Halogen Bonding of N-Halosuccinimides with Amines and Effects of Br?nsted Acids in Quinuclidine-Catalyzed Halocyclizations

Article abstract of DOI:10.1002/hlca.202100080

An arguable expectation in halogen chemistry is that an amine will react oxidatively with an N-halosuccinimide (NXS) to form an N-halogenated species bearing a covalent N?X bond. While likely for NCS under most conditions, we find this expectation simply

Full text of DOI:10.1002/hlca.202100080

doi.org/10.1002/hlca.202100080
FULL PAPER
Halogen Bonding of N-Halosuccinimides with Amines and Effects of
Brønsted Acids in Quinuclidine-Catalyzed Halocyclizations
Jing Li,a Eunsang Kwon,b Martin J. Lear,*c and Yujiro Hayashi*a
a
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan,
e-mail: yujiro.hayashi.b7@tohoku.ac.jp
Research and Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University, Sendai
b
980-8578, Japan
c
School of Chemistry, University of Lincoln, Brayford Pool, Lincoln LN6 7TS, United Kingdom,
e-mail: MLear@lincoln.ac.uk
Dedicated to Professor E. Peter Kündig on the occasion of his 75th birthday in recognition of his outstanding
contributions to catalysis
An arguable expectation in halogen chemistry is that an amine will react oxidatively with an
N-halosuccinimide (NXS) to form an N-halogenated species bearing a covalent NÀ X bond. While likely for NCS
under most conditions, we find this expectation simply not true for NIS and largely inaccurate for NBS. Herein,
we disclose evidence through systematic NMR and X-ray studies that non-covalent halogen bonded amine
complexes of NIS predominate over covalent N-halogenated species, even with primary and secondary amines.
For example, during the catalytic electrophilic halocyclization of gem-disubstituted alkenes by cinchona-like
amines, the quinuclidine complexes of NIS and NBS display lower reactivity than their parent N-halosuccinamides
and require the presence of an appropriate Brønsted acid. Specifically, a Brønsted acid and quinuclidine jointly
catalyze the halo-cycloetherification of γ-alkenyl alcohols with NIS or NBS, while only quinuclidine acts as a
catalyst in the halolactonization of γ-alkenoic acids. Although our evidence confirms a transient N-halogenated
quaternary ammonium salt as the halonium species, it is important to note that NIS predominantly forms ‘off-
cycle’ halogen bonded amine complexes in solution.
Keywords: halocyclization, halogen bonding, halogens, amine catalyst, reaction mechanisms, iodine complex.
damental studies[19] and receptor anion transport have
Introduction
been reported in the last decade.[20,21] The utility and
Halogen bonding is a non-covalent, attractive inter- importance of halogen bonding is now growing in
action that occurs between a halogen atom (a Lewis recognition in the organic synthesis communities,
acid) and a Lewis base.[1–8] Until relatively recently, the whereby halogen bonded complexes have been used
majority of applications of halogen bonding are as reagents[22] and the Lewis acidic nature of electro-
concerned with the solid state, for example, in crystal philic halogen reagents has been used to activate
engineering,[9–11] self-assembly,[12,13] and organic reactions or even initiate catalytic events.[23–30] Indeed,
semiconductors.[14,15] The investigation of halogen we became intrigued by the halogen bonding nature
bonding in the solution-phase has lagged behind of the electrophilic reagents NIS and NBS that are
considerably, although recent applications,[16–18] fun- commonly used in catalytic halo-functionalizations,
specifically their mechanistic role and reactivity in the
halo-cyclization of γ-olefinic alcohols and acids in the
presence of amine catalysts (Scheme 1).[31–42] For
instance, according to literature reports, NIS and NBS
Supporting information for this article is available on the
WWW under https://doi.org/10.1002/hlca.202100080
Helv. Chim. Acta 2021, 104, e2100080
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Helv. Chim. Acta 2021, 104, e2100080
we could find, were halogen bonded complexes
reported between amines and NIS/NBS, DABCO·2NBS
and hexamethylenetetramine·NIS/NBS,[48] and the im-
portance of halogen bonding in amine-catalyzed halo-
functionalizations appears to be underappreciated
(Scheme 1,B, vide infra).
Concerns in this area arose during our develop-
ment of an efficient oxidative amidation of primary
nitroalkanes by the reaction of amines and NIS under
O2, as well as our cyanoalkane oxidative studies.[49–54]
During our mechanistic interrogations, we observed
and isolated a previously unknown 1:1 adduct 1
between allylamine and NIS instead of the N-iodo-
amine, which is the generally expected species
according to traditional reaction modes (Scheme 1,C).
Having identified 1 as a stable halogen-bonded
complex of the primary amine, which is arguably
uncommon according to literature precedence,[55–57]
we began to systematically investigate the reaction of
amines with NIS and NBS in more detail. Herein, we
not only summarize our findings of the fundamental
structure and reactivity of halogen-bonded complexes
between amines and NBS/NIS, but also provide addi-
tional insights into the mechanistic role of NBS/NIS-
amine complexes and Brønsted acids in the quinucli-
dine-catalyzed halocyclization of γ-olefinic alcohols
and acids (Scheme 1,B).
Results and Discussion
Reactivity of NIS and NBS with Amines
First, we investigated the reaction of amines with NIS
(Scheme 2,A). Different primary, secondary, and tertiary
amines, such as allylamine, N-methylbenzylamine, N,N-
dimethylbenzylamine, and quinuclidine (1 equiv.),
were mixed with NIS (1 equiv.) in CDCl3 and monitored
by 1H-NMR spectroscopy. Immediately after mixing,
the methylene signals of NIS were shifted upfield
compared with free NIS, and the proton signals alpha
to the nitrogen of the amine were shifted downfield
compared with the free amine (see Figures S1–S4 in
Supporting Information for spectroscopic details).
Scheme 1. Modes of halogen bonding in relation to amine-
catalyzed halocyclizations: A) Conventional halogenative
modes. B) Rapid halocyclization of γ-alkenoic acids. C) Role of
halogen bonded amine complexes.
are one of the most common reagents used to oxidize
In all cases, the pure halogen bonded complex
NÀ H bonds to NÀ X bonds.[43] Indeed, it is reported could be readily isolated as a solid by evaporating the
that primary and secondary amines are readily solvent and washing with dry Et2O. The thermal
oxidized by NIS to give N-iodo amines,[44] while stability of complexes 1–4 both in solid and solution
secondary amines are readily oxidized by NBS to form depended highly upon the type of amine. For
generate N-bromo amines (Scheme 1,A, equation 1).[45] example, the allylamine NIS complex 1 and the
Also, tertiary amines are reported to react readily with N-methylbenzylamine·NIS complex 2 darkened slowly
NIS or NBS to form N-halo-ammonium salts (Sche- and decomposed to a complex mixture at r.t. within
me 1,A, equation 2).[47] In only two examples, as far as one day. The N,N-dimethylbenzylamine-NIS complex 3
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Scheme 2. Bonding modes of N-halosuccinimides with primary, secondary, and tertiary amines: A) Reactivity of NBS and NIS with
various amines and X-ray structures of isolated NXS-amine complexes 1–5. B) Selected halogen bond information for complexes 1–
5 from XRD data.
decomposed rapidly at r.t. within ten minutes.[46,47] this indicated that Lewis basic quinuclidine donates
°
However, all complexes can be stored at À 30 C for electron density to the Lewis acidic NBS. The bromine
more than three months. The quinuclidine·NIS com- bonded complex 5 was obtained only when quinucli-
plex 4 was found to be very stable and can be stored dine was employed as the tertiary amine. Pure solid 5
at r.t. for more than three months without any was generated after evaporation of the solvent and
decomposition.
washing with Et2O, and this complex was stable at
Next, the reaction of amines with NBS was room temperature for more than three months with-
investigated in CDCl3 (Scheme 2,A). Primary benzyl- out any decomposition. The studies summarized in
amine and secondary N-methylbenzylamine were Scheme 2,A indicate that NIS reacts with primary,
readily oxidized to their N-bromo amines and released secondary, and tertiary amines to form halogen
succinimide even at low temperature, as evidenced by bonded complexes. On the other hand, NBS reacts
1H-NMR spectroscopy (see Supporting Information for with primary and secondary amines to afford oxidized
details).[45] However, when NBS was mixed with products with NÀ Br bonds, while it reacts with
equimolar amounts of quinuclidine, the NBS and quinuclidine to generate a halogen-bonded complex.
quinuclidine signals shifted upfield and downfield,
To provide fundamental data on halogen bonding
respectively. Similar to the NIS-quinuclidine complex 4, characters, the amine complexes 1–5 of NBS/NIS were
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subjected to X-ray structural analysis (see Scheme 2,B). chona alkaloids being widely adopted as quinuclidine-
All angles of NÀ IÀ N of the complexes 1–4 are near to based catalysts in the enantioselective iodo- and
180 , having essentially linear geometry, ranging from bromocyclizations of olefins.[61–67] The results are
°
°
°
175.2 to 178.8 . The corresponding N---I distances of summarized in Scheme 3,A and 3,B. While the N-
the NIS·amine complexes between the Lewis basic halosuccinimides (NXS) are more reactive and provide
amine and NIS vary from 2.369 to 2.433 Å, longer than greater reaction conversions than their halogen-
the NÀ I bond (1.96 Å) of NIS.[58] In addition, the NÀ I bonded counterparts 4 or 5, we can collectively make
bond of NIS varies from 2.165–2.190 Å, which are the following two main observations: 1) the NIS- or
longer than the NÀ I bond (1.96 Å) of NIS.[59] In the case NBS-quinuclidine complex 4 or 5 reacts with the acid
of the NBS-quinuclidine complex 5, the angle of substrate 7 much faster than the alcohol substrate 6,
°
NÀ BrÀ N is essentially linear at 178.3 and the N---Br and 2) the reaction of the acid substrate 7 with
bond is 2.21 Å, which is much shorter than the van der complex 4 or 5 never exceeds 70%, leaving unreacted
Waals radii of the involved atoms (3.40 Å).[60] These reactants and reagents (see Scheme 4,A and 4,B and
linear bond angles and short bond lengths are clear Supporting Information for full reaction profiles).
features of amine halogen bonding.[48,55–57]
Two possible reaction pathways were considered
to explain these observations (Scheme 3,C). In one case
(Path A), the complex 5 reversibly releases the free
quinuclidine ligand from NXS, which we confirmed by
NIS/ NBS-Quinuclidine Complex 4/5 in Halocyclization
At this juncture, we decided to study the reactivity of titration experiments (see Supporting Information for
the NIS/NBS-quinuclidine complexes 4/5 with a view details). The generated quinuclidine then serves as a
to providing mechanistic insights into modified cin- base and reacts with the acid substrate 7 to form an
Scheme 3. Alkene Reactivity of NIS/NBS versus NIS-quinuclidine/NBS-quinuclidine complex 4 or 5: A) Study with alcohol 6 (see
Figures S6,A, S7 and S8 for full reaction profiles). B) Study with acid 7 (see Figures S6,B, S9 and S10 for full reaction profiles). C)
Proposed halogenation of γ-alkenyl acid 7 through sole (Path A) or dual (Path B) activation modes.
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Scheme 4. Effect of catalytic combinations of quinuclidine and sources of acid on halocyclization: A) Bromoetherification of 6 under
various reaction conditions with NBS-based systems to oxolane 8. B) Iodoetherification of 6 under various reaction conditions with
NIS-based systems to oxolane 13. C) NBS·quinuclidine complex 5 catalyzes bromolactonization to 9 (see Figure S9 for full reaction
profiles) and NIS·quinuclidine complex 4 catalyzes iodolactonization to 14 (see Figure S10 for full reaction profiles).
ammonium salt 10. Here the carboxylate part of 10 is
The Path B model is similar to Denmark’s Lewis
more nucleophilic than its acid counterpart and base/Lewis acid co-catalyzed halocyclizations and Lewis
thereby can cyclize with free NBS and afford 9. This base/Brønsted acid co-enhanced seleno- and thio-
process finally releases succinimide as a byproduct cycloetherifications.[69–72] In other words, the Brønsted
and free quinuclidine for another cycle (if used acid would activate the halogen-bonded NXS-quinucli-
catalytically). In the other case (Path B, Scheme 3,C), dine complex 4/5 to form a more reactive ‘X+’ species
the unsaturated acid 7 can reversibly hydrogen bond (12 in this case) through hydrogen bonding and
with the NBS-quinuclidine complex 5. This would form facilitate proton transfer to eventually eject succini-
a protonated intermediate like 11, which can facilitate mide as a byproduct. If this Path B (Scheme 3,C) is to
its dissociation into a reactive N-bromo-ammonium be supported experimentally, Brønsted acids would
carboxylate salt 12 and release succinimide. Here, not not only accelerate halolactonizations but also accel-
only is the N-bromo-ammonium part of 12 more erate haloetherifications through N-halo quinuclidi-
electrophilic than either 5 or NBS, but also the nium salts like 12. These experiments are summarized
nucleophilic component is activated as its carboxylate in Scheme 4.
anion. Subsequent intra- or intermolecular electro-
In the event, a carboxylic acid was indeed found to
philic bromination and carboxylate cyclization would dramatically accelerate the halogenative cyclization
afford the lactone 9, again releasing free quinuclidine reaction of the relatively neutral unsaturated alcohol 6
for another cycle (if used catalytically). To support Path with either NBS or NIS, which neared completion
A (Scheme 3,C) as a possibility, the soluble potassium within 20 minutes (cf. Scheme 4,A and 4,B). Experi-
carboxylate salt of alkene 7 was prepared in CDCl3 by ments using stoichiometric and sub-stoichiometric
treating 7 with potassium carbonate and 18-crown-6 amounts of NXS-quinuclidine complexes 4 or 5, and
before adding NBS. This salt would thus mimic the the addition of an acetic acid to the alcohol substrate
ammonium carboxylate salt 10. In this case, the salt of 6 also support Path B (Scheme 3,C). In short, we can
7 remained largely unreacted after 12 hours. This reason that: 1) the NXS-quinuclidine complex 4/5 is
indicated Path A to be unlikely at the stage of not the actual halogenating species which, under the
converting salt 10 to 9 with free, non-coordinated NBS reaction conditions, generates a less reactive system
species.
than its parent NXS. 2) The reactivity of the NBS
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Brønsted acid, and NBS/NIS. A catalytic amount of
complex 4 or 5 in combination with a catalytic amount
of acid also serves as an efficient system for the
halocyclization of the δ-unsaturated alcohol 6 with
NBS or NIS, whether the complex 4 and 5 is pre-
formed or formed in situ.
Next, halolactonization of the unsaturated acid 7
was studied with catalytic quantities of either the
NBS·quinuclidine complex 5 or the NIS·quinuclidine
complex 4 (Scheme 4,C). From previous experiments
(Scheme 3,B), the reaction of the alkene-acid 7 was
found to be initially fast in the stoichiometric presence
of the NBS·quinuclidine complex 5 (100 mol-%), but
the reaction never surpassed a yield of 70%. This
outcome can be reasoned to occur because of
increasing concentrations of the free amine quenching
sources of free protons from 7. Indeed, the addition of
MeCOOH rapidly completed such reaction cases (yields
<90%). In comparison, the table entries of Scheme 4,C
show that halolactonizations essentially complete
within ten minutes without the addition of extra acid,
only when catalytic amounts of the NXS·quinuclidine
complex 4/5 (10 mol-%) or quinuclidine (10 mol-%)
were used. Clearly, compound 7 serves as its own
source of needed protons to activate the halogen
bonded amine complexes 4/5 to a more reactive ‘X+’
Scheme 5. Proposed catalytic cycle of quinuclidine-catalyzed
halocyclizations from the ‘off-cycle’ halogen bonded amine
complexes 4 or 5 in the presence of a suitably strong Brønsted
acid that can set up equilibria between species 11, 12 and 15.
complex 5 is greatly enhanced by CH3COOH (pKa = species, which again supports Path B of Scheme 3,C.
4.8), while the reactivity of the NIS complex 4 requires Through these collective studies of the reactivity of
a stronger acid ClCH2COOH (pKa =2.9 in water). 3) The the NBS·quinuclidine complex 5 and NIS·quinuclidine
reactivity of NXS is only slightly enhanced by a complex 4, including supporting control studies de-
Brønsted acid in the absence of an amine component. tailed in Figures S11–S17 in the Supporting Information,
4) The order of the addition of NXS, quinuclidine, and we propose the following catalytic cycle for halocycli-
the Brønsted acid is not important for a fast, complete zations (Scheme 5). As evidenced by NMR titration
reaction result. 5) Quinuclidine and MeCOOH can both studies (see Supporting Information), there exists an
function effectively in catalytic quantities.
equilibrium between the NXS complex 4/5 with NXS
These results indicate that a suitably strong acid is (X=I or Br) and quinuclidine. The rate of exchange of
needed to match the halogen bonding strength of the the NIS·quinuclidine complex 4 (X=I) was found to be
NBS or NIS amine complex, which further supports the slower than the NBS·quinuclidine complex 5 (X=Br).
observation that the NIS complex 4 is less reactive Importantly, the NXS complexes 4/5 are not the
(more stable) than the NBS complex 5. It was also reactive halogenating species. However, these species
observed that the NIS complex 4 also works in become protonated with MeCOOH or ClCH2COOH to
catalytic amounts with chloroacetic acid, and that afford a reactive halogenating species (e.g. 12 through
quinuclidine itself works in a catalytic fashion with 11) with the expulsion of succinimide. As these
chloroacetic acid, both giving superior yields and reactions are under equilibrium, as evidenced by the
reaction rates (see Scheme 4,B). Furthermore, the order of addition of reagents being independent to
NBS·quinuclidine complex 5 and NIS·quinuclidine com- the reaction outcome, the reaction progress proceeds
plex 4 are clearly less reactive than NBS and NIS used efficiently if quinuclidine, NXS and acid are all present.
in the absence of quinuclidine. A combination of NBS The reactive species 12 would then react with the
or NIS with a suitable Brønsted acid increases the unsaturated alcohol 6 (or unsaturated carboxylic acid
reaction rate moderately and, although reactions go to 7) to afford the halogenated oxacycles 8/13 (or the
completion, the reactions are greatly accelerated by a halogenated lactone 9/14) and generate the proto-
combination of these three components: quinuclidine, nated quinuclidinium salt 15. Salt 15 can then react
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with NBS or NIS to re-generate the active halogenating represents a growing field of applications in catalysis,
species (e.g. 12) and release succinimide.
anion-transport and may even be considered a less
‘unorthodox’ approach to the design of new reactions
and methods in the future.[79–84]
Conclusions
In summary, while the reaction of primary and
secondary amines with NIS are often understood to
Experimental Section
generate NÀ I bonded compounds by analogy to the Full experimental procedures and XRD data with
reactivity of chlorinating agents like NCS, we have analyses are provided in the Supporting Information.
shown that primary, secondary and tertiary amines all
Solution-Phase NMR Studies
react with NIS to predominantly afford halogen
bonded amine complexes 1–4. In addition, tertiary See Figures S1–S5 for the preparation compounds and
amines such as quinuclidine react with NBS to form characterization of 1–5, Figures S6–S10 for full details
the halogen bonded complex 5. Their structural of kinetic plots, Figures S11–S16 for detailed NMR
features and thermal stabilities were then revealed by mechanistic studies in CDCl3 solution.
X-ray crystallographic analysis. As expected, the NBS-
quinuclidine complex 5 and NIS-quinuclidine complex
4 were found to be less reactive as brominating and
Solid-Phase XRD Studies
iodinating reagents than NBS and NIS. However, the Calculation of X-ray structural parameters, normalized
addition of Brønsted acid to 5 and 4 was found to contact distances, calculated second order perturba-
generate a highly reactive halogenating system (e.g. tion energies of the donor (lone pair of amine nitro-
by virtue of the reactivity of 12, Scheme 3). The gen) and acceptor (halogen atom of N-halosuccini-
presence of a suitable Brønsted acid was found to be mide) and stabilization energies of intermolecular
key to defining a fast reaction rate and percentage-of- interactions of all complexes are also provided in
completion for the halocyclization reactions under the Tables S1–S3. The data for the X-ray crystallographic
equilibrium conditions reported herein. Thus, the NBS- structures of 1, 2, 3, 4, 5 are available free of charge
quinuclidine complex 5 and NIS-quinuclidine complex from the Cambridge Crystallographic Data Center under
4 are precursors to a reactive halogenating species. accession numbers CCDC 1031277, 1495217, 1495215,
Reactive, transient species such as 12 can also be 1495214, 1495216, respectively.
generated by mixing NBS or NIS, quinuclidine and acid
in catalytic amounts. In haloetherification reactions of
γ-olefinic alcohols, for example, both quinuclidine and
a Brønsted acid are effective in catalytic amounts, while
Acknowledgements
only catalytic quinuclidine is required in the halolacto- This work was supported by JSPS KAKENHI Grant
nization of γ-olefinic carboxylic acids because of a Number JP20H04801 in Hybrid Catalysis for Enabling
stoichiometric supply of protons in the starting Molecular Synthesis on Demand, and JP19H05630.
material.
We believe the systematic evidence and specific
findings described herein not only provides new
mechanistic guidance in understanding haloaddition
Author Contribution Statement
and halocyclization reactions of alkenes and alkynes, Y. H. and M. L. directed the project. M. L. and J. L. wrote
especially those catalyzed by quinuclidine-bearing the manuscript. Y. H., M. L. and J. L. conceived the
cinchona alkaloids as illustrated by the groups of research strategies for the project. J. L. conducted all
Yeung, Tang, Henneke, Denmark, Ishihara, Yamamoto experiments, isolated all products, and prepared the
and others,[33–42,61–78] but also provides fundamental supplemental material. E. K. analyzed all the X-ray
knowledge in expanding halogen bond-based reac- structure and collected the data. All authors discussed
tions in synthesis, particularly concerning iodine-based the results and commented on the manuscript.
reagents and amine catalysis. Wider implications of
the current work to chalcogen- and pnictogen-based
Lewis acids, which similarly feature sigma-hole accept-
or capabilities, is an intriguing proposition and
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Received May 24, 2021
Accepted July 14, 2021
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