Glycosylation in flow: effect of the flow rate and type of the mixer

Article abstract of DOI:10.1007/s11172-019-2677-y

The influence of the flow rate and the mode of mixing of reagent solutions on the result of glycosylation of isopropyl alcohol with glycooxazoline in 1,2-dichloroethane in the presence of (±)-camphor-10-sulfonic acid was studied. No reaction products were observed at low flow rates (?0.043 mL h^?1) when using two Comet X-01 micromixers. Under these conditions, the disaggregation of supramers of the reagents is apparently inefficient for the reaction between them to occur. However, when one of the Comet X-01 micromixers was replaced with a T-shaped adapter (at the same flow rate), the expected reaction products, glycoside and glycal, appeared in the reaction mixture. This apparently suggests a higher disaggregation of the supramers reagents under these conditions, which allows the chemical reaction between them to occur.

Full text of DOI:10.1007/s11172-019-2677-y

Russian Chemical Bulletin, International Edition, Vol. 68, No. 11, pp. 2126—2129, November, 2019
2126
Glycosylation in flow: effect of the flow rate and type of the mixer
I. V. Myachin,a,b A. V. Orlova,b and L. O. Kononovb,c
aD. I. Mendeleev University of Chemical and Technology of Russia,
9 Miusskaya pl., 125047 Moscow, Russian Federation
bN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. E-mail: kononov@ioc.ac.ru, leonid.kononov@gmail.com
cMoscow Physical Technical Institute (National Research University),
9 Institutsky per., 141701 Dolgoprudnyi, Moscow Region, Russian Federation
The influence of the flow rate and the mode of mixing of reagent solutions on the result of
glycosylation of isopropyl alcohol with glycooxazoline in 1,2-dichloroethane in the presence of
(
)-camphor-10-sulfonic acid was studied. No reaction products were observed at low flow
rates (≤0.043 mL h–1) when using two Comet X-01 micromixers. Under these conditions, the
disaggregation of supramers of the reagents is apparently inefficient for the reaction between
them to occur. However, when one of the Comet X-01 micromixers was replaced with a T-shaped
adapter (at the same flow rate), the expected reaction products, glycoside and glycal, appeared
in the reaction mixture. This apparently suggests a higher disaggregation of the supramers
reagents under these conditions, which allows the chemical reaction between them to occur.
Key words: glycosylation in flow, glycooxazoline, oxazoline method, Comet X-01 micro-
mixer, supramers.
Scheme 1
Two fundamentally different methods for performing
chemical reactions in solutions are known: in a batch
reactor (in a flask) and in a flow type reactor (in flow).1—8
It has recently been shown that the type of reactor can
affect the yields of products and stereoselectivity of gly-
cosylation (flow reactors of various design were compared
with the batch reactor (flask)).9,10 However, the influence
of the flow rate on the result of glycosylation in flow 8—14
was not studied earlier. We decided to fill this gap and
during this study unexpectedly obtained unprecedented
results, which are described below.
The influence of the flow rate on the result of glycosyl-
ation in the flow reactor was studied using glycosylation15—18
of isopropyl alcohol with glycooxazoline 116,19 in 1,2-di-
chloroethane (DCE)18,20—22 in the presence of ( )-cam-
phor-10-sulfonic acid (CSA)23,24 as an example (Scheme 1).
A system consisting of two M1 and M2 mixers (see
Fig. 1) was used as a flow reactor. The system makes it
possible to mix reagents at various temperatures (the
conditions are shown in Scheme 1). In this work, solutions
of oxazoline 1 and CSA in DCE were mixed in the M1
mixer at room temperature (~20 °C). The obtained solu-
tion was further supplied via a capillary to the M2 mixer,
where it was mixed at 80 °C with a solution of isopropyl
alcohol in DCE. The solution coming out from the M2
mixer via a capillary-reactor went into a receiving flask
with a solution of Pri2NEt in toluene (see Fig. 1), where
the reaction was quenched.
Reagents and conditions: i. CSA, DCE, T = 20 °C, mixer M1;
ii. PriOH, DCE, T = 80 °C, mixer M2 (Fig. 1).
After reaction termination, the compositions of the
reaction mixtures were analyzed by 13C NMR spectro-
scopy. When two identical Comet X-01 micromixers14
were used as the M1 and M2 mixers, the amount of the
reaction products, isopropyl glycoside 3 and glycal 4*,
changed with an increase in the flow rate in a complicated
manner, in particular, it decreased (Fig. 2, Table 1) at high
* A low conversion of oxazoline 1 under these conditions should
be mentioned.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2126—2129, November, 2019.
1066-5285/19/6811-2126 © 2019 Springer Science+Business Media, Inc.

Glycosylation in flow
Russ. Chem. Bull., Int. Ed., Vol. 68, No. 11, November, 2019
2127
A
S1
M1
M2
f1
T = 80 °C
S2
S3
T = 20 °C
f2
f3
Pri2NEt + PhCH3
Fig. 1. Scheme of the flow reactor in which glycosylation was conducted; A is the bath. Syringes S1 (solution of 1 in DCE), S2 (solu-
tion of CSA in DCE), and S3 (solution of PriOH in DCE) were used to pump the solutions of the reagents through the М1 and М2
mixers. Flow rate f = f1 = f2 = f3.
flow rates (≥0.4 mL h–1). Note that products 3 and 4
were completely absent at low flow rates (0.03 and
0.043 mL h–1). In this case, only unreacted oxazoline 1
was found in the receiving flask (Fig. 3, а, Table 1).
A decrease in the amount of the reaction products at
the rates higher than 0.4 mL h–1 can be explained by insuf-
ficient duration of contact between the reactants (i.e., the
reaction has no time to complete). At the same time, in
a range of low flow rates and, as a consequence, of a lon-
ger duration of contact between the reactants (residence
time ~30 h, i.e., nearly under static conditions: almost as
in the flask), the absence of products of transformation of
acid-labile25 oxazoline 1 looks very unusual. Moreover,
the expected reaction products 3 and 4 were observed in
the reaction mixture (Fig. 3, b) at a flow rate of 0.03 mL h–1
when a T-shaped adapter (instead of a Comet X-01 micro-
mixer) was used as the M1 mixer. This unexpected result
is consistent with the earlier found9,10,26 data on the influ-
ence of the mode of mixing of reagents on the results of
chemical reactions conducted in flow.
In our opinion, this phenomenon can be described in
terms of the model of structure of solutions proposed by
M. Sedlák.27—29 The model assumes that the solution
contains domains — long-lived supramolecular aggregates
(supramers26) containing molecules of the solute and
solvent. The use of this model for the reaction solution
shows26 that the product cannot be formed from reagent
molecules located inside the domains of the solution, since
they are unable to contact each other. The product is
formed from the molecules located on the surface of do-
mains or between them. Therefore, to achieve high yields
of the product, one should destroy domains (supramers)
of the reagents, which are sensitive to mechanical impact26
and, hence, can partially or completely decompose under
"mild" impact. It was predicted26 on the basis of this hypo-
thesis that the mode of mixing of solutions of reagents can
influence the structure of supramers of reagents and,
hence, their macroscopic reactivity.
ω (arb. units)
In the framework of the considered model, it can be
assumed that at low flow rates (≤0.043 mL h–1) and using
two Comet X-01 micromixers (see Fig. 3, а) the disag-
4
3
2
1
0
Table 1. Amounts of glycoside 3 and glycal 4
(ω) at various flow rates (f) (also see Fig. 2)
f/mL h–1
ω (arb. units)
3
4
0.03
0.043
0.1
0.2
0.4
0.6
1
0
0
0
0
1.67
2.66
0.38
0.30
0.22
3.67
3.33
0.33
0.35
0.17
0.2
0.4
0.6
0.8
f/mL h–1
Fig. 2. Amounts (ω) of glycoside 3 (dashed line) and glycal 4
(solid line) at various flow rates (f); М1 = М2 = Comet X-01
micromixer (see Scheme 1, Fig. 1, and Table 1).

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Russ. Chem. Bull., Int. Ed., Vol. 68, No. 11, November, 2019
Myachin et al.
a
b
2
1
160
140
120
100
80
60
40
20
δ
Fig. 3. 13C NMR spectra of the reaction mixtures obtained by using different М1 mixers and the same flow rate (f = 0.03 mL h–1):
(а) M1 = M2 = Comet X-01 micromixer; (b) M1 = Т-shaped adapter, M2 = Comet X-01 micromixer (see Scheme 1 and Fig. 1);
1, signal of the С(1) atom of glycal 4 (δC 140.6) and 2, signal of the С(2) atom of isopropyl glycoside 3 (δC 55.8).
0.40 m, that between S3—M2 was 1.00 m, and the length of
the outlet capillary was 0.75 m. Solutions were pumped using
an AL-1200 multichannel syringe pump (World Precision
Instruments, www.wpiinc.com). 1H and 13C NMR spectra were
recorded on a Bruker AM-300 instrument (300.13 and 75.47 MHz,
respectively) at 303 K. Anhydrous 1,2-dichloroethane (DCE,
distilled in an argon atmosphere over P2O5 and then over CaH2
and kept over molecular sieves 4 Å under argon) was used for
glycosylation. Propan-2-ol (PriOH) was distilled in argon over
CaO and kept over molecular sieves 4 Å under argon. A solution
of oxazoline 1 (see Ref. 19) (60 mmol L–1) in DCE was prepared
by the dissolution of a dried in vacuo (for 2 h at 0.15 mbar)
sample of oxazoline 1 (296 mg, 0.9 mmol) in DCE (15 mL).
A solution of CSA (25 mmol L–1) in DCE was prepared by the
dissolution of a weighed sample of CSA (5.2 mg, 22.5 μmol) in
DCE (15 mL). A solution of propan-2-ol (180 mmol L–1) in
DCE was prepared by adding PriOH (207 μL, 2.7 mmol) to DCE
(15 mL). All solutions were kept for not more than 2 weeks
and replaced with fresh solutions as they were spent out.
Syringes (nominal volume 5 mL, material polypropylene; Becton,
Dickinson & Co., www.bd.com) were filled with gaseous argon
in an amount sufficient for the complete displacement of all
liquid from the flow system along with solutions of the reagents.
The contents of the syringes were as follows: syringe S1: 3 mL
of a solution of oxazoline 1 in DCE (60 mmol L–1) and 1 mL
of argon; syringe S2: 3 mL of a solution of CSA in DCE
(25 mmol L–1) and 1 mL of argon; and syringe S3: 3.5 mL of
a solution of PriOH in DCE (180 mmol L–1) and 0.5 mL of argon.
The M1 mixer was at room temperature (~20 °C), and the М2
mixer was heated in a glycerol bath (the temperature of the bath
was 80 °C). A capillary-reactor (internal diameter 1.0 mm, length
0.75 m) was placed at the outlet of the М2 mixer. The solution
coming from the capillary-reactor was supplied at ~20 °C to
a receiving flask (50 mL) containing a solution of Pri2NEt
(150 μL, 0.86 μmol, 11.5 equiv. based on CSA) in PhCH3 (2 mL).
After the completion of pumping solutions of all reagents through
gregation of supramers of reagents is inefficient for the
reaction between them to occur. Apparently, tight30 supra-
mers of oxazoline 1 or acid (CSA)* (cf. studies of the
supramolecular structuring of solutions of acids31—33) are
formed under these conditions, and the access of the CSA
molecule to the reaction center of oxazoline 1 is impeded
in these supramers, which is manifested as an enhanced
stability of oxazoline 1 under the action of acid. In the
case of replacement of the M1 mixer with a T-shaped
adapter (at the same flow rate), the formation of reaction
products 3 and 4 seems to indicate a higher disaggregation
of the supramers of the reagents under these conditions,
which makes the chemical reaction between them possible.
Thus, in this work, we experimentally observed the
earlier predicted26 effect of the flow rate and mode of
mixing of solutions of reagents on their reactivity and
advanced a rational explanation of the found facts based
on the application of the supramer approach.26
Experimental
The system of the M1 and M2 mixers (Teflon (PTFE) Comet
X-01 micromixer or a T-shaped adapter (Tee Assembly Tefzel™
(ETFE), for 1/16" (IDEX Health & Science LLC, www.idex-hs.
com)) was used for the reactions in flow assembled as shown in
Fig. 1 using Teflon (PTFE) capillary and connecting unions.
Internal diameters of all capillaries were 1.0 mm. The length of
the capillaries between S1—M1, S2—M2, and M1—M2 was
* Amphiphilic CSA molecules in nonpolar 1,2-dichloroethane
might form supramers structurally similar to reverse micelles in
which the acidic moiety is shielded from the solution with other
reagents, which decreases the reactivity of CSA.

Glycosylation in flow
Russ. Chem. Bull., Int. Ed., Vol. 68, No. 11, November, 2019
2129
the system, the solution in the receiving flask was diluted with
dichloromethane (25 mL) and washed with a saturated aqueous
solution of NaHCO3 (30 mL) and then with water (30 mL). The
organic phase concentrated at a reduced pressure on a rotary
evaporator, and the residue was dried for 3 h in vacuo (0.15 mbar),
after which it was dissolved in CDCl3 (0.6 mL) and analyzed by
13C NMR spectroscopy. Each experiment was carried out once.
The amounts of products 3 and 4 in the reaction mixture (see
Fig. 2 and Table 1) are indicated in arbitrary units (ω) equal to the
ratios of the intensities of the characteristic peaks in 13C NMR
spectra of isopropyl glycoside 3 (δC 55.8, С(2)) and glycal 4
(δC 140.6, С(1)) to the intensity of the peak of the initial oxazol-
ine 1 (δC 14.0, CH3 at the С(2) atom of the oxazoline ring). The
NMR spectra of compounds 1,34,35 3,36 and 4 (see Ref. 34)
coincide with the published data.
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Received July 18, 2019;
in revised form September 13, 2019;
accepted September 17, 2019
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