. Dortmund (FRG)
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