Solvent-induced selectivity of Williamson etherification in the pursuit of amides resistant against oxidative degradation

Article abstract of DOI:10.1039/d0ra04465b

This article reports two discoveries. (1) 2-Methoxyethanol induces unprecedented selectivity for etherification of 5-hydroxy-2-nitrobenzic acids without forming undesired esters. (2) Such compounds are precursors for amides showing unusual robustness agai

Full text of DOI:10.1039/d0ra04465b

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Solvent-induced selectivity of Williamson
etherification in the pursuit of amides resistant
against oxidative degradation†
Cite this: RSC Adv., 2020, 10, 24419
a
b
c
c
James B. Derr,
John A. Clark,
Maryann Morales,
Eli M. Espinoza,
‡
Sandra Vadhin §b and Valentine I. Vullev
abcd
*
Received 8th April 2020
Accepted 26th May 2020
This article reports two discoveries. (1) 2-Methoxyethanol induces unprecedented selectivity for
etherification of 5-hydroxy-2-nitrobenzic acids without forming undesired esters. (2) Such compounds
are precursors for amides showing unusual robustness against oxidative degradation, essential for
molecular electrets that transfer strongly oxidizing holes at about ꢀ6.4 eV vs. vacuum.
DOI: 10.1039/d0ra04465b
rsc.li/rsc-advances
attain a hopping (or incoherent) mechanism, for which the
kinetics exhibits negligible distance dependence beyond about
1 nm.6 In order to prevent oxidative degradation of electrets
Introduction
Williamson etherication (WE), involving alcohols and alkanes
with good leaving groups as starting materials, remains the
most broadly used method for the preparation of ethers.1 WE
offers an important means for adding electron-donating groups
to aromatic conjugates, essential for preparing electron-rich p-
conducting organic materials. Despite its immense importance,
the lack of selectivity presents challenges for the utility of WE.1c
To harness dipole effects on charge transfer (CT),2 we
develop bioinspired molecular electrets that are based on
polypeptide structures composed of anthranilamide (Aa) resi-
dues.3 (Electrets are systems with ordered electric dipole
moments.) The amide and hydrogen bonds of the electrets are
a source for their intrinsic dipole moments.4 The side chains of
Aa, R1 and R2 (Chart 1a), on the other hand, provide a means for
controlling their electronic properties.4a,5 Indeed, electric
dipoles present key paradigms for controlling CT, which is of
tremendous importance for energy conversion and organic
electronics, among many other elds.2a Molecular dipoles
rectify CT,2b,2c,3c,3d affecting charge separation and charge
recombination.3c
mediating such hole hopping, it is crucial for the comprising Aa
residues to form stable radical cations, Aaꢁ+.5a–c For attaining
such stability, we have determined that: (1) the spin density
distribution (SDD) of Aaꢁ+ should not extend over its C-terminal
amide;5b and (2) the reduction potentials for oxidizing Aa,
should not be too large, i.e., EAaꢁ+|Aa < 1.5 V vs. SCE, to prevent
the inherent oxidative degradation of the amides.5b The latter
places a limit on how oxidizing the transferred holes can be.
Hole hopping along moieties with as positive EAaꢁ+|Aa as
possible ensures the potency of the holes for attaining large
open-circuit voltages and for driving chemical transformations.
Because placing alkoxy side chains on Aa residues brings the
reduction potentials of their radical cations, Aaꢁ+, to the limit of
Electron-donating side chains afford hole-transfer elec-
trets.5d For long-range CT in organic materials, it is important to
aDepartment of Biochemistry, University of California, Riverside, CA 92521, USA.
E-mail: vullev@ucr.edu
bDepartment of Bioengineering, University of California, Riverside, CA 92521, USA
cDepartment of Chemistry, University of California, Riverside, CA 92521, USA
dMaterials Science and Engineering Program, University of California, Riverside, CA
92521, USA
† Electronic supplementary information (ESI) available: Experimental section and
structural and photophysical details. See DOI: 10.1039/d0ra04465b
‡ Present address: College of Bioengineering, University of California, Berkeley,
CA 94720, USA.
Chart 1 (a) Molecular anthranilamide (Aa) electret with its permanent
electric dipole. (b–e) Electret Aa residues with either side chains that
are highlighted.
§ Present address: School of Chemical and Biomolecular Engineering, Cornell
University, Ithaca, NY 14853, USA.
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Table 1 Reaction yields of direct formation of 3 from 1 and X–Ra
1.5 V vs. SCE,5a–c such ether conjugates present a key paradigm
in the pursuit of organic derivatives that can transduce strongly
oxidizing charge carriers.
X ¼
Established peptide-synthesis procedures, used on aromatic
b-amino acids with protected amines, lead to non-reactive cyclic
intermediates, preventing the formation of Aa derivatives.5f,7
Therefore, in the synthesis of Aa conjugates, we introduce each
residue as its 2-nitrobenzoic acid (NBA) analogue.
–R ¼
I
Br
Cl
–(CH2)3CH3
97%
40%
34%
15%
–CH2CH(CH3)2
–CH(CH3)CH2CH3
–C(CH3)3
19%
Traceb
Traceb
N.D.c
41%
Traceb
Traceb
Traceb
WE offers a means for synthesizing alkyloxy derivatives of
NBA from alkyl halides and the corresponding NBA hydroxy
analogues, 1 (Scheme 1a).5a Because the carboxyl of 1 has
a smaller pKa value than the hydroxyl, both are deprotonated
under the basic conditions of WE and can act as nucleophiles,
leading to the formation of the esters of the alkoxy NBA deriv-
atives, 2 (Scheme 1a).5a This lack of selectivity of WE sets the
requirement for an additional step, i.e., hydrolysis, for obtain-
ing the free-acid precursor, 3, for Aa synthesis (Scheme 1a).5a
Herein, we present the discovery of conditions for WE that
allow for selective etherication of 1 without forming the
undesired esters. Employing 2-methoxyethanol (2ME) as
a solvent for WE of 1 with 1-iodobutane under microwave irra-
a
Yields are based on isolated and puried products, 3 (Scheme 1a).
Products are not apparent on TLC but are detected using HRMS.
Not detected with HRMS.
b
c
SCE.8 Therefore, these ether Aa conjugates have the potential to
transduce strongly oxidizing holes making them comparable to
a wide range of inorganic CT materials.
Results and discussion
Attaining selectivity for Williamson etherication
diation, affords 5-butoxy-2-nitrobenzoic acids, 3, in quantitative Others and we have shown the two-step synthesis of 3, starting
yields (R ¼ n-C4H9, Scheme 1a, Table 1). Reacting 1 with other with the preparation of 2 using polar solvent media at about
butyl halides under the same conditions, also results in direct 150 ꢂC (Scheme 1a).5a,9 To lower the temperature and consid-
production of 3 without formation of the ester, 2, or other side erably shorten the reaction times, we resort to microwave
products. Reversing the WE paradigm, by taking advantage of radiation instead of conventional heating. Microwaving
the propensity of electron-decient NBA uorides to undergo mixtures of 1 and various butyl halides dissolved in different
nucleophilic aromatic substitution, provides routes to phenoxy solvents that are traditionally used for this reaction, such as
NBA derivatives (Scheme 1b). As examined with cyclic voltam- N,N-dimethylacetamide and N,N-dimethylformamide (in the
metry (CV), the electrochemical oxidation of the butoxy Aa presence of Cs2CO3), does not produce even detectable amounts
derivatives barely shows any reversibility at scan rates of about of either 2 or 3, as conrmed with high-resolution mass spec-
0.1 V sꢀ1 or less. Conversely, some of the phenoxy Aa conjugates trometry (HRMS) of the reaction mixtures.
show not only improved chemical reversibility, but also EAaꢁ+|Aa
Polar solvents, however, are not usually benecial for
exceeding 1.5 V vs. SCE by about 200 mV. This result appears microwave-driven reactions. Medium polarity and hydrogen
surprising because aliphatic and aromatic carboxamides readily bonding can, indeed, stabilize transition states and lower acti-
undergo irreversible oxidative degradation at about 1.5 V vs. vation energies. In such reaction mixtures, however, the polar
solvents, rather than the reactants, tend to be the principal
absorbers of the microwave energy. Conversely, non-polar
solvents with high boiling points ensure that reactants absorb
substantial amount of the microwave radiation. This direct
transfer of energy to the reactants is a principal advantage that
microwave-driven chemical conversions have over reactions
under conventional heating.
Using low-polarity solvents, such as toluene and ethyl
acetate, allows the formation of only traces of 3, as detected with
HRMS. This minute conversion of 1 to 3 renders it impractical.
Medium-polarity aprotic solvents, such as tetrahydrofuran
(THF) and halogenated alkanes, do not produce even traces of 2
or 3. This lack of conversion extends even to the neat-reaction
conditions, i.e., when the butyl halide reactant is the solvent.
Conversely, when 2ME is the solvent for the same WE reac-
Scheme 1 Etherification of 2-nitrobenzoic acid (NBA) derivatives. (a)
–X ¼ –Cl, –Br, –I; –R ¼ –(CH2)3CH3, –CH2CH(CH3)2, –CH(CH3)C2H5, tion of 1 with butyl halides, we observe the formation solely of
–C(CH3)3; for direct conversion of 1 to 3, 1 equiv. 1, 4 equiv. RX and 3
the free acid, 3, as NMR analysis, i.e., NOESY, conrms (see
equiv. Cs2CO3; microwave heating: 2ꢃ 30 s, 60 W, temperature set to
ESI†). Using other alcohols as solvents, such as isopropanol,
130 ꢂC, and ambient-pressure control; or conventional heating: 12 h,
also affords traces of 3 without 2, as HRMS reveals. While
pressure tube at 130 ꢂC; (b) –Ar ¼ –C6H5, –2,6-C6H3(CH3)2 and ꢀ2,6-
employing ethylene glycol for WE results in chromatographi-
cally detectable amounts of 3, the minute yields of a few percent
C6H3(CH3)2; 1 equiv. 4, 2–4 equiv. ArOH and 3–6 equiv. Cs2CO3;
conventional heating: 12 h, pressure tube at 110 ꢂC.
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renders it impractical. Ether solvents, such as THF and 1,2- perfect proticity resulting in pH of the reaction mixture that
dimethoxyethane, conversely, do not mediate the conversion of ensures the ether formation, but makes the ester unstable. Even
1 to 3. While similar to ethylene glycol and 1,2-dimethoxyethane if the ester 2 forms, the traces of water that build up with the
(R0O–CH2CH2–OR00, R0 and R00 ¼ H or CH3), 2ME provides progress of the reaction can drive its hydrolysis.
a unique reaction environment that under microwave radiation
Switching the WE pattern allows for pursuing the synthesis
allows for etherication of the phenol OH of 1, without the side of phenoxy Aa precursors. Instead of starting with halide
reaction of esterication of the carboxyl. This nding of the derivatives of the side chains (Scheme 1a), we introduce the side
2ME-mediated selectivity of WE is a key breakthrough of this chains as the WE nucleophiles (Scheme 1b). Fluorines on
study, eliminating the need for the second step, i.e., hydrolysis electron-decient aromatic rings are immensely susceptible to
of 2 (Scheme 1a).
nucleophilic aromatic substitution. Hence, introducing the side
As a variation of WE, Purdie–Irvine alkylation, involving chain as the corresponding phenolate to uorinated NBA, 4,
Ag2O as a reagent with high affinity for the formed halide ions, allows for making the precursors, 5, for phenoxy Aa residues
allows for monomethylation of diols.10 Cs+ are the only available (Scheme 1b). The reaction yields for the phenoxy and 2,4-
metal ions in the WE for converting 1 into 3 (Scheme 1a), and dimethylphenoxy analogues of 5, i.e., the precursors for Fox and
they do not have the chelation properties of Ag+. Conversely, Dox24 (Chart 1c and e), are about 90%. The synthesis of the
strongly basic conditions involving treating alcohols with NaH precursor of Dox, however, proceeds with yields smaller than
or Na, and excess of these alkoxides when reacting them with 45%, most likely because of the steric hindrance induced by the
chloro- or bromo-acetic acid, produce ethers capped with free two methyl groups at the ortho positions of the phenoxy side
carboxylates.10c,11 Such conditions keep the media dry and the chain (Chart 1d).
dryness of the base is important for enhancing the WE yields.12
Attempts to employ this nucleophilic aromatic substitution
In the contrary to the previously reported synthesis of ethers (Scheme 1b) for the synthesis of alkoxy Aa derivatives prove
with free carboxylates, we use: (1) a relatively mild base, Cs2CO3, unfeasible. While the formation of the alkoxide ions, using
(2) a hydroxyl-carboxyl starting material, 1, and (3) halides in metal sodium or strong imide bases, is quite trivial, 4 appears
four-fold excess (Scheme 1a). In addition to its selectivity, all unstable under such extremely basic conditions.
these features represent key advantages of the 2ME-mediated
WE.
The reaction yields of the direct synthesis of 3 from 1
manifest dependence not only on the halide, but also on the
Oxidation reversibility at relatively high potentials
alkyl chain. Improving the leaving group, by varying the starting Converting the ether NBAs (3 and 5, Scheme 1) to their amide
materials from chloride to bromide and iodide, increases the analogues capped with alkyls (Chart 1b and e), allows for exam-
reaction yields (Table 1). Concurrently, branched primary ining the electrochemical properties of these Aa residues.5a–c,5e
butyls, X–CH2CH(CH3)2, show lower yields than the linear ones, We select one aliphatic and three aromatic ether derivatives: Box
X–(CH2)3CH3. The yields decrease further for secondary butyls, (with isobutyl), Fox (with phenyl), Dox (with 2,6-dimethylphenyl)
X–CH(CH3)C2H5; and for tertiary, X–C(CH3)3, we observe only and Dox24 (with 2,4-dimethylphenyl) (Chart 1b and e). In Dox and
traces of 3 or no product at all (Table 1). These effects of the Dox24, the ortho and para positions of the electron-donating
halides and the alkyl chains on the yields are consistent with the methyls ensure strong electronic coupling with the Aa ring.
SN2 mechanism expected for such WE reactions. In addition, the When both methyls are ortho to the oxygen, they can enforce
inherent instability of t-butyl ethers of electron-decient orthogonality between the two aromatic rings and impede rota-
phenols reects the negligible and no yields of 3 when tions around the ether linker, which represent the principal
R ¼ C(CH3)3.
difference between Dox and Dox24 (Chart 1d and e).
The cleanliness of this WE reaction represents a principal
At moderate scan rates, Box exhibits irreversible oxidation at
advantage. Reacting 1 with 1-iodobutane produces the n-butyl about 1.5 V vs. SCE for dichloromethane (DCM) media (Fig. 1a),
analogue of 3 in quantitative yields (Table 1). For the other butyl which is consistent with the behaviour of other Aa residues with
halides the isolated-product yields are under 50%. Nevertheless, alkyloxy side chains.5a Replacing the aliphatic with aromatic
the reason for these yields was a lack of conversion despite the ether, methylated at the two ortho positions, leads to reversible
le over starting material 1, rather than a production of side oxidation at potential of about 1.7 V vs. SCE (i.e., Box vs. Dox,
products. Increasing the reaction times does not increase the Fig. 1b and Table 2), which is unprecedented for amides.
ratio between 3 and 1, and does not improve the yields.
At the same scan rates of 0.1 V sꢀ1 and smaller, the other two
Transferring this microwave synthetic procedure to pressure- aromatic-ether residues, Fox and Dox24, exhibit irreversible
tube settings provides the means for scaling up and for using oxidation similar to Box. Like Dox, however, Fox and Dox24
less expensive conventional heating sources. Heating for 12 oxidize at more positive potentials than Box (Fig. 1a).
hours at 130 C, i.e., about 5ꢂ above the boiling point of 2ME
Increasing the scan rates beyond 0.5 V sꢀ1 leads to partial
ꢂ
under normal pressure, results in similar selectivity of the oxidation reversibility of Box, Fox and Dox24, as evident from the
production of 3. Monitoring the progress of the reaction, using small cathodic peaks that appear in their voltammograms
TLC and HRMS, reveals formation of the ester 2, but with iso- (Fig. 1c). These ndings indicate that the lifetimes of their radical
lated yields that do not exceed 1%. Oen, 2 disappears with cations are in the order of 1 s, which is sufficiently long for most
extended reaction times. This nding suggests that 2ME has the CT applications. This oxidation reversibility (even if only partial),
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Table 2 Reduction potentials and optical excitation energies of Aa
ether residues
ð1=2Þ
E
|Aa=V vs: SCEa
E
00=eVb
Aaꢁþ
DCM
MeCN
DCM
MeCN
Box
Fox
Dox
Dox24
1.56 ꢄ 0.05
1.82 ꢄ 0.03
1.69 ꢄ 0.02
1.70 ꢄ 0.04
1.42 ꢄ 0.07
1.57 ꢄ 0.02
1.55 ꢄ 0.03
1.56 ꢄ 0.04
3.48
3.53
3.52
3.51
3.52
3.56
3.55
3.55
a
Values for neat solvents, i.e., extrapolated to Cel ¼ 0 M (Fig. 1b) from
cyclic voltammograms recorded at 0.05 and 0.1 V sꢀ1. For irreversible
oxidation, the values of the half-wave potentials at various Cel are
obtained from the inection points at the rise of the anodic peaks.13
b
Estimated from the wavelengths, l00
, where the normalized
5c,14
absorption and uorescence spectra cross, E00 ¼ hy=l00
rough approximation for the transition-dipole-moment
representation.14a
;
which is
a
The Hammett constants and the eld Swain–Lupton
parameters of phenyloxy groups are more positive than those of
alkyloxy substituents.15 When the conformations supress the
resonance effects, allowing the inductive ones to dominate, the
phenyloxy groups are stronger electron-withdrawers than the
alkyloxy ones, which is consistent with our ndings.
Why do the methyls at the ortho positions of the phenyloxy
substituent provide extra stability of the radical cations of Dox?
The sterics of the ortho-methyls forces orthogonality between
the two aromatic rings of Dox, and SDD does not extend over the
phenyl side chain. That is, Dox and Box manifest similar SDD
that extends over the N-terminal amide and the ether oxygen
(Fig. 2). Conversely, the aromatic rings of Fox and Dox24 are not
orthogonal to each other, and the SDD expands over the phenyls
of the side chains (Fig. 2).
Fig. 1 Cyclic voltammograms of Aa ether residues (Chart 1b and e) for
DCM in the presence of an electrolyte, N(n-C4H9)4PF6, with varied
concentration, Cel. (a) Irreversible oxidation of Box, Fox and Dox24 at
scan rate, v ¼ 0.1 V sꢀ1, and Cel ¼ 100 mM. (b) Oxidation of Dox
showing reversibility at 0.1 V sꢀ1. Inset: dependence of the half-wave
potential on Cel and extrapolation of its value for neat DCM, i.e., for
Cel ¼ 0 M. (c) Partial reversibility of the oxidation of Box, Fox and Dox24
These contrasts between SDD of Doxꢁ+ and of the radical
cations of the other two aromatic ethers could account for the
difference between the reversibility of their oxidation.
at 0.75 V sꢀ1
.
at potentials as high as 1.7 and 1.8 V vs. SCE, reveals an important
effect that ethers have on aromatic amides.
Employing acetonitrile (MeCN) as a solvent yields the same
trends as DCM. As expected, the reduction potentials for MeCN
are not as positive as those for DCM (Table 2).
The Aa residues with aromatic ethers are harder to oxidize
than the one with an alkyloxy group. Adding two methyls to the
phenyloxy substituents causes a slight negative shi in the
reduction potentials, i.e., Fox vs. Dox and Dox24 (Table 2). While
the latter agrees with the methyl electron-donating properties,
the former appears counter-intuitive assuming that the phenyl-
oxy groups extend the p-conjugation of the residues. Neverthe-
less, the zero-to-zero energies, E00; of all ether residues are
similar, around 3.5 eV (Table 2), regardless the aromatic vs.
aliphatic nature of the substituent. It suggests that the resonance
effect of the aromatic ethers on the p-conjugation does not Fig. 2 Spin-density distributions (SDDs) of the radical cations of the Aa
ether residues (anti conformers) showing the delocalization of the
positive charge. For the DFT computations, the alkyls chains are
truncated to ethyls.
necessarily dominate the electronic properties of the residues.
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Conversely, Dox shows reversibility at low scan rates, while Box that, along with their newly discovered electronic properties,
does not. Yet, they have quite similar SDDs (Fig. 2).
opens new doors for organic electronics and energy science.
Two conformers of Dox provide orthogonality between its
aromatic rings: i.e., with the phenyloxy at syn vs. anti orientation
in relevance to the C-terminal amide. While the computed
Conflicts of interest
energy differences between the syn- and anti-Dox are compa- There are no conicts to declare.
rable to the thermal energy, kBT at T z 20 ꢂC, the NMR spectra
show a single set of peaks for the 2,6-dimethylphenyloxy
protons. We ascribe it to an interexchange between the two
Acknowledgements
conformers that is faster than the NMR acquisition timescales. The USA National Science Foundation, Division of Chemistry,
The structural features of Dox make the electronic properties of supported this study with a grant CHE 1800602 and an AGEP
its radical cation similar to those of Boxꢁ+, rather than Foxꢁ+ and supplement for J. A. C.
Dox24ꢁ+. Unlike Boxꢁ+, however, Doxꢁ+ has a polarizable
aromatic side chain.
Notes and references
This strategy for decreasing the susceptibility of aromatic
amides to oxidative degradation by adding ether substituents is
considerably more attractive than an alternative means
involving modication of their –CONH– groups. Introducing
capping groups with quaternary carbons that connect to the
amides of Aa residues does not detectably improve the stability
of their radical cations. Oligomers of Aa residues that oxidize
irreversibly, still show irreversible voltammograms.5f
Conversely, converting the C-terminal amide, Aa–CONH–R, to
a tertiary amide, i.e., to Aa–CONR2, induces partial reversibility
in the voltammograms of residues that oxidize irreversibly.5b It
is consistent with the importance of the proton of the C-
terminal amide for the pathways of oxidative degradation. In
an Aa oligomer (Chart 1a), however, the introduction of such
tertiary amides along its back bone would disrupt the hydrogen-
bonding pattern that is important for its extended conforma-
tion and macrodipole. The C-terminal protons of such oligo-
mers are not involved in the hydrogen bonding network, as
NMR studies show.3b Therefore, capping the C-terminus of an
Aa oligomer with tertiary amide will not disrupt its conforma-
tional integrity. Still, computational analysis show that the
positive charge of a singly oxidized oligomer, composed of
identical Aa units, localizes on the N-terminal residue. There-
fore, tertiary amide on C-terminus would prove benecial only if
the hole transfer away from the C-terminal residue is slower
than its oxidative degradation. In light of this discussion,
gaining oxidation reversibility via adding ether side chains is
a superb strategy because it does not involve disruption of the
amides along the backbone that maintain the extended
secondary conformation of the Aa oligomers.
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Conclusions
Ether substituents show important propensity for stabilizing
oxidized amides. Ethers are strong enough electron-donating
groups to remove the positive charge in the radical cations
from the amide groups susceptible to oxidative degradation, but
not strong enough to cause drastic negative shis in reduction
potentials. Orthogonality of the aromatic rings of such ether
substituents is especially promising for the design of hole-
transfer amides. Selectivity for etherication of aromatic
hydroxyls in the presence of other nucleophilic groups is
important for the synthesis of such charge-transfer conjugates
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