Testing the veracity of claims of Lewis acid catalysis

Article abstract of DOI:10.1016/j.tetlet.2018.11.006

Are reactions employing Lewis acids really catalysed by those Lewis acids, or by “hidden Br?nsted acids”, i.e. Br?nsted acids generated in situ by hydrolysis? Testing of a series of reactions using Sc(III), Fe(III), In(III) and Y(III) by addition of 2,6-di-t-butyl-4-methylpyridine reveal that all are likely to follow the latter pathway. A reaction claimed to be catalysed by CBr₄ through halogen bonding is also likely to be Br?nsted acid catalysed.

Full text of DOI:10.1016/j.tetlet.2018.11.006

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Testing the Veracity of Claims of Lewis Acid Catalysis
Ivan Šolić, Hong Xuan Lin, Roderick W. Bates
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https://doi.org/10.1016/j.tetlet.2018.11.006
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Please cite this article as: Šolić, I., Lin, H.X., Bates, R.W., Testing the Veracity of Claims of Lewis Acid Catalysis,
Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.11.006
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Tetrahedron
Testing the Veracity of Claims of Lewis Acid Catalysis
Ivan Šolić, Hong Xuan Lin and Roderick W. Bates*
Division of Chemistry & Biological Chemistry, School of Physical & Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore
637371
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Are reactions employing Lewis acids really catalysed by those Lewis acids, or by “hidden
Brønsted acids”, i.e. Brønsted acids generated in situ by hydrolysis? Testing of a series of
reactions using Sc(III), Fe(III), In(III) and Y(III) by addition of 2,6-di-t-butyl-4-methylpyridine
reveal that all are likely to follow the latter pathway. A reaction claimed to be catalysed by CBr4
through halogen bonding is also likely to be Brønsted acid catalysed.
Available online
2018 Elsevier Ltd. All rights reserved.
Keywords:
Lewis
Brønsted
Catalysis
Hydrolysis
Hidden
1. Introduction
especially in the context of mechanisms proposed in papers on
synthetic methods.12
The introduction of the concept of Lewis acidity, as opposed
to Brønsted acidity, had a profound effect on synthetic organic
chemistry.1 Numerous reactions, reagents and catalysts are based
upon this concept. Many reagents employed as Lewis acids are
metal salts. It is known that some salts can undergo hydrolysis in
situ to generate a Brønsted acid. Thus, when such salts are used,
it may be the case that they are not acting as Lewis acids, but as
precursors for Brønsted acids, i.e. they may be pre-catalysts, and
a so-called “hidden Brønsted acid” mechanism is operating. This
has been demonstrated in a number of specific cases. In
2. Results and Discussion
Our own experience with “hidden Brønsted acids” had been
with Sc(OTf)3, therefore we initially selected two simple, but
useful, transformations in which this was claimed as a catalyst:
one desilylation of TBS ether 1 (Scheme 1)13 and one ene or
Prins-type reaction (Scheme 2).14 In each case, when the reaction
was attempted in the presence of 2,6-di-t-butyl-4-methylpyridine,
no conversion could be detected. We, therefore, conclude, that
both of these reactions are really catalysed by in situ generated
TfOH.15
particular, Spencer et al. showed that this can operate in the
context of aza-Michael additions.2 Protonation has been
demonstrated in metal “catalysed” hydroamination.3 In situ
generated Brønsted acid has been implicated in an intramolecular
Friedel-Crafts reaction,4 and in THP formation.5 The
participation of triflic acid derived from silver triflate has been
Scheme 1. Desilylation.
established.6 We have shown that this is the case in
deoxygenative allylation of benzyl alcohols.7 Despite these
specific studies, there has not, to our knowledge, been a survey of
reactions involving Lewis acids to screen for this phenomenon. A
test is readily available: 2,6-di-t-butyl-4-methylpyridine is known
to neutralise only Brønsted acids but not Lewis acids due to the
steric crowding of the nitrogen lone pair.8 Amongst others,
Spencer,2 Evans,5 Vidović,9 and Oestreich10 as well as ourselves7
have used this test.11 Despite the availability of this simple test,
the issue is “rarely alluded to”.10 We, therefore, set out to screen
a series of reactions reportedly catalysed by Lewis acidic metal
salts. While the independent verification (or otherwise) would
appear to be a fundamental component of the scientific method, it
appears to be the exception and not the rule in organic chemistry,
Scheme 2. Ene or Prins reaction.
We further examined two deoxygenative allylations of
benzylic substrates 5 and 7: one using FeCl3.6H2O16 and one
using Fe(OTf)3 generated in situ from FeCl3.6H2O and AgOTf
(Scheme 3).17 Again, each reaction failed to proceed in the
presence of 2,6-di-t-butyl-4-methylpyridine indicating a hidden
Brønsted acid mechanism. Indium salts have acquired a certain
vogue in organic synthesis. We tested the reported indium(III)

2
Tetrahedron
catalysed hydrolysis of acetal 9 (Scheme 4).18 When the
Although the 2,6-di-t-butyl-4-methylpyridine test is not as
reaction was conducted in the presence of 2,6-di-t-butyl-4-
methylpyridine, a mere trace of the aldehyde was detectable,
although complete hydrolysis occurred under the same conditions
in its absence. This, again, indicates that a hidden Brønsted acid
mechanism operates and the true catalyst is HOTf.
clear cut in this case as in the others, the operation of Occam’s
razor demands that the simplest explanation of this set of
cyclisation experiments is that the reaction is Brønsted acid
catalysed.22 The initial cyclisation step would, therefore, be on
ketene iminium ion 16, giving 15 after deprotonation. This also
illustrates that experiments with 2,6-di-t-butyl-4-methylpyridine
as a test reagent must be interpreted with care.
Halogen bonding has been promulgated in recent years as a
new method to facilitate reactions.23 The concept is that vacant
orbitals associated with the halogen atom accept electron density
from the substrate i.e. they act as Lewis acids. To the best of our
knowledge, the possibility of hidden Brønsted acid catalysis has
not been suggested in this context. Recently, it has been reported
that carbon tetrabromide can catalyse the Claisen-Schmidt
condensation of acetophenones, such as 17, with aromatic
aldehydes, such as 10, through halogen bonding (Scheme 6).24
When this reaction was tested in the presence of 2,6-di-t-butyl-4-
methylpyridine, no conversion could be detected. It therefore
appears likely that the true catalyst is HBr. As commercially
available CBr4 is often supplied containing 5-10% water,
hydrolysis on long term storage appears likely.
Scheme 3. Deoxygenative allylation.
Scheme 4. Acetal hydrolysis.
A spectacular yttrium(III) catalysed route to eight membered
rings has recently been reported (Scheme 5).19 The postulated
mechanism involves formation of a η1-vinyl yttrium species 14,
presumably arising from nucleophilic attack on a η2-alkyne
yttrium complex 13.20 The original report employed
Scheme 6. Claisen-Schmidt condensation.
chlorobenzene as solvent. We found that the reaction works
equally well in acetonitrile. Interestingly, when the reaction was
carried out in chlorobenzene in the presence of 2,6-di-t-butyl-4-
methylpyridine, the product 12 was still obtained in good yield.
In contrast, repeating the cyclisation in acetonitrile in the
presence of 2,6-di-t-butyl-4-methylpyridine resulted in a mere
20% conversion. It must be born in mind that when 2,6-di-t-
butyl-4-methylpyridine reacts with a Brønsted acid, a new
Brønsted acid, a pyridinium salt, is formed. Indeed, when
ynamide 11 was treated with PPTS, complete conversion to the
product 12 was observed. Ynamide 11 is, therefore, sufficiently
acid sensitive that even a pyridinium salt is capable of catalysing
this transformation. Ynamides are known to react with just
carboxylic acids at room temperature.21
3. Conclusion
For all of the reactions examined in this study, the evidence
strongly suggests that a hidden Brønsted acid mechanism
operates in each case. It seems likely that this is also the case for
many other reactions for which Lewis acid catalysis has been
claimed or implied. It should be further noted that this
phenomenon is not limited to metal triflates, although it is most
often observed in such cases. The results presented here do not
detract from the synthetic utility of the reported procedures.
Indeed, the use of a metal salt as a Brønsted acid precursor may
in some cases be more convenient than the use of the same acid
directly. Nevertheless, a correct understanding of the mechanism
is not only intellectually important, but also essential for further
developments, such as asymmetric variants or use in flow
chemistry. In addition, as hydrolysis and activity may vary with
water content,7 the reproducibility of the reported procedures
may be in question.
4. Experimental section
All experiments were carried out as reported in the original
literature, then repeated in the presence of 2,6-di-t-butyl-4-
methylpyridine (10 mol%).
Acknowledgments
We thank Nanyang Technological University and the Agency
for Science Technology and Research (A-Star) for financial
support of this work (PSF grant number 1321202095).
Scheme 5. Eight membered ring formation.

16. Han, J.; Cui, Z.; Wang, J.; Liu, Z. Syn. Commun. 2010, 40, 2042.
17. Chan, L. Y.; Kim, S.; Chung, W. T.; Long, C.; Kim, S. Synlett,
2011, 415.
18. Gregg, B. T.; Golden, K. C.; Quinn, J. F. J. Org. Chem. 2007, 72,
5890.
References and notes
1.
(a) Lewis, G. N. Valence and the Structure of Atoms and
Molecules Chemical Catalog Co., New York, 1923, p. 142 (b)
Lewis Acids in Organic Synthesis, (Ed.: H. Yamamoto), Wiley,
Weinheim, 2002.
19. Zhou, B.; Li, L.; Zhu, X.-Q.; Yan, J.-Z.; Guo, Y.-L.; Ye, L.-W.
Angew. Chem. Int. Ed. 2017, 56, 4015.
2.
3.
Wabnitz, T. C.; Yu, J.-Q.; Spencer, J. B. Chem. Eur. J. 2004, 10,
484.
(a) McBee, J. L.; Bell, A. T.; Tilley T. D. J. Am. Chem. Soc. 2008,
130, 16562; (b) Taylor, J. G.; Adrio, L. A.; Hii, K. K. Dalton
Trans. 2010, 39, 1171.
20. It appears unlikely that a hard complex such as Y(OTf)3 would
activate a soft moiety such as an alkyne. Precedents for such a
simple lanthanide-alkyne complex seems to be sparse: T. J.
Marks, R. D. Ernst in Comprehensive Organometallic Chemistry
I, Vol. 3, (Ed.: G. Wilkinson, F. G. A. Stone, E. W. Abel),
Pergamon, Oxford, 1982, pp. 205-206.
4.
5.
6.
Cai, X.; Kesharz, A.; Omaque, J. D.; Stokes, B. J. Org. Lett. 2017,
19, 2626.
Evans, P. A.; Cui, J.; Gharpure, S. J.; Hinkle, R. J. J. Am. Chem.
Soc. 2003, 125, 11456.
(a) Dang, T. T.; Boeck, F.; Hintermann L. J. Org. Chem. 2011, 76,
9353; (b) Jin, H. J.; Kim, J. H.; Kang E. J. Synthesis 2017, 49,
3137.
21. Hu, L.; Xu. S.; Zhao, Z.; Yang, Y.; Peng, Z.; Yang, M.; Wang, C.;
Zhao, J. J. Am. Chem. Soc. 2016, 138, 13135.
22. It might be argued that 2,6-di-t-butyl-4-methylpyridine inhibits
protonolysis of the C-Y bond. While this can be the case with a C-
Au bond (LaLonde, R. L.; Brenzovich, Jr., W. E.; Benitez, D.;
Tkatchouk, E.; Kelley, K.; Goddard, III, W. A.; Toste F. D. Chem.
Sci. 2010, 1, 226), it would not be expected for a highly ionic C-Y
bond (ref. 18, p. 13).
23. Breugst, M.; von der Heiden, D.; Schmauck, J. Synthesis 2017, 49,
3224.
24. Kazi, I.; Guha, S.; Sekar G. Org. Lett. 2017, 19, 1244.
7.
Šolić, I.; Seankongsuk, P.; Loh, J. K.; Vilaivan, T.; Bates, R. W.
Org. Biomol. Chem. 2018, 16, 119.
8.
9.
Kanner, B.; Brown, H. C. J. Am. Chem. Soc. 1953, 75, 3865.
(a) Liu, Z.; Ganguly, R.; Vidović, D. Dalton Trans. 2017, 46, 753;
(b) Liu, Z.; Vidović D. J. Org. Chem. 2018, 83, 5295.
10. Schmidt, R. K.; Müther, K.; Mück-Lichtenfeld, C.; Grimme, S.;
Oestreich, M. J. Am. Chem. Soc. 2012, 134, 4421.
11. For a recent example, see Kuciński, K.; Hreczygho, G. Org.
Process Res. Dev. 2018, 22, 489.
Supplementary Material
1H NMR spectroscopic results for all experiments (PDF file).
12. For a recent and notable exception, see (a) Ryan, W.; Bedard, K.;
Baidilov, D.; Tius, M.; Hudlicky, T. Tetrahedron Letters 2018, 59,
2467; (b) Riviera, M. J.; Sarotti, A. M. Org. Biomol. Chem. 2018,
16, 1442.
13. Oriyama, T.; Kobayashi, Y.; Noda, K. Synlett, 1998, 1047.
14. Sultana, S.; Bondalapati, S.; Indukuri, K.; Gogoi, P.; Saha, P.;
Saikia, A. K. Tetrahedron Lett. 2013, 54, 1576.
15. For an example of a reaction shown to be genuinely Sc(OTf)3
catalysed, see, Kaźmierczak, J.; Kuciński, K.; Hreczygho, G.
Inorg. Chem. 2017, 56, 9337.

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Testing the Veracity of Claims of Lewis Acid
Catalysis
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Ivan Šolić, Hong Xuan Lin and Roderick W. Bates*
Division of Chemistry & Biological Chemistry, School of Physical & Mathematical Sciences, Nanyang
Technological University, 21 Nanyang Link, Singapore 637371
HX
MXn
Lewis Acid
Catalysis
Metal Salt
Metal Salt
hydrolysis
coordination
Brønsted Acid
Catalysis
MX
MXnn

4
Highlights
Highlights

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
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Brønsted vs. Lewis acid catalysis is tested
For claimed scandium(III) catalysis
Indium(III) catalysis
Iron(III) catalysis
Yttrium(III) catalysis
Halogen bonding