Aryl Radical Selectivity in Biphasic Systems

Article abstract of DOI:10.1021/acs.orglett.9b04237

Aryl radicals generated in the aqueous phase of biphasic mixtures have-regardless of a comparably low polarity- A strong preference to react with aromatic substrates in the aqueous phase and not to undergo phase-transfer into a lipophilic phase, independent from the presence of a surfactant. These results represent an important prerequisite toward future studies in biological systems, which typically consist of various compartments of either hydrophilic or lipophilic character.

Full text of DOI:10.1021/acs.orglett.9b04237

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Aryl Radical Selectivity in Biphasic Systems
̈
Lisa-Marie Altmann, Michael C. D. Furst, Eva I. Gans, Viviane Zantop, Gerald Pratsch,
and Markus R. Heinrich*
†
†,‡
§
Department of Chemistry and Pharmacy, Pharmaceutical Chemistry, Friedrich-Alexander-Universitat
Nikolaus-Fiebiger-Strasse 10, 91058 Erlangen, Germany
̈
Erlangen-Nurnberg,
̈
*
S Supporting Information
ABSTRACT: Aryl radicals generated in the aqueous phase of biphasic
mixtures haveregardless of a comparably low polarity a strong preference
to react with aromatic substrates in the aqueous phase and not to undergo
phase-transfer into a lipophilic phase, independent from the presence of a
surfactant. These results represent an important prerequisite toward future
studies in biological systems, which typically consist of various compartments
of either hydrophilic or lipophilic character.
adical aryl−aryl coupling reactions have recently gained
Scheme 1. Radical Arylation in Biphasic Mixtures
1
R
more and more importance, especially through the
2
manifold developments in the field of photoredox catalysis
and other advances related to mild initiation and broadly
3
applicable conditions. Through several newly discovered
reactions, it has been shown that the high reactivity of aryl
radicals toward many substrates can be controlled much better
4
than previously assumed, whereas the choice of a suitable
5
solvent also plays an important role.
Against this background, it is interesting to note that radical
arylations in biological systems, which would be a highly
6
attractive field of application, have not yet been reported.
Recent studies in our group have shown that small peptides
such as the hexapeptide NT8−13 (H-Arg-Arg-Pro-Tyr-Ile-
Leu-OH) and the pentapeptide Leu-enkephalin (H-Tyr-Gly-
Gly-Phe-Leu-OH) can selectively be modified at the phenol
unit in the tyrosine side chain, whereas the peptide backbone is
has previously been observed in a study comparing the
reactivity of 2-hydroxyphenyl and 4-bromophenyl radicals in a
1
0
biphasic mixture. In these experiments, the polar 2-
hydroxyphenyl radical showed a strong preference for reactions
in the aqueous phase whereas the corresponding 4-bromo
derivative underwent phase transfer to the lipophilic phase, as
indicated by the predominant reaction with a lipophilic
scavenger.
7
not attacked by the highly reactive aryl radical intermediates.
But what additional requirements would have to be met to
successfully conduct a radical arylation not only on a biological
substrate but also in a biological system?
Nevertheless, the actual degree of phase transfer of aryl
radicals 2 can be expected to depend on the rate of reaction kH
At first, radical generation would need to proceed under
mild and biocompatible conditions, which could be envisaged
from a number of aryl radical precursors including protected
with a hydrophilic substrate [X
PT followed by trapping (k ) with a lipophilic substrate [X ]
L
] relative to the phase transfer
H
k
L
8
diazonium species such as aryldiazosulfides. Second, the
(Scheme 1). As the phase transfer step can potentially be
reversible (k−PT), the overall setup is comparable to that of a
reversible radical clock experiment with two irreversible
newly generated aryl radical should show phase selectivity in the
sense that the radical preferably reacts in an either lipophilic or
11
9
termination steps leading to the final adducts 3 and 4.
hydrophilic environment (Scheme 1). Assuming that
To evaluate the potential applicability of aryl radicals in
biological systems, two general questions can be addressed:
Might typical, naturally occurring and hydrophilic aryl radical
protected diazonium derivatives 1 with high polarity are
used, the aryl radicals 2 arising from these precursors would
necessarily be released in the aqueous phase, but depending on
12
1
scavengers such as tyrosine units in peptides be sufficiently
reactive to compete with phase transfer of even lipophilic aryl
radicals? And, is the phase-transfer step significantly influenced
the substitution pattern (R ) on the aromatic core, a more or
less preferred uptake into a lipophilic compartment could take
place. At this point, one might argue that the high reactivity of
aryl radicals toward many substrates could prevent phase
transfer, as the trapping reaction of the aryl radical is simply
too fast. That this is not the case, at least not in a general sense,
Received: November 25, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04237
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1
3
by the presence of surfactants that generate an artificial
monolayer membrane? In this work, we give insights into the
phase selectivity of substituted aryl radicals in biphasic mixtures.
These results represent a valuable basis regarding future studies
in more complex compartmental systems including biological
benzene was now observed. The most extensive phase transfer
(biphenyl 9a: 21%) occurred in the experiment with 4-
ethoxyaniline (6c), whereas the methyl ethers 6b,d,e led to less
biphenyl formation (≤6%).
5
,19
Almost all experiments with potassium iodide as initiator
1
4
applications.
In the present work, aryl diazonium chlorides
as highly water-soluble radical precursors to study the
competition between water-soluble substrates and benzene,
whereas the latter forms the organic phase and simultaneously
acts as competing aryl radical scavenger (k ∼ 4.5 × 10 M
s ) (Scheme 2). Substituted benzenes have been reported
resulted in a significant formation of the Sandmeyer products,
the iodobenzenes (21−74%), with the exception of the donor-
substituted 4-methoxyphenyldiazonium salt 5c. Nevertheless,
an interesting effect could be observed. Apparently, the iodide-
mediated arylations of 6a remain selective for the aqueous
5
,15
were used
5
−1
1
phase when the aryl radical bears a polar substituent such as R
−1
16a
= OMe, CN, CO Me, albeit at significantly lower product
2
1
1
yields. For the unpolar substituents R = Cl and R = Br, a
remarkable arylation of benzene occurs. Independent from the
scavenger 6a−e, this can be explained by a certain, but so far
unknown stability of lipophilic diazonium iodides
Scheme 2. Phase Selectivity of Aryl Radicals in Reactions
with Phenols 6a,f and Phenyl Ethers 6b−e
a
20
Ar−N = N−I, which enables transfer to the benzene phase
before radical generation.
Not unexpectedly, 4-cresol (6f), which distributes between
the aqueous and the benzene phase with a ratio of 1:9, gave
lower yields of 8k than 8a from 6a. At this point, it is
important to note that phenols are known as potent
antioxidants and hydrogen atom transfer reagents in organic
solvents. This ability is, however, strongly reduced in aqueous
environments, which is a further key to the successful radical
21
arylations of phenols described herein. Reduced products,
such as methyl benzoate formed from 5e via hydrogen atom
transfer, could be detected by TLC directly in the reaction
mixture.
Having observed that the radical scavenger in the aqueous
phase plays a major role in phase selectivity, we turned to the
more reactive, fully water-soluble heterocycles 3-hydroxypyr-
4
,17
idine (11) and furfurylamine (12) (Scheme 3).
The increased reactivity of 11 and 12 toward aryl radicals
led to higher product yields, and, not surprisingly, to full phase
1
selectivity for all substituents R = Cl, Br, OMe, CN, CO Me
2
Scheme 3. Phase Selectivity in Reactions with 3-
a
Hydroxypyridine (11) and Furfurylamine (12)
a
1
Yields determined by H NMR using internal standards (%).
as slightly more reactive toward aryl radicals than benzene
itself, whereas anisole displayed a relative reactivity of only 1.7
16b
including all positions on the aromatic cores.
The overall
setup was chosen to ensure that radical formation takes place
in the aqueous phase and that radicals entering the organic
phase are trapped to a high extent.
17
In titanium(III)-mediated reactions with 4-aminophenol
1
(
6a), the aryl radicalregardless of its substituent (R = Cl,
Br, OMe, CN, CO Me)selectively reacts in the aqueous
2
phase to give 8a−8e, whereas the corresponding biphenyls
9
a−9e could not be detected. In contrast to that, the phenyl
ethers 6b−6e turned out as insufficiently reactive aryl radical
18
a
1
scavengers to prevent phase transfer, so that arylation of
Yields determined by H NMR using internal standards (%).
B
DOI: 10.1021/acs.orglett.9b04237
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
in titanium(III)-mediated reactions. Experiments with iodide
as initiator confirmed the previous assumptions, as the
arylations with polar diazonium ions (R1 = OMe, CN,
ether (MTBE), dichloromethane, or ethyl acetate resulted in
yields of 42%, 44%, 43%, and 29% for 8a, respectively.
Trapping with styrene was not observed in any of the four
reactions, so that the lower yield obtained with ethyl acetate
might possibly be due to increased hydrogen atom transfer at
the interface.
CO Me) remained selective for the aqueous phase. The
2
1
more lipophilic diazonium ions (R = Cl, Br) were again
carried over to the benzene phase, most likely as Ar−N = N−I,
which consequently resulted in a remarkable formation of the
biphenyls 9a and 9b (14−30%).
The experiments summarized in Scheme 4 show that the
phase selectivity of titanium(III)-mediated radical arylations
The full phase selectivity of the 4-chlorophenyl radical was
confirmed using L-tyrosine methyl ester (17) as a water-soluble
substrate (Scheme 5, bottom). Again, the addition of styrene
(15) to the reaction mixture resulted in an only minor drop in
17c
yield of 3-aryltyrosine 18 from 40% to 38%. This nicely
demonstrates that a phenol unit in the side of tyrosine is
sufficiently reactive to fully keep even lipophilic aryl radicals in
the aqueous phase.
a
Scheme 4. Phase Selectivity under a Variety of Volumes
To obtain a first impression on the behavior of aryl radicals
under more biomimetic conditions, surfactants were finally
added to the reaction mixture to generate artificial membrane-
23
like layers (Scheme 6). In preliminary studies, the critical
Scheme 6. Phase Selectivity in the Presence of the
Surfactants 19−21 as a Model for Biological Membranes
a
a
1
Yields determined by H NMR using internal standards (%).
does not depend on the relative size of the phases. The first
entry with a water/benzene ratio of 77/23 (v/v) yielding 13a
in 63% yield corresponds to the conditions used previously
(
Schemes 2 and 3). The water content of the reaction mixture
was then gradually reduced to a ratio of 14/86 (v/v) whereas
the yield of 13a slightly dropped to 54%, but full phase
selectivity remained. In all experiments reported herein, the
biphasic reaction mixtures were stirred at ca. 400 rpm. A
control experiment with a lower stirring rate of 100 rpm gave
no deviation in product distribution.
To exclude that radical transfer to the benzene phase would
take place, but trapping of the aryl radical by benzene was too
slow, 5 equiv (relative to 5a) of the highly reactive lipophilic
8
−1 −1
a
1
scavenger styrene (15) (k ∼ 3 × 10 M s ) was added to
Yields determined by H NMR using internal standards (%).
22
the reaction mixture (Scheme 5, top). In this experiment,
neither trapping products of the general structure 16 could be
detected, nor did the yield of 8a (50%) remarkably decrease
compared to the styrene-free reaction (cf. 8a: 53%, Scheme 2).
Repetitions of this experiment, in which the lipophilic
solvent benzene was exchanged for isohexane, methyl tert-butyl
micelle concentrations (cmc) were determined for triton X-
100 (19), sodium dodecyl sulfate (SDS) (20), and
hexadecyltrimethylammonium chloride (CTAC) (21) in
hydrochloric acid/water/benzene mixtures using UV/vis
scattering (see the Supporting Information). For each of
the three surfactants 19−21, two arylation reactions were
carried out, one employing the surfactant above and one at a
concentration below its individual cmc.
24
Scheme 5. Phase Selectivity in the Presence of the Highly
a
Reactive Lipophilic Scavenger Styrene (15)
In all six experiments, the 4-chlorophenyl radical showed full
phase selectivity, thereby indicating that neither an uncharged
surfactant such as 19, nor charged surfactants such as 20 and
2
1 are able to enhance the transfer of the aryl radical. The
slightly lower yields observed for 8a (40−47% compared to
3%, cf. Scheme 2) can be attributed to a more complex
5
workup of the reactions mixtures, especially regarding phase
separation after extraction.
In summary, we have shown that aryl radicalsregardless of
a comparably low polarityexhibit a strong preference to react
with phenols in the aqueous phase and not to undergo phase
transfer into a lipophilic phase. Less reactive scavengers such as
phenyl methyl ethers 6b−e enable transfer to small extent,
whereas the more reactive heterocyclic substrates 11 and 12
react with full phase selectivity. For phenols, this selectivity is
also not influenced by the addition of diverse surfactants. Thus,
a
1
Yields determined by H NMR using internal standards (%).
C
DOI: 10.1021/acs.orglett.9b04237
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
these results represent an important step toward future studies
in biological systems, which typically consist of various
compartments of either hydrophilic or lipophilic character.
Moreover, our findings can be of value for the initiation of
biphasic polymerizations and other phase transfer related
reactions, especially the hitherto unexploited feature that
unpolar phenyldiazonium iodides apparently possess a low but
sufficient stability to undergo phase transfer.
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ASSOCIATED CONTENT
Supporting Information
■
(
1
*
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04237.
(
Experimental procedures, characterization data, and
spectra of new compounds (PDF)
4
(
Eur. J. 2011, 17, 4104.
(11) (a) Griller, D.; Ingold, K. U. Acc. Chem. Res. 1980, 13, 317.
AUTHOR INFORMATION
■
(
b) Renaud, P.; Sibi, M. P. Radicals in Organic Synthesis Vol. 1: Basic
Principles; Wiley-VCH: Weinheim, 2001; 1; Chapter 3.1, pp 317−335.
12) For modifications of tyrosine unit in peptides, see: (a) Struck,
Corresponding Author
*Phone:+49-9131/85-65670. Email: markus.heinrich@fau.de.
(
ORCID
A.-W.; Bennett, M. R.; Shepherd, S. A.; Law, B. J. C.; Zhuo, Y.; Wong,
L. S.; Micklefield, J. J. Am. Chem. Soc. 2016, 138, 3038. (b) Bottecchia,
̈
C.; Noel, T. Chem. - Eur. J. 2019, 25, 26.
(13) Sienkiewicz, A.; Losada-Barreiro, S.; Bravo-Díaz, C. J. Phys. Org.
Chem. 2019, 32, 3817.
Markus R. Heinrich: 0000-0001-7113-2025
Present Addresses
‡(
M.C.D.F.) Klocke Pharma Service GmbH, 77767 Appenwe-
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(
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G.P.) Landeskriminalamt Baden-Wurttemberg, 70372 Stutt-
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013, 11, 1582. (b) Trusova, M. E.; Kutonova, K. V.; Kurtukov, V. V.;
Filimonov, V. D.; Postnikov, P. S. Resource-Efficient Technologies 2016,
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Author Contributions
†L.-M.A. and M.C.D.F. contributed equally.
Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
We thank Prof. Dr. Franziska Gro
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bner, H.; Gmeiner, P.; Heinrich, M. R.
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hn (FAU) for helpful
discussions. We are also grateful for support by the Deutsche
Forschungsgemeinschaft (DFG) and the Graduate School
Molecular Science (GSMS) (L.-M.A.). The financial support
by the Studienstiftung des Deutschen Volkes (M.C.D.F.) is
also gratefully acknowledged.
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DOI: 10.1021/acs.orglett.9b04237
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