Selective Secondary Face Modification of Cyclodextrins by Mechanosynthesis

Article abstract of DOI:10.1021/acs.joc.5b00697

α-, β-, and γ-cyclodextrins (CDs) were modified on their secondary face by mechanosynthesis at room temperature using a laboratory-scale ball-mill. Mono-2-tosylated α-, β-, and γ-CDs were obtained in good yield from mixtures of native α-, β-, and γ-CDs, r

Full text of DOI:10.1021/acs.joc.5b00697

Subscriber access provided by NEW YORK UNIV
Article
Selective secondary face modification of cyclodextrins by mechanosynthesis
Stephane Menuel, Bertrand Doumert, Sébastien SAITZEK, Anne
Ponchel, Laurent Delevoye, Eric Monflier, and Frédéric Hapiot
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00697 • Publication Date (Web): 22 May 2015
Downloaded from http://pubs.acs.org on May 26, 2015
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 27
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
Selective secondary face modification of cyclodextrins by
mechanosynthesis
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Stéphane Menuel,† Bertrand Doumert,‡ Sébastien Saitzek,† Anne Ponchel,† Laurent Delevoye,§ Eric
Monflier,† and Frédéric Hapiot*,†
†Unité de Catalyse et de Chimie du Solide ꢀ UCCS, CNRS UMR 8181, Université d’Artois, Faculté
des Sciences Jean Perrin, SP18, 62307 Lens Cedex, France
Eꢀmail address: frederic.hapiot@univꢀartois.fr
‡Fédération M.E. Chevreul, CNRS FR2638, Université de Lille, Cité Scientifique, Bâtiment C4 ꢀ BP
90108 59652 Villeneuve d'Ascq Cedex, France
§Unité de Catalyse et de Chimie du Solide ꢀ UCCS, CNRS UMR 8181, Ecole Nationale Supérieure de
Chimie de Lille, Université de Lille, Cité Scientifique, Bâtiment C7 ꢀ BP 90108, 59652 Villeneuve
d'Ascq Cedex, France
Keywords: cyclodextrins • green chemistry • solidꢀstate synthesis • hydrophobic effect • hostꢀguest
systems
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 27
1
2
3
4
5
6
7
8
9
Abstract: αꢀ, βꢀ and γꢀcyclodextrins (CDs) were modified on their secondary face by
mechanosynthesis at room temperature using a laboratory scale ball mill. Monoꢀ2ꢀtosylated αꢀ, βꢀ and
γꢀCDs were obtained in good yield from mixtures of native αꢀ, βꢀ and γꢀCDs, respectively, Nꢀ
tosylimidazole and an inorganic base, each of them being in the solid state. The yields appeared to be
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
dependent upon the nature of the base and the reaction time. A kinetic monitoring by H NMR
spectroscopy demonstrated that the highest yields in monoꢀ2ꢀtosylꢀCDs were measured using KOH as
a base in very short reaction times (up to 65% in 80 s). Monoꢀ(2,3ꢀmannoꢀepoxide) αꢀ, βꢀ and γꢀCDs
were subsequently synthesized by ballꢀmilling a mixture of monoꢀtosylated αꢀ, βꢀ and γꢀCDs,
respectively, and KOH. The characterization of the modified CDs was carried out by XꢀRay
diffraction, mass spectrometry, solidꢀstate NMR and Diffuse Reflectance UVꢀVis (DR UVꢀVis)
spectroscopies. Clues on the supramolecular arrangement of the molecules in the solid state provide
information on the reaction mechanism.
Introduction
During the past forty years, countless publications relating to cyclodextrins (CDs) and their
applications have contributed to the academic and industrial development of supramolecular
chemistry.1 CDs are torusꢀlike macrorings built up from αꢀDꢀglucopyranose units linked together by αꢀ
1,4 glycosidic bonds (Scheme 1). The ability of native (unmodified) CDs to include molecular guests
within their cavity has been widely exploited in many different fields such as drug formulations,2,3
polymer properties control,4,5 rotaxanes6 and hydrogels preparation,7,8 photochemistry,9 metalꢀorganic
framework.10 However, the range of organic substrates capable of being supramolecularly recognized
by the cavity of native CDs is limited. To enrich the number of CDs as molecular hosts, synthetic
procedures to chemically modify their structure have been developed. Many functional groups or
substituents have been covalently grafted onto the CD primary and/or secondary face and the scope of
applications has then been broadened to an impressive extent. For example, substituted CDs found
ACS Paragon Plus Environment

Page 3 of 27
The Journal of Organic Chemistry
1
2
3
4
5
application in catalysis,11ꢀ16 enzyme mimics,17,18 materials19,20 or drug delivery systems,21,22 to name
only a few possible uses.
6
7
8
9
While random substitution is relatively easy to perform, selective modification of the CD structure is a
much more delicate task. Extensive efforts have been made to selectively substitute the CD primary
and/or secondary faces.23ꢀ29 However, most of the synthetic procedures implemented for these
modifications required the use of organic solvents, tedious workups and timeꢀconsuming
purifications.21,22 Accordingly, the utilization of substituted CDs on a large scale is hardly conceivable,
thus hampering their industrial development. To translate scientific innovations into productive and
costꢀeffective technology, novel chemical processes should be developed so that modified CDs are
accessible in large quantities.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Recently, mechanochemistry30 appeared as an ecoꢀfriendly alternative to access inorganic,31ꢀ34
organic35ꢀ44 or metalꢀorganic compounds,45,46 and even supramolecular host47 and complexes48 showing
different properties to those prepared by conventional routes. For example, antiꢀinflammatory
CD/drug composites with much higher dissolution rates were mechanochemically prepared by high
energy milling.49 Mechanosynthesis is related to chemical reactions induced by mechanical energy.
The mechanical constraints greatly enhanced the reaction selectivity thus limiting the number of
purification steps. Mechanosynthesis is usually carried out using ball mills that grind and homogenize
powders quickly and efficiently by impact and friction. Concurrently to mechanochemical milling
derivatization of saccharides,50,51 the technique has already been successfully applied to native CDs or
their derivatives to favour complexation of organic molecules52 or organic reactions in the solid state
within the CD cavities.53,54 However, nothing has been described so far on the mechanosynthesis of
modified CDs. In this context, we envisaged mechanosynthesis as a tool to modify the secondary face
of CDs. We focused our efforts on monoꢀ2ꢀtosylꢀCDs (α: 1, β: 2, γ: 3) and monoꢀ(2,3ꢀmannoꢀ
epoxide)ꢀCDs (α: 4, β: 5, γ: 6) (Scheme 1) which are common precursors to functionalize the CD
secondary face.23 Although the synthesis of monoꢀ6ꢀtosyl CDs has been widely optimized throughout
the past thirty years,55ꢀ57 tosylation on the 2ꢀOH remains very tricky and low yields are mainly
obtained.58ꢀ66 Herein we clearly demonstrate that mechanosynthesis is a valuable tool to access these
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 27
1
2
3
4
5
6
7
8
9
compounds in good yields on a very short reaction time. We especially describe the solventꢀfree
synthetic procedure and characterization of the obtained products. With the support of XꢀRay
diffraction, mass spectrometry, solidꢀstate NMR (SSNMR) and DR UVꢀVis spectroscopy, a
mechanism is also proposed to explain the high selectivity of tosylation at the Cꢀ2 position.
Additionally, we also demonstrate that the monoꢀ(2,3ꢀmannoꢀepoxide)ꢀCDs 4, 5 and 6 are readily
accessible from 1, 2 and 3 by mechanosynthesis in good yields very rapidly.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. Synthesis of monoꢀ2ꢀtosyl CDs (α: 1, β: 2, γ: 3) and monoꢀ(2,3ꢀmannoꢀepoxide) CDs (α:
4, β: 5, γ: 6). TsIm: Nꢀtosylimidazole.
Results and Discussion
Synthesis of monoꢀ2ꢀtosylꢀCDs
To tackle the very challenging selective 2ꢀOH monoꢀtosylation, we used a laboratory scale ball mill
(Retsch MM400) equipped with 10 mL zirconia grinding jars containing a zirconia ball (9 mm ∅).
The grinding jars performed radial oscillations in a horizontal position. Native CDs and Nꢀ
tosylimidazole (TsIm) in the solid state (stoichiometric proportions) were poured in the grinding jars
which were subsequently shaken at room temperature at a 30 Hz ball milling frequency (frequency of
the rocking backꢀandꢀforth motion conducted by the reaction jar holder). Samples were regularly
1
collected, dissolved in DMSOꢀd6 and analysed by H NMR to determine (by comparison with
reference spectra) the conversion and selectivity. Considering αꢀCD as starting material, no reaction
took place even after 1.5 h without any base whatever the frequency. Similarly, no product could be
obtained using 1 equiv. NaHCO3 or Li2CO3 as a base. Conversely, other carbonates (Na2CO3, K2CO3,
ACS Paragon Plus Environment

Page 5 of 27
The Journal of Organic Chemistry
1
2
3
4
5
Rb2CO3 and Cs2CO3) proved to be effective to activate the Cꢀ2 position. As shown in Fig. 1,
conversions of TsIm not only depended on the nature of the base but also on the reaction time.
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. Conversion of TsIm with time using Li2CO3 (ꢀ), Na2CO3 (ꢀ), K2CO3 (ꢀ), Rb2CO3 (ꢀ) and
Cs2CO3 (ꢀ) for the synthesis of 2.
Optimal conversions were almost reached within 6 min. Longer reaction times did not significantly
improve the conversions. From sodium carbonate to rubidium carbonate, there seemed to be a
correlation between both the water solubility and the size of the base counterion and the ability of the
base to rapidly activate the 2ꢀOH group of αꢀCD (see the Supporting Information, S34). In this
context, the size of the most water soluble Rb2CO3 appeared to be the most appropriate to react with
the 2ꢀOH function. Though the reaction proceeded in the solid state, it is known that the CDs contain
residual water molecules (especially outside the hydrophobic cavity). Their presence might favor both
the diffusion of the base through the aqueous interstitial channels of the CD solid network and the
subsequent activation of the Cꢀ2 hydroxyl group. Note that the larger size of cesium could explain the
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 27
1
2
3
4
5
6
7
8
9
lower conversion measured using Cs2CO3 as a base (see Supporting Information, S30). Other insights
will be given below to substantiate the effect of the base on the 2ꢀOH activation. Interesting results
were also observed using hydroxyl bases. LiOH, NaOH and KOH gave similar results whatever their
water content. Indeed, an experiment realized with dried KOH led to the same conversion and
selectivity. Hydroxyl bases all proved to be faster than carbonates to activate the Cꢀ2 position. Indeed,
a rapid conversion of native αꢀCD and TsIm (more than 90% conv. within 1 min) into 1 was observed
(Fig. 2). Nowhere in the literature does one find such a rapid process to convert native CDs into CDs
functionalized on their secondary face. However, performing the reaction over a longer period of time
(>15 min.) strongly affected the yield in 1 which was slowly converted into monoꢀ(2,3ꢀmannoꢀ
epoxide)ꢀCDs. Small quantities of polytosylated sideꢀproducts were also detected by mass
spectrometry (see Supporting Information, S39).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 2. Variation of the proportions of TsIm and products with time at room temperature and 30 Hz
frequency using αꢀCD as a starting material and KOH as a base. TsIm (ꢀ), 1 (ꢀ), pꢀtoluenesulfonic
acid (ꢀ), polytosylated sideꢀproducts (ꢀ).
ACS Paragon Plus Environment

Page 7 of 27
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
The CD hydration rate was also varied to assess its impact on the tosylation reaction. Experiments
were carried out with anhydrous βꢀCD (prepared by azeotropic distillation with toluene) and the
results were compared to those obtained with βꢀCD containing 10% weight water. No difference was
observed neither in terms of conversion nor selectivity.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
We then sought to optimize the syntheses by varying the ball milling frequency and the reaction time
using two different methods. In the first approach (Method A), the CD and TsIm were ball milled in
stoichiometric proportions for 2 min and KOH (1 equiv.) was added afterwards. In a second approach
(Method B), the CD and KOH were first mixed together in stoichiometric proportions and TsIm (1
equiv.) was subsequently added. Whatever the method (A or B), the mixtures were shaken at 15, 25 or
30 Hz. From the TsIm conversion, kinetic profiles were drawn at three different frequencies as a
function of the reaction time (Fig. 3).
Figure 3. TsIm conversion with time for αꢀCD as starting material and KOH as a base using: Method
A at 15 Hz (ꢀ), Method A at 25 Hz (ꢀ), Method A at 30 Hz (ꢀ), Method B 15 Hz (ꢀ), Method B at
25 Hz (ꢀ), Method B at 30 Hz (ꢀ).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 27
1
2
3
4
5
6
7
8
9
Apart from the experiments realized at 25 Hz for which the same conversion was observed within 11
min following a different profile, no significant difference was noticed between Method A and
Method B in terms of reactivity. The best results were obtained at 30 Hz, suggesting that higher
frequencies led to an increase in both the temperature and the surface area with beneficial effects on
the chemical activity of the powders. In that case, 100% and 98% TsIm were converted within 1 min
using Method A and Method B, respectively. However, Method A was more selective than Method B
as higher proportion of 1 were formed using Method A (69% vs 59% for Method B). Accordingly, the
order of addition of the reactants is not inconsequential. Mixing first the CD and the base (Method B)
favored the formation of polytosylated CDs upon addition of TsIm, thus affecting the yield in 1. In
terms of purity and yields, the current approach was far more effective than synthetic procedures from
the literature for which a preliminary protection of the CD primary face was often required and low
yields of products were isolated.58,67,68
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The scalingꢀup of the process was carried out using a 50 mL stainless steel grinding jars containing
one steel ball (25 mm ∅, 63.2g) using Method A. 100% TsIm were converted within 2 min. Though
already high compared to literature data, the conversions could probably be further optimized by a
judicious choice of the ball milling apparatus, especially for large quantities of reactants.
Characterization
To get more information on the selectivity of the tosylation reaction in 2ꢀposition, reactants and
products were analysed through 13C CP/MAS solidꢀstate NMR experiments. As previously reported by
Pessine et al.,69 13C chemical shift of molecular guests were affected by several ppm as an evidence of
encapsulation into the CD cavity. The 13C NMR spectrum of a 1/1 mixture of native βꢀCD and TsIm
was compared to those of the separated components (Fig. 4a).
ACS Paragon Plus Environment

Page 9 of 27
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 4. 13C CP/MAS NMR spectra of a) TsIm and b) a 1/1 mixture (1.3 mmol each) of native βꢀCD
and TsIm at 25 °C.
No chemical shift change of the 13C signals assigned to the CD (region 59ꢀ105 ppm) was evidenced.
No amorphization occurred during mechanosynthesis as revealed by the similar 13C linewidths
measured for native CD and in the mixture. However, a clear variation of the chemical shift was
observed for those aromatic protons of the TsIm in the mixture (Fig. 4b), suggesting an interaction
between the native βꢀCD and tosylimidazole.
As a complement to 13C CP/MAS NMR and in order to probe the spatial proximity of TsIm and βꢀCD,
1
we resorted to Hꢀ1H doubleꢀquantum/singleꢀquantum (DQꢀSQ) spectroscopy. It must be emphasized
that DQꢀSQ makes use of the homonuclear dipoleꢀdipole coupling to yield correlations between pairs
of protons in a twoꢀdimensional (2D) fashion. In practice, crossꢀpeaks at chemical shift δ1+δ2 in the
DQ dimension, reflect the short distance, thus the proximity, between protons of two types at chemical
shift δ1 and δ2 in the SQ dimension.70,71 The 1Hꢀ1H 2D spectrum of a 1/1 mixture of native βꢀCD and
TsIm (1.3 mmol each) is presented in Fig. 5. Here, the use of highꢀfield (B0=18.8 T) and ultraꢀhigh
spinning speed (MAS spinning frequency of 60 kHz) was highly beneficial in terms of resolution, as
1
1
demonstrated by the H 1D MAS NMR spectrum (top projection, Fig. 5). The H MAS NMR
spectrum showed two chemical shift regions, assigned to the CD (2 to 7 ppm) and to TsIm (7 to 8
ppm). The DQꢀSQ spectrum clearly revealed crossꢀcorrelation between the aromatic imidazolium
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 27
1
2
3
4
5
protons (in the 8.5ꢀ7.5 ppm region) and the βꢀCD protons (in the 4.2ꢀ3.5 ppm region), indicative of the
inclusion of the imidazole moiety into the CD cavity.
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
Figure 5. Hꢀ1H DoubleꢀQuantum MAS NMR spectrum of a 1/1 mixture of native βꢀCD and
tosylimidazole (1.3 mmol each) at 25 °C.
DR UVꢀvisible spectroscopy was also informative on the formation of new species during the course
of the reaction. When increasing amounts of TsIm were added to native CDsꢀcontaining solutions, an
absorption characteristic of a new electronic transition was revealed in the 270ꢀ280 nm region (see
Supporting Information, S35). The changes in the position and intensity of the band are assumed to
results from changes in the solid microenvironment upon inclusion of TsIm into the CD cavity. The
red shift in the absorbance maximum (bathochrome effect) was presumably caused by the imidazole
ring being complexed in the hydrophobic interior of the CD cavity as already shown for other aromatic
guests.72 Knowing that the thermodynamic activity of pure substances in the solid phase is normally
ACS Paragon Plus Environment

Page 11 of 27
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
taken as unity, the stoichiometry of the CD/TsIm complexes could be determined by DR UVꢀvis
spectroscopy through a method of continuous variation (Job’s plot). As an example, the Job’s plot of
the αꢀCD/TsIm couple is given in Fig. 6. Although the solid CD/TsIm mixture could not be as
homogeneous distributed as in solution, the DR UVꢀvis data tend to support the hypothesis of a 2:1
equilibrium with a maximum shift of 0.08 at f(TsIm) 0.3, meaning that two CDs interacted with only
one TsIm (SI). Increasing the size of the CD cavity (βꢀCD and γꢀCD) also led to a 2:1 stoichiometry
for the CD/TsIm complex (see Supporting Information, S36 and S37).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 6. Continuous variation plot (Job’s plot) derived from UVꢀvis measurements realized at 20 °C
and 30 Hz for 2 min (see Supporting Information) for αꢀCD/TsIm mixtures. f(TsIm) =
[TsIm]/([TsIm]+[αꢀCD]). A = absorbance of αꢀCD/TsIm mixtures (total amount = 2.65 mmol). A0 =
absorbance of TsIm (2.65 mmol).
The interaction between the CDs and imidazole was also highlighted by XꢀRay Diffraction (XRD).
Fig. 7 shows the XRD patterns of βꢀCD and βꢀCD/KOH as prepared by ballꢀmilling (30 Hz, 2 min).
The XRD pattern of βꢀCD (Fig. 7a) presents a crystalline structure similar to that described by C.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 27
1
2
3
4
5
6
7
8
9
Betzel et al.73 It crystallized in monoclinic structure with P21 space group and whose lattice parameters
were a = 21.261 (6) Å, b = 10.306 (3) Å c = 15.123 (4) Å and β = 112.3 (5)°. The XRD pattern of βꢀ
CD/KOH (Fig. 7b) had the same characteristic peaks than the unmixed βꢀCD. Only a slight
amorphization resulting in a broadening of the diffraction peaks (beginning of the formation of an
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
amorphous halo between
2θ =16.5° and 22°) was observed. KOH is a deliquescent solid through air
moisture. Therefore it is possible that it deteriorated, thus explaining the absence of any diffraction
peak. To check whether there was a deliquescence of KOH, a XRD pattern of KOH was performed
after ball milling. The diffractogram was achieved immediately after grinding under dry atmosphere,
as for the βꢀCD/KOH sample. The XRD pattern (inset in Fig. 7) showed that KOH crystallized in its
hydrated form (KOH,H2O) with a monoclinic structure (JCPD No. 36ꢀ0791). No peak attributable to
the KOH,H2O phase was identified in the βꢀCD/KOH sample (Fig. 7). The absence of peak could be
explained by the deliquescence of KOH resulting from the βꢀCD crystallization water molecules
during the ballꢀmilling process. However, this did not explain the shift of the diffraction peaks toward
smaller angles values. Indeed, this shift could be explained by a slight increase in the crystallographic
cell compared to the initial βꢀCD, probably caused by an interaction between βꢀCD and KOH.
Fig. 8 shows the XRD patterns of βꢀCD, TsIm and βꢀCD/TsIm compound obtained by ballꢀmilling (30
Hz, 2 min). The diffractograms of the βꢀCD/TsIm and the initial compounds differ markedly in their
diffraction peaks positions. In other words, the XRD pattern obtained for βꢀCD/TsIm compound was
not the direct superposition of diffractograms from starting compounds. It was no longer possible to
distinguish the characteristic peaks of TsIm (arrows in Fig. 8b). This behaviour could be explained by
the encapsulation of the "guest" molecule into the βꢀCD cavity or the reaction between the two
precursors giving rise to a new crystallized structure.
ACS Paragon Plus Environment

Page 13 of 27
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 7. XRD patterns of βꢀCD (a), βꢀCD/KOH (b) and KOH (c) after mixing in a ballꢀmill at 30 Hz
for 2 min.
Mechanism
Spectroscopic and diffraction data outlined above prompted us to propose a mechanism to explain the
selectivity of the tosylation at the 2ꢀposition. In the first step, CD/TsIm supramolecular complexes
formed rapidly by inclusion of the hydrophobic methylphenyl moiety of TsIm into the CD cavity
(Scheme 2). In the second step, the 2ꢀOH and 3ꢀOH protons are deprotonated. Indeed, they have
similar pKA and can undergo a rapid deprotonation.74
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 27
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 8. XRD patterns of (a) βꢀCD, (b) TsIm and (c) βꢀCD/TsIm after mixing in a high energy ballꢀ
milling at 30 Hz for 2 min.
However, the above data clearly showed that the existence of a supramolecular CD/TsIm complex
selectively oriented the tosylation reaction on the 2ꢀOH group. Indeed, once TsIm was included into
the CD cavities, only the deprotonated 2ꢀOH groups (inwardly facing the CD cavities) could react in a
third step with the tosylate functions, thus leading selectively to monoꢀ2ꢀOꢀtosyl CDs. The
ACS Paragon Plus Environment

Page 15 of 27
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
deprotonated 3ꢀOH group, for its part, remained unchanged as it pointed outside the CD cavity. Thus,
the 2ꢀtosylation was controlled by the relative positions of the reactants in the constrained environment
of the CD cavity (reactionꢀcavity concept).75ꢀ77 Additionally, as recently described in the literature for
CDs dissolved in aqueous solution,78 we suggest that the replacement of highꢀenergy water molecules
in CD cavities by hydrophobic TsIm guests is the essential enthalpic driving force for complexation
and diffusion of TsIm along the hydrophobic CD channels. Thus, though the experimental conditions
of the ballꢀmilling process are very far from those relative to aqueous solution, the same hydrophobic
effects can be incriminated to explain the selectivity of the substitution reaction. Note that a control
experiment carried out with the nonꢀcyclic methylꢀαꢀDꢀglucopyranoside (7) (see Supporting
Information) in the same reaction conditions led exclusively to a 6ꢀtosylation, thus highlighting the
role of the CD cavity toward the reaction selectivity.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Proposed mechanism for the twoꢀstep synthesis of monoꢀ2ꢀOꢀtosylated CDs by ball
milling.
Synthesis of monoꢀ(2,3ꢀmannoꢀepoxide)ꢀCDs
The beneficial effect of mechanosynthesis on the selective modification of CD was further
demonstrated in the synthesis of other secondary face functionalized CDs, namely monoꢀ(2,3ꢀmannoꢀ
epoxide)ꢀCDs 4, 5 and 6 (Scheme 1). These CDs are key reactants for the synthesis of various CDs
substituted on their secondary face.23 They were synthesized by mechanosynthesis from 1, 2 and 3,
respectively as follows: a stoichiometric mixture of monoꢀ2ꢀOꢀtosylꢀCD and KOH was ballꢀmilled at
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 27
1
2
3
4
5
6
7
8
9
30 Hz for 2 h. The resulting powder was purified by flash chromatography using a CH3CN/H2O
mixture to give 4, 5 and 6 as white powders in good yields (61%, 63% and 67%, respectively). A
kinetic profile (see Supporting Information, S38) showed a rapid conversion of 2 into 5 (50% monoꢀ2ꢀ
OꢀtosylꢀβꢀCDs was converted within only 20 min). Afterwards, the conversion levelled off to reach
70%. Note that the direct synthesis of 4, 5 and 6 was also attempted from native CDs using 2 equiv.
KOH but the high reactivity of the hydroxyl anions toward the 2ꢀOH groups (compared to the
nucleophilic substitution rate) led to numerous deprotonations resulting in the formation of
polytosylated CDs, as already commented above for the CD 2ꢀtosylation.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Conclusions
Though grinding has already been extensively applied to the supramolecular concepts,79 nothing was
described so far on the selective mechanosynthesis of CDs functionalized onto their secondary
hydroxyl rim through supramolecular means. In this study, the synthesis of two key CDꢀbased
building blocks was performed by ball milling. While the synthesis of monoꢀ2ꢀOꢀtosyl CDs and
monoꢀ(2,3ꢀmannoꢀepoxide) CDs is a very delicate task using the classical tools of organic chemistry,
solidꢀstate reactions allowed us to obtain rapidly and selectively large amounts of these compounds
with very good purity. Moreover, we demonstrated that supramolecular chemistry is involved in the
conversion of native CDs into functionalized CDs using grinding technique.
ACS Paragon Plus Environment

Page 17 of 27
The Journal of Organic Chemistry
1
2
3
4
5
Experimental Section
Material and methods
6
7
8
9
All chemicals were used as received. Analytical thinꢀlayer chromatography (TLC) was performed on
aluminiumꢀbacked silica gel. Reactions were carried out using a laboratory scale ball mill (Retsch
MM400) equipped with 10 mL zirconia grinding jars containing one zirconia ball (9 mm ∅, 5.4 g).
The frequency of the ball mill represents the oscillation of the milling beakers. It is not related to the
number of impacts which depends on the frequency of the ball mill, the number of balls and the filling
degree. The data were collected as follows: the ball mill was stopped at a given time. A sample of the
powder was collected and analyzed. The ball mill was then restarted. The procedure was repeated as
often as necessary. Each reaction was repeated twice to ensure the repeatability of the results. Each
data point is the average of the two obtained values. Compounds were identified using UV
fluorescence and/or staining with a solution of 5% vol. sulfuric acid in ethanol. NMR spectra were
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
recorded on a spectrometer operating at 300 MHz for H nuclei and 75 MHz for 13C nuclei in CDCl3
(99.50% isotopic purity), DMSOꢀd6 (99.80% isotopic purity) or D2O (99.92% isotopic purity). Solidꢀ
state NMR spectra were acquired on a spectrometer operating at 100.62 MHz for 13C nuclei and a
1
spectrometer operating at 800.13 MHz for H nuclei. For the 13C MAS spectra, a crossꢀpolarisation
(CP) from the protons was used to generate the initial 13C signal, followed by data acquisition under
1
1H decoupling. Contact time (CT) RFꢀfield amplitudes were set to 70 and 60 kHz for H and 13C,
respectively, with the use of a ramp on the 1H channel. The 1H decoupling RF field amplitude was set
to 80 kHz using a SPINAL64 decoupling scheme.80 A total of 1024 transients were added, with a
relaxation delay of 5 s between each scan, a CP contact time of 1.5 ms, at a MAS spinning speed of 10
kHz. A lorentzian line broadening function of 5 Hz was applied for 13C CP/MAS spectra presented in
1
ESI and of 25 Hz in Fig. 4 of the article. Twoꢀdimensional Hꢀ1H double quantum magicꢀangle
5
spinning spectrum was performed at 60 kHz spinning speed using the R122 symmetryꢀbased
recoupling scheme applied for 110 ꢁs at an RF field strength of 180 kHz.81 The recycling delay was
set to 1 s and 256 transients were added for each of the 64 t1 increments. Chemical Shifts were given
in ppm with respect to TMS as external reference for 1H and 13C NMR spectra. The UVꢀvis spectra of
the solid samples were recorded in the diffuse reflectance mode on spectrophotometer equipped with a
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 27
1
2
3
4
5
60 mm integrating sphere. The solid powders were placed in quartz sample holders while BaSO4 was
used as a white standard. Spectra were plotted in F(R∞) KubelkaꢀMunk units with:
6
7
8
9
(1− R∞ )2
F(R∞ ) =
2R∞
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
where R∞ is the diffuse reflectance of an infiniteꢀthickness layer. Job Plots were drawn from UVꢀvis
measurements as follows: a series of solutions containing CD and TsIm were prepared such that the
sum of their total concentration remained constant (2.65mM). The TsIm mole fraction f(TsIm) was
varied from 0.1 to 1.0. The corrected absorbance (AꢀA°)×f(TsIm) at 280 nm was plotted against the
molar fraction of the TsIm solution. Each reaction was repeated twice to ensure the repeatability of the
results. Each data point is the average of the two obtained values. Mass spectra were recorded on a
MALDIꢀTOF–TOF spectrometer in positive reflectron mode with 2,5ꢀDHB as matrix. Organic
compounds were characterized by XꢀRay Diffraction (XRD). The XRD pattern was recorded on a
diffractometer (in BraggꢀBrentano geometry) equipped with copper Xꢀray source (λKα1=0.15406 and
λKα2=0.15449 nm) and Soller slits. A nickel filter was used to remove the Cu Kβ radiation. The pattern
was recorded for angular range (2θ) from 5° to 50° with a step of 0.04° and counting time of 10 s per
step. The CD water content was calculated by gravimetric measurements. The weight difference
between hydrated CD and anhydrous CD allowed determining the CD water content. To obtain
anhydrous βꢀCD, βꢀCD was dried using a DeanꢀStark apparatus in boiling toluene. After removing
toluene by azeotropic distillation using a rotary evaporator, anhydrous βꢀCD was preserved under
vacuum at 120 °C overnight before use. Anhydrous KOH was prepared under vacuum at 110 °C and
preserved in a vacuum desiccator over P2O5.
Monoꢀ2ꢀOꢀtosylꢀαꢀcyclodextrin (1)
A mixture of αꢀCD82 (1 g, 1.03 mmol) and pꢀtoluenesulfonyl imidazole83 (229 mg, 1.03 mmol) was
ballꢀmilled for 5 min at 30 Hz in a 10 mL zirconia reactor containing one zirconia ball (9 mm ∅). One
equivalent KOH (58 mg, 1.03 mmol) was then added to the mixture and ballꢀmilled at 30 Hz for 80 s.
The powder was collected using 5 mL dry DMSO and filtered. 1 was precipitated by addition of 50
ACS Paragon Plus Environment

Page 19 of 27
The Journal of Organic Chemistry
1
2
3
mL acetone. Further purification by flash chromatography on silica gel using an acetonitrile / water
4
5
1
(8:2) eluent system gave 1 as a white powder. Isolated yield: 47% (545 mg). H NMR (300 MHz,
6
7
8
9
DMSOꢀd6, 298 K): δ 7.86 ( d, J=8.16 Hz, 2H, Hb) ; 7.45 ( d, J=8.16 Hz, 2H, Hc) ; 5.73ꢀ5.44 (m, 11H,
OH2, OH3) ; 4.79 (m, 6H, H1) ; 4.52ꢀ4.43 (m, 6H, OH6) ; 4.08ꢀ3.98 (m, 4H, H’2, H’3, H’4) ; 3.84ꢀ3.45
(complex m, 25H, H3, H2, H5, H6) ; 3.42 (m, overlapped with H2O) ; 2.42 (s, 3H, CH3). 13C{1H} NMR
(75 MHz, D2O, 298 K): δ 145.5 (Ca) ; 133.1 (Cd) ; 130.4 (Cc) ; 128.6 (Cb) ; 102.8 (C1) ; 99.1 (C’1) ;
82.4 (C4) ; 79.9 (C’2) ; 73.7ꢀ72.6ꢀ72.0 (C3,C2,C5) ; 69.6 (C’3) ; 60.4 (C6) ; 21.6 (CH3). MS: m/z calcd
for [C43H66O32S+H]+ 1127.33, obsd 1130.99 ; calcd for [C43H66O32S+Na]+ 1149.32, obsd 1149.11 ;
calcd for [C43H66O32S+K]+ 1165.29, obsd 1165.10. Anal. Calcd for C43H66O32S.2H2O: C, 44.41; H,
6.07; O, 46.77; S, 2.76. Found: C, 44.48; H, 5.99; O, 46.84; S, 2.83.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Monoꢀ2ꢀOꢀtosylꢀβꢀcyclodextrin (2)
Compound 2 was prepared according to the procedure used for the synthesis of 1 by reacting βꢀCD82
(1 g, 0.88 mmol), pꢀtoluenesulfonyl imidazole (195 mg, 0.88 mmol) and KOH (49 mg, 0.88 mmol).
Isolated yield: 53% (589 mg). 1HNMR (300 MHz, DMSOꢀd6, 298 K): δ 7.95 ( d, J=8.40 Hz, 2H, Hb) ;
7.54 ( d, J=8.40 Hz, 2H, Hc) ; 6.10ꢀ5.75 (m, 13H, OH2, OH3) ; 4.93 (m, 7H, H1) ; 4.57 (m, 7H, OH6) ;
4.34 (d, J=3.9 Hz, 1H) ;4.04 (m, 1H) ; 3.70 (m, 1H) ; 3.74ꢀ3.60 (complex m, 30H, H3, H2, H5, H6) ;
3.47 (m, overlapped with H2O) ; 2.52 (s overlapped with DMSO, CH3). 13C{1H} NMR (75 MHz, D2O,
298 K): δ 145.0 (Ca) ; 132.9 (Cd) ; 129.9 (Cc) ; 128.1 (Cb) ; 101.9 (C1) ; 101.8 (C’1) ; 81.5 (C4) ; 80.9
(C’2) ; 73.0ꢀ72.3ꢀ72.1 (C3,C2,C5) ; 69.3 (C’3) ; 59.9 (C6) ; 21.2 (CH3). MS: m/z calcd for
[C49H76O37S+Na]+ 1311.37, obsd 1310.92 ; calcd for [C49H76O37S+K]+ 1327.34, obsd 1326.90. Anal.
Calcd for C49H76O37S.3H2O: C, 43.82; H, 6.15; O, 47.64; S, 2.39. Found: C, 43.75; H, 6.25; O, 47.65;
S, 2.35.
Monoꢀ2ꢀOꢀtosylꢀγꢀcyclodextrin (3)
Compound 3 was prepared according to the procedure used for the synthesis of 1 by reacting γꢀCD82 (1
g, 0.77 mmol), pꢀtoluenesulfonyl imidazole (171 mg, 0.77 mmol) and KOH (43 mg, 0.77 mmol).
Isolated yield: 21% (234 mg). 1HNMR (300 MHz, DMSOꢀd6, 298 K): δ 7.85 ( d, J=8.25 Hz, 2H, Hb) ;
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 27
1
2
3
4
5
6
7
8
9
7.44 (d, J=8.25 Hz, 2H, Hc) ; 5.70 (m, 15H, OH2, OH3) ; 5.18 (d, J=3.33 Hz, 1H, H’1) ; 4.88 (m, 7H,
H1) ; 4.64ꢀ4.52 (m, 7H, OH6) ; 4.39 (d, J=4.4 Hz, OH6’1H) ; 4.08 (dd, J=3.3 Hz, J=10 Hz, 1H) ; 3.87
(m, 2H) ; 3.65ꢀ3.48 (complex m, 31H, H3, H2, H5, H6) ; 3.40 (m, overlapped with H2O) ; 2.41 (s, 3H,
CH3). 13C{1H} NMR (75 MHz, D2O, 298 K): δ 145.2 (Ca) ; 133.7 (Cd) ; 130.3 (Cc) ; 128.6 (Cb) ; 102.0
(C1) ; 97.6 (C’1) ; 80.9 (C4) ; 78.4 (C’2) ; 73.5ꢀ73.2ꢀ72.6 (C3,C2,C5) ; 69.5 (C’3) ; 60.3 (C6) ; 21.7
(CH3). MS: m/z calcd for [C55H86O42S+Na]+ 1473.42, obsd 1473.12 ; calcd for [C55H86O42S+K]+
1489.40, obsd 1489.10. Anal. Calcd for C55H86O42S.6H2O: C, 42.36; H, 6.33; O, 49.25; S, 2.06.
Found: C, 42.44; H, 6.31; O, 49.27; S, 2.09.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Monoꢀ(2,3ꢀmannoꢀepoxide) αꢀCD (4)
A stoichiometric mixture of 1 (780 mg, 0.69 mmol) and KOH (39 mg, 0.49 mmol) was ballꢀmilled at
30 Hz for 2 h. The resulting powder was chromatographed on silica gel using an acetonitrile / water
1
(8:2) eluent system. 4 was isolated as a white powder. Isolated yield: 61% (401 mg). H NMR (300
MHz, D2O, 298 K): δ 5.24 (s, 1H, H1m); 5.01 (complex m, 5H, H1) ; 3.98ꢀ3.78 (complex m, 21H, H3,
H6, H4m, H5); 3.72ꢀ3.50 (m, 14H, H6m, H3m, H5m, H2, H4) ; 3.44 (d, 1H, J=3.3 Hz, H2m). 13C{1H} NMR
(75 MHz, D2O, 298 K): δ 101.1ꢀ100.8 (C1); 97.3 (C1m) ; 80.8 (C4) ; 72.8ꢀ72.3ꢀ71.6 (C2, C3, C5) ; 70.3
(C4m) ; 69.9 (C5m) ; 61.1 (C6m) ; 60.1 (C6) ; 52.9 (C3m) ; 48.4 (C2m). MS: m/z calcd for [C36H58O29+Na]+
977.30 obsd 977.29 ; calcd for [C36H58O29+K]+ 993.27, obsd 993.29. Anal. Calcd for C36H58O29.2H2O:
C, 43.64; H, 6.31; O, 50.05. Found: C, 43.58; H, 6.37; O, 50.15.
Monoꢀ(2,3ꢀmannoꢀepoxide) βꢀCD (5)
Compound 5 was prepared according to the procedure used for the synthesis of 4 by reacting 2 (636
mg, 0.49 mmol) and KOH (28 mg, 0.49 mmol). Isolated yield: 63% (344 mg). 1H NMR (300 MHz,
D2O, 298 K): δ 5.25 (s, 1H, H1m) ; 5.07 (complex m , 6H, H1) ; 3.98ꢀ3.79 (complex m, 25H, H3, H6,
H4m, H5) ; 3.72ꢀ3.46 (m, 16H, H6m, H3m, H5m, H2, H4) ; 3.46 (d, 1H, J=3.8 Hz, H2m). 13C{1H} NMR (75
MHz, D2O, 298 K): δ 101.5 (C1) ; 97.9 (C1m) ; 80.7 (C4) ; 72.8ꢀ71.8ꢀ71.6 (C2,C3,C5) ; 70.3 ( C4m) ; 69.6
(C5m) ; 61.0 (C6m) ; 60.3 (C6) ; 54.1 (C3m) ; 49.2 (C2m). MS: m/z calcd for [C42H68O34+Na]+ 1139.35
ACS Paragon Plus Environment

Page 21 of 27
The Journal of Organic Chemistry
1
2
3
4
5
obsd 1139.38 ; calcd for [C42H68O34+K]+ 1155.32, obsd 1155.36. Anal. Calcd for C42H68O34.2H2O: C,
43.75; H, 6.29; O, 49.95. Found: C, 43.82; H, 6.30; O, 49.87.
6
7
8
9
Monoꢀ(2,3ꢀmannoꢀepoxide) γꢀCD (6)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Compound 6 was prepared according to the procedure used for the synthesis of 4 by reacting 3 (450
1
mg, 0.31 mmol) and KOH (17 mg, 0.49 mmol). Isolated yield: 67% (265 mg). H NMR (300 MHz,
D2O, 298 K): δ 5.25 (s, 1H, H1m) ; 5.11 (complex m , 7H, H1); 3.95ꢀ3.73 (complex m, 29H, H3, H6,
H4m, H5) ; 3.70ꢀ3.50 (m, 17H, H6m, H3m, H5m, H2, H4) ; 3.45 (d, 1H, J=3.6 Hz, H2m). 13C{1H} NMR (75
MHz, D2O, 298 K): δ 101.3 (C1) ; 97.1 (C1m) ; 80.1 (C4) ; 71.8ꢀ72.1ꢀ71.6 (C2,C3,C5) ; 69.2 ( C4m, C5m) ;
60.8 (C6m) ; 60.2 (C6) ; 54.3 (C3m) ; 49.5 (C2m). MS: m/z calcd for [C48H78O39+Na]+ 1301.40 obsd
1301.41 ; calcd for [C48H78O39+K]+ 1317.38, obsd 1317.41. Anal. Calcd for C48H78O39.4H2O: C, 42.67;
H, 6.42; O, 50.92. Found: C, 42.69; H, 6.49; O, 50.98.
Methylꢀ6ꢀOꢀtosylꢀαꢀDꢀglucopyranoside (7)
MethylꢀαꢀDꢀglucopyranoside (1500 mg, 7.72 mmol) and pꢀtoluenesulfonyl imidazole (245 mg, 1.10
mmol) were ballꢀmilled for 5 min at 30 Hz in a 10 mL zirconia reactor containing one zirconia ball (9
mm in diameter). KOH (62 mg, 1.10 mmol) with regard to methylꢀαꢀDꢀglucopyranoside was then
added and the mixture was ballꢀmilled at 30 Hz for 5 min. The powder was further dissolved in 5mL
dry DMSO. After filtration, the monoꢀtosylated methylꢀ6ꢀOꢀtosylꢀαꢀDꢀglucopyranoside (7) was
precipitated by addition of 100 mL chloroform. The product was further purified by flash
chromatography on silica gel using an acetonitrile/water (8/2, v/v) mobile phase. Isolated yield: 9%
(240 mg). 1H NMR (300 MHz, DMSOꢀd6, 298 K): δ 7.76 (d, 2H, J=8.39 Hz, Hb); 7.49 (d, 2H, J=8.39
Hz, Ha); 5.17 (d, 1H, J=5.89 Hz, OH4); 4.89 (d, 1H, J=5.18 Hz, OH3); 4.82 (d, 1H, J=6.42 Hz, OH2);
4.48 (d, 1H, J=4.27 Hz, H1); 4,21 (dd, 1H, J=1.93 Hz, J=10.68 Hz, H6); 4.05 (dd, 1H, J=6.43 Hz,
J=10.68 Hz, H6’); 3.52ꢀ3.43 (m, 2H, H3ꢀH5); 3.21ꢀ3.09 (m, 4H, OCH3, H2); 2.98 (m, 1H, H4); 2.42 (s,
3H, CH3). 13C{1H} NMR (75 MHz, D2O, 298 K): δ 145.5 (Ca); 132.9 (Cd); 130.8 (Cc); 128.2 (Cb);
100.3 (C1); 73.6 (C3); 72.2 (C2); 70.9 (C6); 70.3 (C4); 70.0 (C5); 55.1 (OCH3); 21.7 (CH3).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 27
1
2
3
4
5
6
7
8
9
Acknowledgements
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Roquette Frères (Lestrem, France) is gratefully acknowledged for generous gifts of cyclodextrins. We
thank Dr. Nicolas Kania and D. Prevost for technical assistance.
Supporting Information: NMR data, UVꢀvis spectra, water solubility of carbonate bases, mass
spectra, kinetic profiles. This material is available free of charge via the Internet at http://pubs.acs.org/.
References
[1]
H. Dodziuk in Cyclodextrins and Their Complexes: Chemistry, Analytical Methods,
Applications, Ed. H. Dodziuk, WileyꢀVCH, Weinheim, 2006.
[2]
[3]
[4]
[5]
Arun, R.; Ashok Kumar, C. K.; Sravanthi, V. V. N. S. S. Sci. Pharm. 2008, 76, 567–598.
Loftsson, T.; Duchêne, D. Int. J. Pharm. 2007, 329, 1–11.
Jazkewitsch, O.; Ritter, H. Macromolecules 2011, 44, 375–382.
Perry, C.; Hébraud, P.; Gernigon, V.; Brochon, C.; Lapp, A.; Lindner, P.; Schlatter, G. Soft
Matter 2011, 7, 3502–3512.
[6]
[7]
[8]
[9]
Harada, A.; Li, J.; Kamachi, M. Nature, 1992, 356, 325–327.
Peters, O.; Ritter, H. Angew. Chem. Int. Ed. 2013, 52, 1–6.
Li, J. Adv. Polym. Sci. 2009, 222, 79–113.
Wagner, B. D. in Cyclodextrin Materials Photochemistry, Photophysics and Photobiology, A.
Douhal (Editor), Elsevier Amsterdam, 2006.
[10] Smaldone, R. A.; Forgan, R. S.; Furukawa, H.; Gassensmith, J. J.; Slawin, A. M. Z.; Yaghi, O.
M.; Stoddart, J. F. Angew. Chem. Int. Ed. 2010, 49, 8630–8634.
[11] Woggon, W.ꢀD.; Schlatter, A.; Wang, H. -Cyclodextrin-linked Ru Complexes for Oxidations
β
and Reductions in: Rudi van Eldik, editor: Advances in Inorganic Chemistry, Vol 60, van Eldik. The
Netherlands: Academic Press, 2008, pp. 31–58.
ACS Paragon Plus Environment

Page 23 of 27
The Journal of Organic Chemistry
1
2
3
4
5
[12]
[13]
Schlatter, A.; Woggon, W.ꢀD. Adv. Synth. Catal. 2008, 350, 995–1000.
Machut, C.; Patrigeon, J.; Tilloy, S.; Bricout, H.; Hapiot, F.; Monflier, E. Angew. Chem. Int.
6
7
Ed. 2007, 46, 3040–3042.
8
[14]
[15]
Kanagaraj, K.; Pitchumani, K. Chem. Eur. J. 2013, 19, 14425–14431.
Doyagüez, E. G.; RodríguezꢀHernández, J.; Corrales, G.; FernándezꢀMayoralas, A.; Gallardo,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
A. Macromolecules 2012, 45, 7676–7683.
[16] Hapiot, F.; Bricout, H.; Menuel, S.; Tilloy, S.; Monflier, E. Catal. Sci. Technol. 2014, 4,
1899–1908.
[17]
[18]
[19]
Breslow, R.; Dong, S. D. Chem. Rev. 1998, 98, 1997–2011.
Bjerre, J.; Rousseau, C.; Marinescu, L.; Bols, M. Appl. Microbiol. Biotechnol. 2008, 81, 1–11.
Furukawa, Y.; Ishiwata, T.; Sugikawa, K.; Kokado, K.; Sada, K. Angew. Chem. Int. Ed. 2012,
51, 10566–10569.
[20]
[21]
[22]
Zerkoune, L.; Angelova, A.; Lesieur, S. Nanomaterials, 2014, 4, 741–765.
Tiwari, G.; Tiwari, R.; Rai, A. K. J. Pharm. Bioall. Sci. 2010, 2, 72–79.
OteroꢀEspinar, F. J.; TorresꢀLabandeira, J. J.; AlvarezꢀLorenzo, C.; BlancoꢀMéndez, J. J. Drug
Del. Sci. Tech. 2010, 20, 289–301.
[23]
[24]
Rauf Khan, A.; Forgo, P.; Stine, K. J.; D’Souza, V. T. Chem. Rev. 1998, 98, 1977–1996.
Fukudome, M.; Onizuka, T.; Kawamura, S.; Yuan, D.ꢀQ.; Fujita, K. Tetrahedron Lett. 2007,
48, 6665–6668.
[25]
[26]
[27]
[28]
[29]
Teranishi, K. Tetrahedron 2003, 59, 2519–2538.
Tang, W.; Ng, S.ꢀC. Nature Protocols 2008, 3, 691–697.
Guieu, S.; Sollogoub, M. Angew. Chem. Int. Ed. 2008, 47, 7060–7063.
Ghosh, R.; Zhang, P.; Wang, A.; Ling, C.ꢀC. Angew. Chem. Int. Ed. 2012, 51, 1548–1552.
Zaborova, E.; Guitet, M.; Prencipe, G.; Blériot, Y.; Ménand, M.; Sollogoub, M. Angew. Chem.
Int. Ed. 2013, 52, 639–644.
[30]
James, S. L.; Adams, C. J.; Bolm, C.; Braga, D.; Collier, P.; Friščić, T.; Grepioni, F.; Harris,
K. D. M.; Hyett, G.; Jones, W.; Krebs, A.; Mack, J.; Maini, L.; Orpen, A. G.; Parkin, I. P.; Shearouse,
W. C.; Steed, J. W.; Waddell, D. C. Chem. Soc. Rev. 2012, 41, 413–447.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 27
1
2
3
4
5
6
7
8
9
[31]
[32]
[33]
[34]
Ralphs, K.; Hardacre, C.; James, S. L. Chem. Soc. Rev. 2013, 42, 7701–7718.
Šepelák, V.; BéginꢀColin, S.; Le Caër, G. Dalton Trans. 2012, 41, 11927–11948.
Boldyreva, E. Chem. Soc. Rev. 2013, 42, 7719–7738.
Perejón, A.; Murafa, N.; SánchezꢀJiménez, P. E.; Criado, J. M.; Subrt, J.; Diánez, M. J.; Pérezꢀ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Maqueda, L. A. J. Mater. Chem. C 2013, 1, 3551–3562.
[35]
[36]
Huskić, I.; Halasz, I.; Friščić, T.; Vančik, H. Green Chem. 2012, 14, 1597–1600.
Štrukil, V.; Bartolec, B.; Portada, T.; Đilović, I.; Halaszc, I.; Margetić, D. Chem. Commun.
2012, 48, 12100–12102.
[37]
2329.
[38]
[39]
Stolle, A.; Szuppa, T.; Leonhardt, S. E. S.; Ondruschka, B. Chem. Soc. Rev. 2011, 40, 2317–
Choudhary, G.; Krishna Peddinti, R. Green Chem. 2011, 13, 276–282.
Štrukil, V.; Igrc, M. D.; Fábián, L.; EckertꢀMaksić, M.; Childs, S. L.; Reid, D. G.; Duer, M. J.;
Halasz, I.; Mottillo, C.; Friščić, T. Green Chem. 2012, 14, 2462–2473.
[40] Konnert, L.; Gauliard, A.; Lamaty, F.; Martinez, J.; Colacino, E. ACS Sustainable Chem. Eng.
2013, 1, 1186–1191.
[41]
[42]
[43]
[44]
[45]
Zhu, S.ꢀE; Li, F.; Wang, G.ꢀW. Chem. Soc. Rev. 2013, 42, 7535–7570.
Wang, G.ꢀW Chem. Soc. Rev. 2013, 42, 7668–7700.
Liu, Z.; Fan, G.ꢀP.; Wang, G.ꢀW. Chem. Commun. 2012, 48, 11665–11667.
Fan, G.ꢀP.; Liu, Z.; Wang, G.ꢀW. Green Chem. 2013, 15, 1659–1664.
Štrukil, V.; Fábián, L.; Reid, D. G.; Duer, M. J.; Jackson, G. J.; EckertꢀMaksić, M.; Friščić, T.
Chem. Commun. 2010, 46, 9191–9193.
[46]
[47]
Adams, C. J.; Kurawa, M. A.; Orpen, A. G. Dalton Trans. 2010, 39, 6974–6984.
Içli, B.; Christinat, N.; Tönnemann, J.; Schüttler, C.; Scopelliti R.; Severin, K. J. Am. Chem.
Soc. 2009, 131, 3154–3155.
[48]
Hsu, C.ꢀC.; Chen, N.ꢀC.; Lai, C.ꢀC.; Liu, Y.ꢀH.; Peng, S.ꢀM.; Chiu, S.ꢀH. Angew. Chem. Int.
Ed. 2008, 47, 7475–7478.
[49]
Carli, F. Proceedings of the International Symposium on Controlled Release of Bioactive
Materials 1999, 26, 873–874.
ACS Paragon Plus Environment

Page 25 of 27
The Journal of Organic Chemistry
1
2
3
[50]
Kumar, V.; Taxak, N.; Jangir, R.; Bharatam P. V.; R.Kartha. K. P. J. Org. Chem. 2014, 79,
4
5
3427–3439.
6
7
8
9
[51]
[52]
[53]
[54]
Kumar, V.; Yadav, N.; Kartha K. P. Carbohydr. Res. 2014, 397, 18–26.
Rinaldi, L.; Binello, A.; Stolle, A.; Curini, M.; Cravotto, G. Steroids 2015, 98, 58–62.
Braga, D.; Grepioni, F. Angew. Chem. Int. Ed. 2004, 43, 4002–4011 and references therein.
Lin, H.ꢀL.; Lin, S.ꢀY.; Lin, C.ꢀC.; Hsu, C.ꢀH.; Wu, T.ꢀK.; Huang, Y.ꢀT. Carbohydr. Polym.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2012, 87, 512–517.
[55]
Martina, K.; Trotta, F.; Robaldo, B.; Belliardi, N.; Jicsinszky, L.; Cravotto, G. Tetrahedron
Lett. 2007, 48, 9185–9189.
[56]
[57]
Tan, T.; Ng, S.ꢀc.; Wang, Y.; Xiao, Y. Protocol Exchange 2011, doi:10.1038/protex.2011.214
Law, H.; Benito, J. M.; Garcıa Fernandez, J. M.; Jicsinszky, L.; Crouzy S.; Defaye, J. J. Phys.
Chem. B. 2011, 115, 7524–7532.
[58]
[59]
[60]
494.
[61]
Ueno A.; Breslow, R. Tetrahedron Lett. 1982, 23, 3451–3454.
Rong D.; D’Souza, V. T. Tetrahedron Lett. 1990, 31, 4275–4278.
Teranishi, K.; Watanabe, K.; Hisamatsu, M.; Yamada, T. J. Carbohydr. Res. 1998, 17, 489–
Teranishi, K.; Tanabe, S.; Hisamatsu, M.; Yamada, T. Biosci. Biotechnol. Biochem. 1998, 62,
1249–1252.
[62]
Fukudome, M.; Oiwane, K.; Mori, T.; Yuan, D.ꢀQ.; Fujita, K. Tetrahedron Lett. 2004, 45,
3383–3386.
[63]
Yu, H.; Teramoto, A.; Fukudome, M.; Xie, R.ꢀG.; Yuan, D.ꢀQ.; Fujita, K. Tetrahedron Lett.
2006, 47, 8837–8840.
[64]
[65]
[66]
453.
[67]
Wang, Z.ꢀZ.; He, G.ꢀY.; Lu, R.ꢀH. Monatsh. Chem. 2008, 139, 1109–1111.
Wang, Z.ꢀZ.; Fu, X.ꢀY.; Dai, G.ꢀD.; Quan, H.ꢀF. Monatsh. Chem. 2011, 142, 317–319.
Law, H.; Baussanne, I.; Garcia Fernandez, J. M.; Defaye, J. Carbohydr. Res. 2003, 338, 451–
Pregel, M. J.; Buncel, E. Can. J. Chem. 1991, 69, 130–137.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 27
1
2
3
[68]
van Dienst, E.; Snellink, B. H. M.; von Piekartz, I.; Gansey, M. H. B. G.; Venema, F.; Feiters,
4
5
6
7
8
9
M. C.; Nolte, R. J. M.; Engbersen, J. F. J.; Reinhoudt, D. N. J. Org. Chem. 1995, 60, 6537–6545.
[69] Pessine, F. B. T.; Calderini, A.; Alexandrino G. L. (2012). Review: Cyclodextrin Inclusion
Complexes Probed by NMR Techniques, Magnetic Resonance Spectroscopy, Prof. DongꢀHyun Kim
(Ed.), ISBN: 978ꢀ953ꢀ51ꢀ0065ꢀ2, InTech, Available from:
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
http://www.intechopen.com/books/magneticresonanceꢀspectroscopy/reviewꢀstudyꢀofꢀinclusionꢀ
complexesꢀwithꢀcyclodextrinsꢀbyꢀmrs
[70]
[71]
Saalwächter, K. Macromol. Rapid Commun. 2002, 23, 286–291.
Saalwächter, K.; Lange, F.; Matyjaszewski, K.; Huang, C.ꢀF.; Graf, R. J. Magn. Reson. 2011,
212, 204–215.
[72]
585.
[73]
7557.
[74]
Sivakumar, K.; Hemalatha, G.; Parameswari, M.; Stalin, T. Phys. Chem. Liq. 2013, 51, 567–
Betzel, C.; Saenger, W.; Hingerty, B. E.; Brown, G. M. J. Am. Chem. Soc. 1984, 106, 7545–
Gaidamauskas, E.; Norkus, E.; Butkus, E.; Crans, D. C.; Grincienė, G. Carbohydr. Res. 2009,
344, 250–254.
[75]
[76]
[77]
[78]
[79]
[80]
[81]
Luty, T.; Eckhardt, C. J. J. Am. Chem. Soc. 1995, 117, 2441–2452.
Ohashi, Y. Acc. Chem. Res. 1988, 21, 268–274.
Coville, N. J.; Levendis, D. C. Eur. J. Inorg. Chem. 2002, 3067–3078.
Biedermann, F.; Nau, W. M.; Schneider, H.ꢀJ. Angew. Chem. Int. Ed. 2014, 53, 11158–11171.
Friščić, T. Chem. Soc. Rev. 2012, 41, 3493–3510.
Fung, B. M.; Khitrin, A. K.; Ermolaev, K. J. Magn. Reson. 2000,142, 97–101.
Carravetta, M.; Eden, M.; Zhao, X.; Brinkmann, A.; Levitt, M. H. Chem. Phys. Lett. 2000,
321, 205–215.
[82]
[83]
Schneider, H.ꢀJ.; Hacket, F.; Rüdiger V. Chem. Rev. 1998, 98, 1755–1785.
Van der Eijk, J. M.; Nolte R. J. M.; Zwikker J. W. J. Org. Chem. 1980, 45, 547–548.
ACS Paragon Plus Environment

Page 27 of 27
The Journal of Organic Chemistry
1
2
3
4
5
6
7
Entry for the Table of Content
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment