Vessel Effect in C–F Bond Activation Prompts Revised Mechanism and Reveals an Autocatalytic Glycosylation

Article abstract of DOI:10.1002/ejoc.201901755

Activation of C–F bonds under acidic conditions results in the formation of hydrogen fluoride as the reaction progresses. In the following communication, the effect of the vessel material on such reactions has been investigated and a significant differenc

Full text of DOI:10.1002/ejoc.201901755

A Journal of
Accepted Article
Title: Vessel effect in C‒F bond activation prompts revised mechanism
and reveals an autocatalytic glycosylation.
Authors: Michael Martin Nielsen, Yan Qiao, Yingxiong Wang, and
Christian Marcus Pedersen
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Vessel effect in C‒F bond activation prompts revised mechanism
and reveals an autocatalytic glycosylation.
Michael M. Nielsen,[a] Yan Qiao,[b] Yingxiong Wang,*[b] and Christian M. Pedersen*[a]
In memory of Professor Teruaki Mukaiyama.
Abstract: Activation of C-F bonds under acidic conditions results in
the formation of hydrogen fluoride as the reaction progresses. In the
following communication, the effect of the vessel material on such
reactions has been investigated and a significant difference between
an HF-resistant material and common borosilicate glassware has
been found. HF was found to react rapidly with borosilicate glassware,
seemingly leaching fluorosilicate into solution, but persisted in HF-
resistant materials. Several examples of C-F bond activation on
glycosyl fluorides and benzyl fluorides as well as NMR-studies
suggest a significant effect of the choice of reaction vessel, leading to
the discovery of an autocatalytic glycosylation and a revised
mechanism for the activation of benzyl fluorides, suggesting activation
by SiF4 rather than HF.
When reviewing the literature, it is clear that many methods
for C-F bond activation result in the accumulation of HF in solution,
which in itself has been reported as an active catalyst for C-F
bond activation (vide supra). However, as HF is known to react
with silica, one of the primary components of standard laboratory
equipment, we sought out to investigate whether C-F bond
activations taking place under acidic conditions would be
influenced by changing the reaction vessel to an HF-resistant
material rather than common borosilicate glassware. The fate of
the HF formed during glycosylations with glycosyl fluorides has
previously been ignored in the literature and only mentioned
briefly by Kunz and Sager.[24]
The C-F bond is one of the strongest single bonds in organic
chemistry.[1] In recent years, the activation of C(sp3)-F bonds has
received considerable attention as the C(sp3)-F group has
emerged as a useful electrophile with distinct reactivity.[2–9]
Mukaiyama pioneered the field of anomeric C-F bond activation
in carbohydrate chemistry with the introduction of glycosyl
fluorides as novel electrophiles in glycosylation chemistry[10]
(Scheme 1) that has since become a commonly employed
electrophile for catalytic glycosylations.[11,12]
Several other applications of C(sp3)-F bond activation have
been developed and significant highlights in this vast field of
research has recently been reviewed in detail by Hamel and
Paquin.[3] Often, C-F bonds are activated under either reductive
or basic conditions, but recent years have seen a growing interest
in C-F bond activation under acidic/neutral conditions enabled by
hydrogen bonding (Scheme 1). The Paquin and co-workers have
developed methods for chemoselective benzylic-[13–17], allylic[13]
and propargylic[18] C-F bond activation mediated through
hydrogen bonding, reporting that the hydrogen fluoride developed
during the reaction would function as an active catalyst, resulting
in an autocatalytic kinetic profile. Several other examples of
Lewis- or Brønsted acid-[19–22] and metal-catalyzed[23] C-F bond
activations without employing HF-scavengers have also been
reported.
Scheme 1. Examples of C-F bond activation promoted by acid- or H-bond
catalysis and the work presented in this paper.
[a]
[b]
M. M. Nielsen, Prof. C. M. Pedersen
Department of Chemistry
University of Copenhagen
Universitetsparken 5, 2100 Copenhagen O, Denmark
E-mail: cmp@chem.ku.dk
Prof. Y. Qiao, Prof. Y. Wang,
Initially, the catalytic activation of glucopyranosyl fluoride 1
was investigated by using a simple, primary alcohol as the
nucleophile (Table 1). It has been documented by Mukaiyama that
the anomeric configuration of the electrophile has no effect on the
stereochemical outcome,[25–27] and consequently, a mixture of
Institute of Coal Chemistry
Chinese Academy of Sciences
27 South Taiyuan Road, Taiyuan 030001, People’s Republic of
China
anomers were employed as electrophiles in the glycosylations.
[24,28–30]
BF3∙OEt2
and TfOH[26,27,31] were chosen as common
examples of a strong Lewis- or Brønsted acid catalysts in catalyst
loadings of 1 to 10 mol%. From the initial results (Table 1), it was
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evident that the glycosylations with glycosyl fluorides resulted in
very high yields at 5 to 10 mol% catalyst loadings (entries 1-4 and
7-10), however as the catalyst loading was lowered (entries 5-6),
the yield of the desired product, 2, diminished and increasing
amounts of 2,3,4,6-tetra-O-benzyl-α/β-D-glucopyranose was
formed as an undesired byproduct by hydrolysis. Interestingly,
this byproduct was formed in glassware despite careful flame-
drying of the glass vessels under high vacuum prior to use.
(entry 9+10). Although the total yield in these two reactions was
only 52 and 53% accordingly, the yields based on recovered
starting material were found to be 94 and 72%, which indicates
that the formation of byproducts in the PTFE vessel increases as
the reaction approaches completion.
Table 2. Catalytic glycosylations employing carbohydrate electrophiles.
Table 1. Initial investigation of vessel effect using a simple nucleophile.
Entry
cat. (mol%)
BF3∙OEt2 (10)
BF3∙OEt2 (10)
BF3∙OEt2 (5)
BF3∙OEt2 (5)
BF3∙OEt2 (1)
BF3∙OEt2 (1)
TfOH (10)
Vessel material
Glass
t (h)
4.5
2.25
5.25
3
Yield (%)[a]
90[b]
97
α/β
Entry
ROH
cat.
Vessel mat.
t (h)
Yield (%)
α/β
1
2
3
4
5
6
7
8
9
10
53/47
55/45
52/48
54/46
53/47
56/44
58/42
52/48
56/44
58/42
1
3
3
3
3
4
4
4
4
4
4
4
4
4
4
BF3∙OEt2
BF3∙OEt2
TfOH
Glass
PTFE
Glass
PTFE
Glass
PTFE
Glass
PTFE
PTFE
PTFE
Glass
PTFE
Glass
PTFE
4.5
2.25
5.25
4
69
86
66
80
38
59:41
59:41
62:38
61:39
66:34
‒
PTFE
2
Glass
92[b]
97
3
PTFE
4
TfOH
Glass
23
76[b]
91
5
BF3∙OEt2
BF3∙OEt2
TfOH
5.25
22
PTFE
72
[c]
6
‒
Glass
20
94[b]
96
7
5.25
22
36
63:37
66:34
57:43
64:36
69:31
–
TfOH (10)
PTFE
3.25
22
8
TfOH
25
TfOH (5)
Glass
89[b]
98
9
BF3∙OEt2
TfOH
1.25
1.25
5[b]
0.5
5
52[d]
53[d]
63
TfOH (5)
PTFE
22
10
11[a]
12[a]
13[a]
14[a]
[a] Isolated yield. [b] Yield corrected for 2,3,4,6-tetra-O-benzyl-α/β-D-
glucopyranose.
BF3∙OEt2
BF3∙OEt2
TfOH
[c]
‒
59
49
69:31
54:46
Next, more challenging nucleophiles were glycosylated (Table
2) as more synthetically relevant glycosylations. Using 5 mol% of
the catalysts, the glycosylations with a 6-OH nucleophile 2
(entries 1-4) performed smoothly and still followed the trend of
both increased yields and rate in PTFE compared to the reaction
in a glass vessel. The major byproduct that led to lowered yields
in the glass containers was found to be a mixture of α/α- and α/β-
trehalose via the corresponding hemiacetal that was formed by
hydrolysis of the glycosyl donors.
TfOH
5
[a] Two equivalents of 4 were added. [b] 4 was consumed after 3 h according
to TLC. [c] Contained <10% product. Major product was methyl 2,3,4,6-tetra-
O-methyl-α/β-D-glucopyranoside. [d] Yields BRSM were 94% for entry 9 and
72% for entry 10.
The yields were found to drop dramatically as nucleophile 4,
a much weaker nucleophile than 3, was employed (entries 5-8).
Interestingly, different major byproducts were observed to cause
this decrease in yields; The reactions in glassware resulted in the
formation of trehaloses as byproducts, whereas the
glycosylations in PTFE gave rise to unexpected byproducts,
namely methyl 2,3,4,6-tetra-O-benzyl-α/β-glucopyranosides. The
formation of these methyl glycosides was surprising as these can
only be formed by transfer of the benzyl- or methoxy groups
between the acceptors under the reaction conditions. To
investigate whether the benzyl transfer was caused by an
increasingly more acidic reaction mixture as the reaction
progressed, it was attempted to stop the reaction prematurely
The yields only increased very little as an excess of
nucleophile 4 was employed (entries 11-14) and significant
amounts of the above-mentioned byproducts were still observed.
Interestingly, the reactions in entries 6 and 12 suffered from
comparable problems of protecting group transfer under the
reaction conditions and the decomposition of the starting material
was much faster as the concentration of glycosyl fluoride was
increased (entry 12).
In an attempt to clarify exactly what effect the reaction vessel
had on the chemical environment, a series of NMR experiments
were carried out (Scheme 2; for details, see SI), again using 2-
methoxyethanol as the nucleophile as in Table 1. A fluorinated
ethylene propylene (FEP) NMR liner was used to as HF-resistant
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vessel during NMR experiments. In agreement with the results
from Table 1, it was found that the rate of reaction was higher for
the reactions carried out in FEP compared to reactions in regular
glass NMR tubes (see SI). Furthermore, the addition of crushed
glass (from an NMR tube) to the FEP tube was found to lower the
reaction rate to almost resemble that in glass. In the FEP NMR-
tube, the formation of HF was obvious from 19F-NMR as the
reaction progressed (see SI). Interestingly, the distinct HF-peak
was never detected during the reactions in glass NMR tubes. In
the glass NMR tube, however, a broad singlet at ‒162 ppm was
observed to increase (and shift slightly) as the reaction
progressed. Furthermore, this peak was not detectable when the
NMR tube was washed and a blank sample was recorded, ruling
out a glass-bound species.
Furthermore, it seemed that the use of an electron-poor
electrophile such as fluorobenzene (product 7) gave rise to almost
identical yields as with p-xylene (product 8). As the reactions in
glassware (round bottom flask with nitrogen balloon) did not lead
to the formation of the desired product, the experiments were
conducted under identical conditions as reported by Paquin and
co-workers[15] using sealed glass vials rather than conventional
round bottom flasks.
Scheme 3. Friedel-Crafts alkylations using benzyl fluorides under similar
conditions as reported by Paquin and co-workers. Yields from glass vessel in
red, yield in blue in PTFE vessel. HFIP = hexafluoroisopropanol. [a] Solvent was
CH2Cl2. [b] Solvent was fluorobenzene.
Scheme 2. Summary of NMR-observations.
The peak at ‒162 ppm has recently been reported as SiF4,[32]
a species that has previously been reported to be formed as HF
reacts with a glass surface.[33–39] The identity of SiF4 in glass
vessels was confirmed by headspace GC-MS (see SI for
chromatogram and control experiments) of the reaction mixture.
This explains why the reaction was so strongly influenced by the
choice of reaction vessel as SiF4 has been reported by Noyori as
an efficient catalyst for activation of glycosyl fluorides[40] and
related fluorosilicates have previously been employed as Lewis
acids in glycosylation chemistry.[41] Furthermore, the formation of
large amounts of α/α- and α/β-trehalose is a consequence of the
reaction between HF with the glass surface which results in the
release of water into solution, thus explaining the absence of
trehalose in PTFE vessels. This can also explain why the
consumption of glycosyl fluoride was much faster in glass vessels
when weaker glycosyl nucleophiles (Table 2, entries 5 and 7)
were used as water simply outcompeted the 4-OH glycosyl
nucleophile and resulted in trehalose formation. One can
speculate whether this was also the primary reason why the
Mukaiyama group and others added molecular sieves in order to
obtain acceptable yields in catalytic glycosylations with glycosyl
fluorides.[25–27,31,42–46] The effect of adding drying agents to this
particular glycosylation seems highly important as Toshima has
reported an increase in yield from 32% to 99% of the desired
glycoside when 100 wt% 5Å molecular sieves were added.[47]
As there was a clear difference in the reactivity of the glycosyl
fluoride dependent on the vessel material, it was investigated
whether this would also be the case for the H-bond mediated
Friedel-Crafts alkylations with benzyl fluorides that have been
reported by Paquin and co-workers.[15] As this reaction is reported
to be catalyzed by HF formed in situ,[15,16] it was likely to be
influenced by the vessel material as well.
Furthermore, it was investigated whether the vessel surface
had an effect on the reaction, as three identical vials were
subjected to different conditions prior to reaction; One was pre-
treated with TMSCl to TMS-protect all free OH-groups of the glass
surface, one was pre-treated with HF in CH2Cl2 and one glass vial
was used as purchased. Furthermore, an experiment using
identical conditions in a PTFE-vessel was also conducted. It was
found that all four reactions ran to completion within 24h, yielding
the desired product in yields of >95% in all four cases, ruling out
this hypothesis and confirming the high yields reported by Paquin.
As the reactions in round bottom flasks did not lead to formation
of the desired product, we speculated that the headspace volume
could be influencing the reaction as SiF4 diffuses out of solution.
Two parallel experiments, one in a regular glass NMR tube and
another in an FEP liner were then conducted. Both ran to
completion, albeit HF was only observed, by 19F-NMR, in the FEP
liner, whereas SiF4 was observed in the glass NMR tube (see SI).
Scheme 4. Glycosylations using the Paquin procedure[15] employing
HFIP/CH2Cl2 and HF as reaction initiators.
Next, it was investigated whether the conditions for benzyl
fluoride activation were applicable for glycosylations (Scheme 4).
It was found that the CH2Cl2/HFIP solvent mixture was not able to
efficiently activate the glycosyl fluoride and no conversion was
observed after three days. However, when adding 10 mol% HF,
formed in situ in CH2Cl2, the reaction was found to take place in
the glass vessel, whereas the reaction in PTFE showed no
conversion after three days. This can be explained by the reaction
of HF with the glass surface, resulting in the formation of SiF4
Four reactions involving the benzyl fluorides were performed
(Scheme 3). Surprisingly, there was no conversion of benzyl
fluoride 5 in regular round bottom flasks after 24h. After 20h, all
four reactions showed no conversion by TLC, but after 24h, the
starting material in the two reactions in a PTFE flask were fully
converted, which confirmed the autocatalytic kinetic profile
reported by Paquin and co-workers.
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which is then capable of activating the glycosyl fluoride. To
investigate this hypothesis, both reactions were studied by NMR
and it was found that the glycosylation was in fact autocatalytic
when conducted in a glass NMR tube (Figure 1). This is, to the
best of our knowledge, the first report of an autocatalytic chemical
glycosylation.
CAS President’s International Fellowship Initiative (2015VMB052)
for support.
Keywords: keyword 1 • keyword 2 • keyword 3 • keyword 4 •
keyword 5
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COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
A significant vessel effect during acid
catalyzed C‒F bond activations has
been documented and led to revised
mechanisms for both glycosylations
and benzyl fluoride activation. An
autocatalytic chemical glycosylation
was discovered during this
investigation, further signifying the
significant effect of the vessel material
on a given reaction.
Michael M. Nielsen, Yan Qiao,
Yingxiong Wang* and Christian M.
Pedersen*
Page No. – Page No.
Vessel effect in C‒F bond activation
prompts revised mechanism and
reveals an autocatalytic glycosylation
Keywords: C-F bond activation; vessel effects
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