Synthesis and supramolecular properties of regioisomers of mononaphthylallyl derivatives of v-cyclodextrin

Article abstract of DOI:10.3762/bjoc.13.248

Monosubstituted derivatives of γ-cyclodextrin (γ-CD) are suitable building blocks for supramolecular polymers, and can also serve as precursors for the synthesis of other regioselectively monosubstituted γ-CD derivatives. We prepared a set of monosubstituted 2^I-O-, 3^I-O-, and 6^I-O-(3-(naphthalen-2-yl)prop-2-en-1-yl) derivatives of γ-CD using two different methods. A key step of the first synthetic procedure is a cross-metathesis between previously described regioisomers of mono-O-allyl derivatives of γ-CD and 2-vinylnaphthalene which gives yields of about 16-25% (2-5% starting from γ-CD). To increase the overall yields, we have developed another method, based on a direct alkylation of γ-CD with 3-(naphthalen-2-yl)allyl chloride as the alkylating reagent. Highly regioselective reaction conditions, which differ for each regioisomer in a used base, gave the monosubstituted isomers in yields between 12-19%. Supramolecular properties of these derivatives were studied by DLS, ITC, NMR, and Cryo-TEM.

Full text of DOI:10.3762/bjoc.13.248

Synthesis and supramolecular properties of regioisomers
of mononaphthylallyl derivatives of γ-cyclodextrin
Markéta Bláhová1, Sergey K. Filippov2, Lubomír Kováčik3, Jiří Horský2,
Simona Hybelbauerová4, Zdenka Syrová3, Tomáš Křížek5 and Jindřich Jindřich*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 2509–2520.
1Department of Organic Chemistry, Faculty of Science, Charles
doi:10.3762/bjoc.13.248
University, Hlavova 8, 128 43 Prague 2, Czech Republic, 2Institute of
Macromolecular Chemistry, Academy of Sciences of the Czech
Republic, Heyrovsky Sq. 2, 162 06 Prague 6, Czech Republic,
Received: 08 July 2017
Accepted: 03 November 2017
Published: 27 November 2017
3
Institute of Biology and Medical Genetics, First Faculty of Medicine,
Charles University, Albertov 4, 128 01 Prague 2, Czech Republic,
Department of Teaching and Didactics of Chemistry, Faculty of
4
This article is part of the Thematic Series "Superstructures with
cyclodextrins: Chemistry and applications IV".
Science, Charles University, Hlavova 8, 128 43, Prague 2, Czech
Republic and 5Department of Analytical Chemistry, Faculty of
Science, Charles University, Hlavova 8, 128 43, Prague 2, Czech
Republic
Guest Editor: G. Wenz
©
2017 Bláhová et al.; licensee Beilstein-Institut.
Email:
License and terms: see end of document.
Jindřich Jindřich* - jindrich@natur.cuni.cz
*
Corresponding author
Keywords:
γ-cyclodextrin; naphthylallyl derivatives; regioselective alkylation;
supramolecular properties; synthesis
Abstract
Monosubstituted derivatives of γ-cyclodextrin (γ-CD) are suitable building blocks for supramolecular polymers, and can also serve
as precursors for the synthesis of other regioselectively monosubstituted γ-CD derivatives. We prepared a set of monosubstituted
2
I-O-, 3I-O-, and 6I-O-(3-(naphthalen-2-yl)prop-2-en-1-yl) derivatives of γ-CD using two different methods. A key step of the first
synthetic procedure is a cross-metathesis between previously described regioisomers of mono-O-allyl derivatives of γ-CD and
-vinylnaphthalene which gives yields of about 16–25% (2–5% starting from γ-CD). To increase the overall yields, we have de-
2
veloped another method, based on a direct alkylation of γ-CD with 3-(naphthalen-2-yl)allyl chloride as the alkylating reagent.
Highly regioselective reaction conditions, which differ for each regioisomer in a used base, gave the monosubstituted isomers in
yields between 12–19%. Supramolecular properties of these derivatives were studied by DLS, ITC, NMR, and Cryo-TEM.
Introduction
Cyclodextrins [1] (CDs) are cyclic oligosaccharides with a or 8 glucose units, respectively. Both chemically modified and
cone-shaped cavity formed by α-1,4-linked D-glucopyranose native CDs are used in numerous applications, e.g., in separa-
units. The most widely used CDs are α-, β-, and γ-CD with 6, 7 tion methods [2,3] or in the pharmaceutical industry [4,5]. CDs
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are well-known as host molecules for various guest substances Naphthylallyl derivatives of any CD have not been described
in aqueous solutions [4]. Derivatives of CDs are attractive yet.
building blocks for various types of supramolecular structures
[
6,7]. Necessary non-covalent interactions depend on the type Supramolecular properties of the prepared derivatives were
and derivatization of CD, on lipophilicity, shape, and size of the studied by a set of methods allowing characterization of supra-
guest molecule, and on conditions such as temperature, pH, or molecular behavior at various levels – from binary complex-
solvent used [8]. In supramolecular polymers [9] multifunc- ation, over supramolecular oligomers to large assemblies;
tional molecules are assembled in a regular manner. To avoid namely by isothermal titration calorimetry (ITC) [16],
branching, monosubstituted CDs are required for a linear supra- 1H nuclear magnetic resonance spectroscopy (1H NMR),
molecular polymer of CDs with guest groups attached.
dynamic light scattering (DLS) [18-21] and cryo-transmission
electron microscopy (Cryo-TEM) [22-24].
Monosubstituted derivatives of CDs [10] include three regio-
Results and Discussion
isomers, namely 2I-O-, 3I-O-, and 6I-O-substituted ones. To
separate pure regioisomers from their mixture is tricky. Their Synthesis
direct regioselective synthesis is possible, although not easy, We present two approaches for the synthesis of naphthylallyl
because hydroxy groups at different positions of CD have dif- (NA) derivatives. The first approach is a cross-metathesis of
ferent properties; the hydroxy group at position 6 is the most peracetylated allyl derivatives of γ-CD with 2-vinylnaphthalene.
nucleophilic and basic one, the hydroxy group at position 2 is The main advantage of this procedure is that a pure regio-
the most acidic, and the group at position 3 is most sterically isomer of the product is obtained due to the regio-purity of the
hindered. Therefore, regioselective monosubstitution to posi- starting material. Unfortunately, this reaction is quite low-
tions 2 and 6 can be controlled by the amount and strength of yielding, and the isolation of the products is hard to perform.
the base used in the reaction, whereas monosubstitution at posi- Moreover, the starting compound for this reaction has to be pre-
tion 3 can be achieved by complexation of the alkylation agent pared from γ-CD in two steps involving complicated chromato-
to the CD cavity and orientation of the agent´s reactive center graphic separations. Thus, the overall yields of the pure NA
towards the 3-OH group [11-13].
regioisomers were only 2–5%. Therefore, we turned our focus
to developing another method for the preparation of naphthyl-
Here, we report the preparation of regioisomers of novel allyl derivatives, which is based on a direct alkylation of γ-CD
mononaphthylallyl γ-CD (NA-CD), i.e., 3-(naphthalene-2- with 2-(3-chloroprop-1-enyl)naphthalene.
yl)prop-2-en-1-yl γ-CD, which is interesting for several reasons.
Compared to α- or β-CD, the number of publications dealing Cross-metathesis
with γ-CD is quite small, e.g., [14,15]. The naphthyl group is Mono 2I-O-, 3I-O- and 6I-O-naphthylallyl-γ-CDs (2-O-
well known for its ability to make inclusion complexes with NA-γ-CD, 2a, 3-O-NA-γ-CD, 2b, 6-O-NA-γ-CD, 2c) were pre-
CDs [16]. The allyl connecting linker is relatively rigid and pared from peracetylated O-allyl derivatives [14] by cross-me-
should support the formation of supramolecular polymers of tathesis with 2-vinylnaphthalene (Scheme 1) in the presence of
CD–guest type [17]. Moreover, the double bond of the allyl the Hoveyda–Grubbs 2nd generation catalyst. After deacetyl-
group allows a subsequent conversion of these compounds to ation, column chromatography afforded the naphthylallyl
other regiospecifically monosubstituted γ-CD derivatives. derivatives in yields between 16–25%, which is comparable to
Scheme 1: Preparation of 2I-O-, 3I-O- and 6I-O-naphthylallyl derivatives of γ-CD by cross-metathesis.
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the results of other metathesis reactions of allylated CDs
11,25]. In all cases, only the isomer with E configuration of the
Table 1: Preparation of 2-O- (2a), 3-O- (2b) a 6-O- (2c) NA derivatives
of γ-CD by direct alkylation with 2-(3-chloroprop-1-enyl)naphthalene.
[
NA double bond was observed by 1H NMR. Reactions were
performed in benzene at 75 °C or dichloromethane at 45 °C, the
latter giving lower yields. Prior to the isolation, it was neces-
sary to perform deacetylation of the reaction mixture because
the product had the same Rf as the starting material. After the
deprotection, a substantial amount of the pure γ-CD was isolat-
ed as the only byproduct containing CD. Apparently, a concur-
rent reaction – the cleavage of allyl ether – also took place. The
use of similar ruthenium complexes as catalysts for the cleavage
of allyl ethers and allyl esters was described before by Tanaka
et al. [26,27].
entry
base, solvent
yieldsa (%)
2a
2b
2c
1
2
3
4
5
6
7
8
9
1.5 equiv EtONa, DMSO
4 equiv EtONa, DMSO
15 equiv EtONa, DMSO
1.5 equiv LiH, LiI, DMSO
15 equiv LiH, LiI, DMF
10 equiv NaOH, DMSO
15 equiv NaOH, DMSO
20 equiv LDA, DMSO
15 equiv NaH, DMSO
1
6
19
<1
–
–
–
15
3
23
–
24
<1
<1
–
13
14
16
11
<1
–
–
5
<1
–
–
12
Naphthylallylation
aIsolated yields; <1 no isolated yield, – not observed.
The same naphthylallyl derivatives of γ-CD 2a–c were also pre-
pared by direct alkylation of γ-CD with 2-(3-chloroprop-1-
enyl)naphthalene [28] as the alkylation reagent (Scheme 2). small amount of the 3-O-derivative can be present in the reac-
This reagent is easy to prepare on a large scale without a need tion mixture as well. However, in the case of NA derivatives,
of purification by chromatography. Yields of the NA regio- the 3-O-derivative is formed preferentially (Table 1, entries 1
isomers 2a–c were, after isolation by column chromatography, and 4), which is the same outcome we have observed earlier in
in the range 1–24% (Table 1). The optimization experiments for the case of the 3-O-cinnamyl-β-CD [35].
this procedure, followed by TLC, revealed that the products are
formed in all cases, but the yields and regioselectivity depend During the attempts to prepare the 6-O-substituted derivative,
substantially on the amount and the type of a base. Anhydrous we came across unusual changes in the regioselectivity of the
DMSO was selected as a solvent because it often proved to be substitution. In previous publications, we have shown that the
superior to DMF in our previous experiments in alkylations of substitution to the position 6 can be achieved by using an excess
CDs.
of NaOH (30 equiv) in aqueous solvents [11,30,35]. Unfortu-
nately, this method is not applicable for the reaction described
Direct alkylation methods have been studied in CD chemistry in this paper because the alkylation reagent hydrolyzes too fast
over last twenty years [11,14,29-34]. As mentioned before, it is and the desired product is not formed. Attempts to use 30 equiv
possible to direct the alkylation to the specific position just by of a base in nonaqueous solvents also lead only to decomposi-
changing the amount of a base used for the reaction. For exam- tion of the alkylation agent. Therefore, a new set of optimiza-
ple, the alkylation of the secondary rim of CDs can be achieved tion experiments for developing suitable reaction conditions for
by using an equimolar amount of the base. In these cases, the preparation of the 6-O-derivative had to be made. Different
perdominantly the 2-O-substituted product is formed, but a amounts (1.5–20 equiv) and types of bases were used. Interest-
ingly, the highest yields of 6-O-isomer gave 15 equiv of a base;
however, the same conditions gave unexpectedly also the 2-O-
derivative. In experiments with more than 1.5 equiv of a base
(
Table 1, entries 2, 5, 6, 8), the 2-O-derivative was obtained
almost regiospecifically, but entries 3 and 7 gave mixtures of
-O- and 6-O-derivatives. However, the 6-O-derivative can be
obtained regioselectively with 15 equiv of NaH (Table 1, entry
). The robustness of this method was confirmed by an experi-
2
9
ment using just 12 equiv of NaH resulting in practically the
same outcome.
The 2-O-, 3-O- and 6-O-NA regioisomers of γ-CD offer a sig-
nificant advantage – they are separable by column chromatogra-
phy in the elution mixture PrOH/H2O/NH3, which cannot be
achieved for other monoderivatives of α-, β- and γ-CD with
Scheme 2: Preparation of 2-O-, 3-O- and 6-O-NA derivatives of γ-CD
by direct alkylation (see Table 1 for the yields and conditions).
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smaller substituents such as allyl and propargyl having similar small amount of large aggregates might dominate the scattering
Rf and must be peracetylated prior to other separation processes. making the contribution of small particles negligible.
Dynamic light scattering (DLS)
The long-time evolution of all the isomers after filtration was
The supramolecular properties of all regioisomers of NA-γ-CD evaluated according to the approach of Bonini [22] and
2-O-, 3-O-, 6-O-) were investigated by DLS. We analyzed the González-Gaitano [21]. The distribution function of the 3-O-
(
dependence of self-assembling of the isomers on external stimu- isomer shows the presence of a dominant mode with 2.5 nm
li such as agitation and temperature. The 3-O-isomer 2b shows particles immediately after the filtration, which stays intact
co-existence of two types of aggregates: large aggregates throughout the experiment. A minor fraction of larger aggre-
(
around 600 nm in diameter) and smaller aggregates (around gates is formed in solution shortly after filtration whose size
40 nm in diameter, Figure 1). Aggregates formed by 2-O- continuously fluctuate (Supporting Information File 1, Figure
1
isomer 2a were similar to those of the 3-O-sample. On the other S5), which could be easily monitored by scattering intensities
hand, the 6-Ο-isomer 2c produced different results. Since the behavior. The evolution of the 2-O-isomer in time has also been
measurement of this isomer was complicated due to its low investigated, but no trend was observed in this case (Support-
solubility in water, the sample was first dispersed in water and ing Information File 1, Figure S6). The long-time evolution of
then heated to 120 °C in a sealed ampule. The solution became the 6-O-filtered sample revealed that the size of particles contin-
turbid after cooling, which manifests the presence of large parti- uously increased with time (Supporting Information File 1,
cles. Indeed, the DLS experiments revealed large particles of Figure S6), starting from 2 nm particles appearing immediately
the 6-O-sample with sizes larger than 1 μm, exceeding the limit after the filtration and reaching larger particles that grew in the
of the instrument used.
sample standing overnight.
To assess the influence of filtration on the self-assembly of Subsequently, the effect of different solvents on the size of
naphthylallyl regioisomers, samples were then passed through aggregates was investigated by a method proposed by us for
0
.22 μm pores. The volume-weighted DLS distribution func- monocinnamyl-α-CD (Cin-α-CD) derivatives [20]. Two other
tion of the 2-O- and 3-O-samples show a dominant presence of water-solvent mixtures were tested. In 50% MeOH (v/v) solu-
.5 nm particles immediately after the filtration. The sample of tion 2-O- and 3-O-isomer formed aggregates with diameters
the 6-Ο-isomer showed the distribution of sizes ranging from around 200 nm, but the 2-O-derivative contained 50 nm aggre-
2
3
2
0 nm to 200 nm after filtration through 0.22 μm pores and gates as well. Interestingly, the 6-O-isomer formed aggregates
00 nm aggregates after filtration through 1 μm pores. In either with a broad size distribution with a peak at 100 nm (Figure 2).
case, the 6-O-isomer formed aggregates with a broader distribu-
tion of sizes than the 2-O- and 3-O-isomers and no 2–3 nm par- We observed that the 6-O-isomer has a low solubility in water
ticles were observed in the sample. Nevertheless, small parti- and 50% MeOH solution, but it is more soluble in 50% PrOH
cles still may be present in solution because the intensity of (v/v). Consequently, the assembling of the 6-O-derivative was
light scattered by hard spheres is proportional to R6 (R being the investigated in 50% PrOH, which revealed that just 1.4 nm par-
radius) which means that large particles scatter significantly ticles were present in the solution. This means that the 6-O-de-
more light than the same mass of small particles. Thus, a fairly rivative does not form any aggregates in 50% PrOH.
Figure 1: Volume-weighted distribution functions for water solutions of 2-O- (2a), 3-O- (2b), and 6-O- (2c) NA-γ-CD regioisomers before (left) and
after (right) filtration.
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tion function (Figure 3) corresponding to sizes of aggregates
around 80 nm and 400 nm. At 40 °C, just one peak around
3
00 nm appeared, and at 65 °C, two peaks appeared again,
around 100 nm and 300 nm. The 2-O-sample did not show any
temperature dependence.
Transmission cryo-electron microscopy (Cryo-TEM)
The supramolecular properties of the individual regioisomers
(
2-O-, 3-O-, 6-O-) of NA-γ-CD 2a–c and the dependence of the
formation of the self-assembled structures on their concentra-
tion were also determined by Cryo-TEM.
While the 2 mM sample of the 3-O-derivative 2b formed irregu-
lar clumps of fibers of the thicknesses 1–2 and 4–7 nm having a
size of 50 to 100 nm (Figure 4A), the 20 mM sample contained
Figure 2: Distribution functions for 2-O- (2a), 3-O- (2b), and 6-O- (2c)
NA-γ-CD regioisomers in 50% MeOH (v/v).
We investigated the temperature dependence of the aggregate
size of the regioisomers in similar ways as González-Gaitano
[
21] and as we did for Cin-α-CD [20]. The temperature was
raised from 5 °C to 65 °C (5 °C steps) across 2.5 h, which led to
substantial changes in sizes of the aggregates (Figure 3). A shift
of the correlation curve, caused by the change of viscosity, is
noticeable for the 3-O-isomer (Supporting Information File 1,
Figure S4). Up to 30 °C, two peaks around 150 nm and
6
00–700 nm were detected, whereas at 35 °C and above, just
one peak around average size (300–400 nm) appeared. The
increase in hydrophobic interaction at the higher temperature
may be responsible for the observed behavior. The effect of
temperature was not as pronounced as in the case of Cin-α-CD
[
20]. The sample of the 6-O-isomer had to be filtered through
μm pores because of its high turbidity. The sample was equili-
Figure 4: Effect of increasing concentration and sonication on the mor-
phology of the 3-O-derivative 2b. A to C: 2 mM, 20 mM, and 100 mM
unsonicated specimens; D: fibers of the 2 mM specimen after sonica-
tion. Inset: high-magnification detail of the fibers; E: fibers and aggre-
gates of the 100 mM specimen. Scale bars: A–C: 50 nm,
D–E: 100 nm, inset: 20 nm.
1
brated for 3 h before the measurement. The temperature behav-
ior of the 6-O-derivative was similar to the 3-O-isomer. At the
low temperature (25 °C), two peaks are visible on the distribu-
Figure 3: Volume-weighted distribution functions for the 3-O- (2b) and 6-O- (2c) NA-γ-CD regioisomer at different temperatures.
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Beilstein J. Org. Chem. 2017, 13, 2509–2520.
smaller spherical clusters of size 20 to 30 nm (Figure 4B),
which formed large aggregates with the size of hundreds of nm
in the 100 mM sample (Figure 4C). It is evident that the method
of aggregation and the morphology of the specimen vary with
increasing concentration. Sonication, conducted for 2 mM and
1
00 mM samples, resulted in a diametrically different arrange-
ment of the fibers (Figure 4D and E). Both sonicated solutions
contained several µm long bundles of fibers with thicknesses of
1
.5–10 nm; in the 100 mM sample, also particles having diame-
ters from 30 to 120 nm were present.
Smaller spherical particles of β-CD, which tend to combine into
larger aggregates, were also observed by Bonini et al. [22], who
described the presence of clusters of different sizes and shapes
in one sample as well as the dependence of the cluster proper-
ties on the concentration. The 2 mM and 20 mM solution of
2
-O-derivative 2a formed clusters of similar shape and size as
the 3-O-derivative 2b (Figure 5A and B). In the 100 mM sam-
ple, the presence of large quantities of material rarely forming
large particles, was evident (Figure 5C). A 10-minute sonica-
tion led just to the disappearance of the larger aggregates, no
fibers in a μm scale were detected.
Figure 6: Effect of increasing concentration and sonication on the mor-
phology of the 6-O-derivative 2c. A: 0.5 mM specimen after sonication.
Inset: enlarged area indicated by the white dashed rectangle. Arrows
indicate the NA-γ-CD fibers; B: 5 mM sonicated specimen;
C: 5 mM unsonicated specimen. Scale bars: 50 nm, inset: 10 nm.
The 6-O-derivative 2c, due to its low solubility, was measured pure solvent and to the dilute solution in subsequent injections
only at low concentrations of 0.5 mM and 5 mM (Figure 6A, (see Supporting Information File 1 for more details and the
B). In the 0.5 mM solution, only short fibers were found, model description).
whereas in the 5 mM sonicated solution, fibrous aggregates,
similar to those of 2 mM unsonicated samples 2-O- and 3-O- The fit of experimental and calculated values of the normalized
derivatives, were observed. In an unsonicated 5 mM prepara- heat per injection (NDH) was quite satisfactory for 2-O- (2a)
tion, we observed many sheet-like structures (Figure 6C), corre- and 3-O- (2b) NA-γ-CD at all measured temperatures. Fits for
sponding to the observations of Bonini et al [22].
the less soluble 6-O- (2c) were less satisfactory at 10 and 25 °C
and failed at 45 °C. Results at 10 °C are shown in Figure 7.
Isothermal titration calorimetry (ITC)
ITC experiments on NA-γ-CD cannot be carried out as clas- Estimated thermodynamic parameters and average degrees of
sical titration experiments, i.e., by injecting the ligand solution polymerization at various temperatures are collected in Table 2.
into a solution of the receptor [36], because complementary The values for 6-O-NA-γ-CD at 45 °C are omitted and the
complexing moieties are covalently bonded. Instead, the values for 6-O-NA-γ-CD at 10 °C and 25 °C are given in paren-
so-called dissociation [37] or release [38] experiment had to be theses because of their low reliability. Nevertheless, even those
used, in which a solution of a complex is injected initially into a values, as well as those for 2-O-NA-γ-CD and 3-O-NA-γ-CD at
Figure 5: Effect of increasing concentration and sonication on the morphology of the 2-O-derivative 2a. A: 2 mM unsonicated specimen;
B: 20 mM unsonicated specimen; C: 100 mM sonicated specimen. The arrow indicates an aggregated particle. Scale bars: 50 nm, inset: 10 nm.
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Beilstein J. Org. Chem. 2017, 13, 2509–2520.
Figure 7: Heat change for injection per mole of NA-γ-CD added as a function of the total concentration of NA-γ-CD at 10 °C. Symbols are used for ex-
perimental values; lines for fits: 6-O-NA-γ-CD 2c squares and a dashed line; 2-O-NA-γ-CD 2a diamonds and a full line; 3-O-NA-γ-CD 2b
triangles and a dashed-dotted line.
Table 2: Estimated thermodynamic parameters for complexation of NA-γ-CD regioisomers.
sample
T (°C)
K (dm3/mol)
ΔH (cal mol−1)
TΔS (cal mol−1)
nna
nwb
2c
2b
2a
10
(1215)
(418)
–
(−2783)
(−2439)
–
(1395)
(1176)
–
(4.02)
(2.60)
–
(7.04)
(4.20)
–
2
5
5
4
10
2857
2644
1193
5657
3489
1619
−2903
−3654
−4463
−3303
−3667
−4466
1795
1328
317
5.87
5.67
3.99
8.04
6.43
4.55
10.74
10.33
6.98
2
5
5
4
10
1806
1490
533
15.08
11.86
8.11
2
5
5
4
aNumber-average degree of polymerization calculated for 10 mM solution. bWeight-average degree of polymerization calculated for 10 mM solution.
all three temperatures correspond to values found for γ-CD and weight average degrees of polymerization (nn and nw) are given
aromatic compounds [39]. Binding of the 2-O-regioisomer is by standard relations derived for polycondensation [40]
stronger than that of the 3-O-regioisomer, and consequently,
longer oligomers can be expected for it.
(2)
The fraction of suprapolymer with polymerization degree n is
then given for negligible cyclisation as
(1)
The values of nn and nw calculated from ITC results for 10 mM
solutions of NA-γ-CD are also presented in Table 2.
where θ is the degree of occupation, i.e., the probability that the
particular group, either naphthyl or CD, is in a bound state. θ is NMR spectroscopy
determined by the binding constant and NA-γ-CD concentra- The supramolecular behavior of the regioisomers was further
tion (see Supporting Information, File 1). Number average and examined by 1H NMR. The measurements were performed in
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D2O, where the strongest intermolecular interactions are ex- Chemical shifts of hydrogen signals of 3-O-derivative at con-
pected. The concentration dependence of chemical shifts was centrations 100 and 10 mM do not significantly differ
taken as their indicator. The 6-O-isomer 2c was excluded from (Figure 9). However, a change in the shape of signals and the
these experiments because its solubility in water is very limited; narrowing (0.12 ppm) of the signals are apparent in the
samples cannot be prepared at concentrations greater than aromatic region (A). For the 1 mM sample, chemical shifts in
5
mM.
the aromatic and double bond areas evidently move downfield;
however, shapes of peaks do not much differ from the 10 mM
Spectra for 2-O- (2a) and 3-O- (2b) derivatives were measured sample. It is also worth noting, that while the distance between
at concentrations of 100, 10, and 1 mM. Although these regio- signals B and C increased (by about 0.07 ppm), the area of
isomers are quite soluble in water, turbidity becomes noticeable aromatic protons A narrowed (about 0.21 ppm).
after a longer time, and in the case of 100 mM specimens, even
precipitation of a solid was observed. The turbidity caused the For all of the above cases, the changes of chemical shifts and
worse quality of 1H NMR spectra; however, chemical shifts and shapes of signals in the CD hydrogens’ area were minimal.
changes in the shape of the peaks are clearly visible.
Also, NOESY and ROESY experiments did not indicate any
interaction between the NA group and the CD cavity (data not
For the 2-O-derivative, chemical shifts of hydrogens of the shown).
aromatic region and hydrogens of the double bond moved
Summarization and discussion of results of
upfield with increasing concentration; therefore, their values are
lower (Figure 8). The change in the signal shapes, especially of different methods
aromatic hydrogens (A), is also evident. With increasing con- We have successfully employed two synthetic approaches to
centration, the distance between signals B and C of the double 2I-O-, 3I-O- a 6I-O-NA derivatives of γ-CD. The first approach
bond hydrogens is reduced (about 0.05 ppm), as well as the is based on a cross-metathesis reaction between corresponding
extent of the area of aromatic hydrogens A (0.13 ppm).
regioisomers of mono-O-allyl derivatives of γ-CD and 2-vinyl-
Figure 8: 1H NMR spectra of 2-O-derivative 2a in D2O at concentrations of 100, 10, and 1 mM.
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Figure 9: 1H NMR spectra of 3-O-derivative 2b in D2O at concentrations of 100, 10, and 1 mM.
naphthalene yielding 16–25%; however, the overall yield from also inserted into the CD cavity which would increase the dis-
γ-CD is only 2–5%. The second approach is based on the direct tance between CD and NA hydrogens. Thus, the co-existence of
alkylation of γ-CD, with easy to prepare 3-(naphth-2-yl)allyl various interactions such as inclusion of NA to various depths
alkylation reagent, yielding up to 24%. Moreover, we achieved of the CD cavity, stacking of naphthyl rings either inside or
high regioselectivity in preparations of all regioisomers using outside the CD cavity (possibly leading to micellization or
the second approach, so this method proved to be superior.
aggregation) must be expected.
From the NMR experiments, we conclude that the signals of The intermolecular interactions were quantified by ITC. The
hydrogens of the naphthylallyl group of 2-O- and 3-O- obtained values of binding constants were in the upper range of
derivatives differ not only in the shape of peaks, but also in the values usually found for the inclusion complexation of γ-CD
value of the chemical shifts. For both regioisomers the concen- [42] and decreased in the order (i) 2-O-, (ii) 3-O-, and (iii) 6-O-,
tration dependence of chemical shifts in aromatic and allyl areas as well as with temperature. The values were obtained from the
indicates intermolecular association such as inclusion of the fit to the model in which NA-γ-CD is taken as a ditopic mono-
naphthylallyl moiety into the cavity of γ-CD or π stacking of mer of the AB type with groups A and B undergoing an associa-
naphthyls. The absence of the significant concentration depen- tion of 1:1. However, a number of alternate or competing inter-
dence of chemical shifts of the CD hydrogens does not actions may occur, as mentioned above, γ-CD is known to form
disqualify inclusion complexation because changes of chemical also inclusion complexes of 2:1 stoichiometry and formation of
shifts by 0.01 ppm or less were observed upon inclusion of an cyclic supramolecular structures my also occur. Moreover to
aromatic guest into the γ-CD cavity [41]. To reconcile the make the situation more complex, the change of the stoichiome-
absence of interactions CD/NA in NOESY and ROESY experi- try from 1:1 to 2:2 upon the increase in concentration has been
ments with NA inclusion into CD is more difficult. Neverthe- reported for a naphthalene–β-CD complex; the concurrently ob-
less, the change in chemical shifts was observed also for the served increase in excimer indicated close pairing of naphtha-
allyl hydrogens which indicates that the allyl group might be lene molecules [43]. Nevertheless, the good fit, observed at
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Beilstein J. Org. Chem. 2017, 13, 2509–2520.
least for the 2-O- and 3-O-regioisomers, identifies the 1:1 com- ed regioisomers. The difference is easier to explain considering
plexation as the probably dominant associative process.
inclusion complexation of NA-γ-CD rather than interaction of
NA groups only. Consequently, even though no direct evidence
The presence of unimers and/or short oligomers was confirmed for inclusion complexation of NA-γ-CD was obtained it should
by DLS even though objects with corresponding hydrodynamic not be omitted from considerations, especially because the
diameters of a few nm were observed only in solutions of the inclusion complexation of naphthalene derivatives with CDs
2
0
-O- and 3-O-regioisomers after filtration through a filter with (including γ-CD) is so well established [42].
.22 μm pores. Indeed, larger particles with diameter in the
range of tens and hundreds nm dominate the scattering, and The experiments performed clearly demonstrate the supramo-
such large objects of various morphologies were also detected lecular behavior of newly synthesized NA-γ-CDs in solution; at
by cryo-TEM. In this respect, the behavior of NA-γ-CD regio- the same time, the experiments showed the anticipated forma-
isomers is similar to native CDs for which unstable large tion of linear NA-γ-CD suprapolymers based on inclusion com-
objects are also observed [22]. Thus, the supramolecular behav- plexation as a somewhat naive concept – other interactions, e.g.,
ior of NA-γ-CD seems to be determined not only by the interac- naphthalene stacking may occur between two NA-γ-CD mole-
tions of NA and γ-CD but also by interactions of the subparts of cules; in addition, mutual interactions of more than two
the same type, i.e., NA/NA and γ-CD/γ-CD. In Figure 10 NA-γ-CD molecules may occur, leading to branched supramo-
various putative interactions of NA-γ-CD are schematically lecular structures or aggregation. It is to be hoped that the future
depicted indicating how small supramolecular structures such as research not only reveals details of NA-γ-CD interactions but
supramolecular oligomers or micelles as well as large one such also show how to utilize them in construction of functional
as aggregates can originate.
supramolecular assemblies.
Conclusion
New methods for highly regioselective mononaphthylallylation
of γ-CD to positions 2-O-, 3-O-, and 6-O- were developed. The
alkylation reagent 2-(3-chloroprop-1-enyl)naphthalene, used for
the reactions, can be easily prepared in large quantities without
the need for chromatographic separation. The method origi-
nally expected to be used for the preparation of the regio-
isomers based on the metathesis of allyl-γ-CD derivatives
proved to be inferior, giving about a 6 times lower overall yield
than the mononaphthylallylation procedure. Compared to allyl
derivatives, the NA-γ-CD derivatives are easy to prepare and
purify. Due to the presence of the double bond in the NA group,
they can be used as starting compounds for preparation of other
monosubstituted γ-CD derivatives.
Figure 10: Putative objects and interactions in naphthylallyl-γ-CD solu-
tion, depicted schematically for 6I-O-naphthylallyl-γ-CD (2c). (a) Cyclic
supramolecular dimer based on inclusion complexation. (b) Interac-
tions between naphthyl groups (stacking) leading to micellization or
aggregation. (c) Inclusion complexation of naphthyl into the CD cavity
leading to supramolecular polymerization. (d) Free 2c. (e) Interaction
between CD moieties leading to aggregation or precipitation.
We demonstrated that the supramolecular properties of indi-
vidual NA-γ-CD regioisomers substantially differ. The largest
difference is being observed between 2-O- and 3-O-isomers on
one hand and the 6-O- on the other. To explain the differences
As all three NA-γ-CD regioisomers were prepared, the effect of in the size of objects observed by different methods, various
the substituent position could be assessed. Particularly, differ- types of interactions have to be taken into account.
ent behavior was observed especially between the 2-O-, 3-O-
regioisomers on the one hand and the 6-O-one on the other.
Supporting Information
There are two underlying structural differences: (i) NA groups
face the wider CD side in the head-tail arrangement of 6-O-
Supporting Information File 1
isomers, (ii) the spacer of the 6-O-isomer is elongated by a CH2
group of glucose unit. The details of differences in behavior in
water could not be fully assessed due to the low solubility of the
Experimental part and data for compounds 2a, 2b, and 2c:
copies of NMR spectra and DLS.
[http://www.beilstein-journals.org/bjoc/content/
6
-O-regioisomer. In fact, the low solubility of the 6-O-regio-
supplementary/1860-5397-13-248-S1.pdf]
isomer is the most striking difference in behavior of investigat-
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2
4.Gèze, A.; Aous, S.; Baussanne, I.; Putaux, J.; Defaye, J.;
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The work has been supported by the Czech Science Foundation
(
project No. 13-01440S and 17-07164S), the Charles Univer-
25.Šnajdr, I.; Janoušek, Z.; Jindřich, J.; Kotora, M. Beilstein J. Org. Chem.
sity (project No. UNCE 204022), and the Ministry of Educa-
2010, 6, 1099–1105. doi:10.3762/bjoc.6.126
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7
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