Green halogenation of aromatic heterocycles using ammonium halide and hydrogen peroxide in acetic acid solvent

Article abstract of DOI:10.1139/cjc-2013-0058

The green generation of X⁺ (X = Br, I) using hydrogen peroxide in aqueous acetic acid allows access to aromatic heterocyclic halides in yields and purities comparable to syntheses employing N-bromosuccinimide. In activated and unsubstituted thiophene rings, regioselectivity is quantitative for positions α to the sulfur; pyrroles also give quantitative reactions, at least initially. Deactivated rings, including furans and thiazoles, as well as thiophenes with strongly electron-withdrawing groups showed little to no reactivity under the conditions investigated. The reaction shows remarkable functional group tolerance (to alcohol, nitro, alkyl, halo, and carbonyl groups), as shown through reaction with substituted phenols. In all bromination reactions, reaction yields and regiochemistry were very similar to reactions involving N-bromosuccinimide in tetrahydrofuran solvent.

Full text of DOI:10.1139/cjc-2013-0058

679
ARTICLE
Green halogenation of aromatic heterocycles using ammonium halide
and hydrogen peroxide in acetic acid solvent
Danielle N. D’Aleo, Sheena R. Allard, Cassandra C. Foglia, Shawna L.M. Parent, David J. Rohr, Christine Gottardo, and Craig D. MacKinnon
Abstract: The green generation of X+ (X = Br, I) using hydrogen peroxide in aqueous acetic acid allows access to aromatic
heterocyclic halides in yields and purities comparable to syntheses employing N-bromosuccinimide. In activated and unsubsti-
tuted thiophene rings, regioselectivity is quantitative for positions ␣ to the sulfur; pyrroles also give quantitative reactions, at
least initially. Deactivated rings, including furans and thiazoles, as well as thiophenes with strongly electron-withdrawing
groups showed little to no reactivity under the conditions investigated. The reaction shows remarkable functional group
tolerance (to alcohol, nitro, alkyl, halo, and carbonyl groups), as shown through reaction with substituted phenols. In all
bromination reactions, reaction yields and regiochemistry were very similar to reactions involving N-bromosuccinimide in
tetrahydrofuran solvent.
Key words: bromination, iodination, thiophenes, green chemistry, heterocyclic chemistry.
Résumé : La production verte de X+ (X = Br, I) au moyen de peroxyde d’hydrogène dans une solution aqueuse d’acide acétique
donne accès aux halogénures hétérocycliques aromatiques avec des rendements et des puretés comparables a` ceux des synthèses
en utilisant le N-bromosuccinimide. Dans les noyaux thiophènes activés et non substitués, la régiosélectivité est quantitative
pour les positions en ␣ du soufre; les pyrroles donnent aussi des réactions quantitatives, du moins initialement. Les noyaux
désactivés, y compris les furanes et les thiazoles, ainsi que les thiophènes porteurs de groupes fortement électroattracteurs ne
manifestent que peu de réactivité, voire aucune, dans les conditions étudiées. La réaction présente une tolérance remarquable
aux groupements fonctionnels (groupes alcool, nitro, alkyle, halo et carbonyle), comme le montre la réaction avec des phénols
substitués. Dans toutes les réactions de bromation, le rendement et la régiosélectivité étaient très semblables a` ceux des
réactions faisant appel au N-bromosuccinimide en solution dans le tétrahydrofurane. [Traduit par la Rédaction]
Mots-clés : bromation, iodation, thiophènes, chimie verte, chimie hétérocyclique.
metal-free. Previous synthetic generations of “X+” have tended to
Introduction
use a metal-based catalyst,12–14 but elimination of even trace
The tenets of green chemistry1 include the use of nontoxic sol-
amounts of metals is vitally important in semiconductors, where
vents and atom economy, and pursuing green alternatives to com-
incidental doping will damage device performance. Similarly, the
mon reactions is an area of current interest. One such focus is
pharmaceutical industry would prefer metal-free reactions when
synthetic routes to organic halides, as the halide functionality is
possible to avoid accumulation of toxic metals in long-term med-
common in many C−C bond-formation reactions (e.g., via the
ication regimens.
Suzuki,2 Stille,3 and Sonogashira4 methods); this topic has been
One metal-free generation of “Br+” uses nitric acid,15 which is
recently reviewed.5 Green halogenations of phenyl rings are avail-
too oxidizing for thiophenes.16 Another uses Br2/HBr, but multi-
able, provided the ring is activated and (or) if a metal-based cata-
bromination occurs.17 The remaining oxidants that met our re-
quirements were hydrogen peroxide18,19 and oxone.20 The latter
contains a mixture of potassium salts, so we chose the peroxide as
having a smaller environmental footprint and better atom econ-
omy. The “Br+” is generated by mixing hydrogen peroxide in gla-
cial acetic acid with the ammonium halide, which gives CH3CO2X
(Scheme 1).
lyst is used. The key step is the creation of “Cl+”, “Br+”, or “I+”
using a nontoxic oxidant. Oxidizing the elemental halogen X2
gives the greatest atom economy, but X2 must have been previ-
ously generated from a naturally occurring halide salt that in the
case of bromine is a toxic and corrosive liquid and in the case of
Cl2 is a toxic and corrosive gas. Thus, ways to generate “X+” in situ
are preferable. Brominations and iodinations are more important
targets because their compounds are much more commonly used
in coupling reactions than chlorinated organics.
Green halogenations of aromatic heterocycles have not been
systematically investigated, except in the case of the pyrazole
ring.6 Our interest in substituted oligothiophenes7–9 as molecular
semiconductors10,11 led us to search for a green route to bromo-
and iodothiophenes for use in subsequent C−C coupling reac-
tions. Our substrate and its end-use as a semiconductor material
suggested some initial design requirements: the oxidant cannot
oxidize the thiophene sulfur to the S,S-dioxide and it should be
Herein, we show that this reaction will generate the same prod-
ucts, in comparable yield, as the reaction of N-bromosuccinimide
(NBS) in tetrahydrofuran solvent. The heterocyclic substrates
tested contain a thiophene, furan, thiazole, or pyrrole ring. We
also include the reactions of several substituted phenols to test
the functional group tolerance of the reaction conditions.
Results and discussion
The full results are reported in Tables 1 and 2 (Scheme 2 gives
the abbreviation codes). Reactions were followed by GC using a
Received 8 February 2013. Accepted 31 March 2013.
D.N. D’Aleo, S.R. Allard, C.C. Foglia, S.L.M. Parent, D.J. Rohr, C. Gottardo, and C.D. MacKinnon. Department of Chemistry, Lakehead University, 955 Oliver Road, Thunder Bay, ON P7B
5E1, Canada.
Corresponding author: Craig D. MacKinnon (e-mail: craig.mackinnon@lakeheadu.ca).
Can. J. Chem. 91: 679–683 (2013) dx.doi.org/10.1139/cjc-2013-0058
Published at www.nrcresearchpress.com/cjc on 11 April 2013.

680
Can. J. Chem. Vol. 91, 2013
Scheme 1. Green halogenation reactions of this study.
zene (100), benzonitrile (100), and nitrobenzene (100). The lack of
reactivity of thiazole and imidazole is likely due to the acidic
conditions of the reaction, which caused protonation of the
pyridine-like nitrogen (to create =NH+–), thereby deactivating the
ring to electrophilic aromatic substitution. Akin to the previously
observed reactivity of p-nitroaniline,18,22 the donor−acceptor
compound p-nitrophenol did react (entries 31 and 32), but the
sulfur in the thiophene ring is apparently not sufficiently activat-
ing in 3-methylthiophene-2-carbonitrile or 3-methylthiophene-2-
carboxaldehyde.
There are also cases where bromination will occur, while iodi-
nation will not, i.e., brominated thiophenes will react with “Br+”
but not with “I+”. As such, 2-bromo-5-iodothiophene 1-BrI is not
accessible by iodinating bromothiophene, but is accessible
through bromination of iodothiophene (entry 13) if the stoichiom-
etry is strictly kept at 1:1. Otherwise, some dibromothiophene
1-Br2 is created (entry 14).
Although peroxide is sufficient to oxidize chloride from HCl in
petroleum ether solvent,23 we saw no evidence of chlorination
using an ammonium chloride − hydrogen peroxide mix under our
conditions. Furan did not react cleanly and benzofuran was
mostly starting material even after 24 h of reaction time. The in
situ GC results appear promising for pyrrole (entries 23−26), but
the regiochemical location of the halogen could not be deter-
mined. Attempts at isolating the product(s) consistently gave an
intractable black material, presumably a form of polypyrrole,
which is unsurprising given that the first synthesis of polypyrrole
involved an oxidative coupling using hydrogen peroxide.24,25
Both phenol (entries 27 and 28) and aniline (entries 33 and 34)
undergo o- and p-substitution (Table 2), indicating that the reac-
tive species is the neutral phenol and aniline. There is no evidence
of m-substitution, even though the acidic conditions should create
a significant fraction of protonated molecules, which would be
m-directing. We conclude that the deactivating nature of the
–NH+3 and –OH+2 groups prevents reaction with any molecules on
the protonated side of the equilibrium, thereby preventing
m-substitution from occurring. These results are consistent with
those previously published.18
This reaction can be considered green because of the relative
environmental benignity of the solvent, reactants, and byprod-
ucts. There are several metrics used to measure greeness. One of
the most common is Sheldon’s E-factor, but it neglects to take into
account the nature of the materials and solvents,26 which is the
parameter we are improving upon. A more useful metric for our
purposes is the EcoScale,27 which applies “penalty points” to toxic
or flammable materials, inefficient steps in a synthesis, etc.
Table 3 shows the EcoScale calculation, which gives a result of
2−16 penalty points in favour of our green reaction over a typical
NBS reaction.
flame ionization detector for quantitation. Yields were calculated
as relative amounts compared with the total area under the GC
peaks. When necessary, the reaction mixture was spiked with a
known amount of nitrobenzene (which does not halogenate
under these conditions) to ensure that all of the substrate is ac-
counted for in the product GC. When possible, we also cross-
checked the GC ratios with 1H NMR integration ratios by isolating
the product mixtures. Peroxide was found to be an appropriate
oxidant, as there is no evidence for S,S-dioxides in any of the
thiophene reactions, nor was there any reaction with the ammo-
nium from the bromide and iodide salts. The regiochemistry of
the products was determined by comparison of GC retention
times with those of the commercially available halogenated prod-
uct(s). When unavailable, presumed products were synthesized by
literature methods and GC times compared, or the products were
identified by a combination of NMR and GC−MS. Reactions were
allowed to run for a maximum of 20 h under ambient conditions;
as a corollary to our desire to utilize a green reaction, we wanted
a simple methodology, using minimal equipment and time.
For comparison, brominations using NBS in tetrahydrofuran
were performed (in the dark) over the same length of time as the
“Br+” brominations. Selected results are given in Tables 1 and 2;
the full results are included in the supplemental material. They
show that the regioselectivity of the green reaction is similar to
that of the NBS reaction. In one case (compare entries 2 and 6), the
green halogenation method significantly outperforms the NBS
method in selectivity, if not in time.
Functional group tolerance was tested on a number of substi-
tuted thiophenes; to increase the variety of functional groups, we
also used aniline and a number of substituted phenols,21 as the
latter are more readily available and cheaper than the equivalent
thiophenes. As shown in Tables 1 (thiophenes) and 2 (benzenes),
the peroxide does not react with any of the electron-donating
functional groups tested, nor with halogens (with the exception of
entry 14). Substrates with electron-withdrawing groups (benzalde-
hyde, cyanobenzene, nitrobenzene, and chlorobenzene) also
showed functional group tolerance, but unfortunately, in concor-
dance with what was previously observed for other phenyl sub-
strates,18,19 the electron-withdrawing groups deactivated their
rings to substitution. Thus, several substrates did not react with
“Br+” or “I+” to any significant extent, defined herein as having
greater than 90% starting material remaining after 20 h with a 1:1
stoichiometry. They are as follows (percentage of starting material
remaining in parenthesis): 3-methylthiophene-2-carbonitrile
(100),1,3-thiazole(100),imidazole(100),benzofuran(91),chloroben-
For the GC reactions, we used a standard organic/aqueous sep-
aration workup primarily to ensure that salts, etc., did not clog up
the GC column; such a workup would not normally be considered
“green”. To show that this extraction step would not be necessary
in preparatory-scale reactions, we performed two reactions (1-Br
¡ 1-Br2 and 4 ¡ 4-Br2) on a preparatory scale with a green
workup. The procedure involved removal of the acetic acid by
rotary evaporation followed by addition of water to dissolve the
product salts and unreacted starting materials. For 1-Br2, the
product is an insoluble oil, which was isolated using a Pasteur
pipette. The nonoptimized yield was only 36%. However, when
isolating the solid product 4-Br2 by filtration, the yield is consid-
erably better at 76%. In both cases, the purity is very high (no
evidence of any impurities, starting materials, or side-products in
1
the H NMR; see Figs. S1 and S2 in the supplementary informa-
tion), indicating the potential for a truly green isolation process
once conditions are optimized.
Published by NRC Research Press

D’Aleo et al.
681
Table 1. Results for bromination and iodination reactions using heterocyclic substrates.
Species in final reaction mixture (relative
ratios by GC)
Halide source, Time Unreacted
1:1
product
2:1
product
Other
productsa
Identification
methodb
Entry Substrate molar ratio
(h)
substrate
Notes
1c
1
1
1
1
1
1
Br+, 1 equiv.
Br+, 2 equiv.
I+, 1 equiv.
20
20
20
20
4
12%
80% 1-Br
8% 1-Br2
99% 1-Br2
trace 1-I2
trace 1-I2
18% 1-Br2
41% 1-Br2
7% 2-Br2
99% 2-Br2
1% 2-I2
GC
GC
GC
GC
GC
GC
2c
3
23%
24%
3%
76% 1-I
76% 1-I
4
5
6
7
8
9
I+, 2 equiv.
NBSd, 1 equiv.
NBSd, 2 equiv.
Br+, 1 equiv.
Br+, 2 equiv.
I+, 1 equiv.
79% 1-Br
59% 1-Br
93% 2-Br
Trace 2-Br
98% 2-I
No change after 4 h
No change after 4 h
4
2
2
2
2
3
3
1-I
1-I
4
4
4
4
5
5
5
5
6
6
7
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
4
NMR/MS
NMR/MS
NMR/MS
NMR/MS
NMR/MS
NMR/MS
NMR/MS
NMR/MS,GC
GC
1%
10
11
12
13
14
15c
16c
17
18
19
20
21
22
23
24
25
26
I+, 2 equiv.
90% 2-I
10% 2-I2
Br+, 1 equiv.
Br+, 2 equiv.
Br+, 1 equiv.
Br+, 2 equiv.
Br+, 1 equiv.
Br+, 2 equiv.
I+, 1 equiv.
14%
86% 3-Br
93% 3-Br
99% 1-BrI
57% 1-BrI
63% 4-Br
e
7% 3-Br2
40% 1-Br2
7%
31% 4-Br2
99% 4-Br2
18% 4-I2
GC
9%
72% 4-I
9% 4-I
NMR/MS
NMR/MS
NMR/MS
NMR/MS
NMR/MS
NMR/MS
MS
I+, 2 equiv.
91% 4-I2
Br+, 1 equiv.
Br+, 2 equiv.
NBSd, 1 equiv.
NBSd, 2 equiv.
Br+, 1 equiv.
Br+, 2 equiv.
Br+, 1 equiv.
Br+, 2 equiv.
52%
27%
48% 5-Br
99% 5-Br
73% 5-Br
99% 5-Br
69% 6-Bre
99% 6-Bre
99% 7-Bre
99% 7-Bre
e
29% 6-Br2
Could not isolate
Decomposes within 20 h MS
Could not isolate MS
Decomposes within 20 h MS
20
4
Trace
Trace
7
aBecause the substrates are reagent grade, trace byproducts appear in the gas chromatogram.
bGC, product identified using retention times of known materials; NMR, product identified by NMR; MS, product identified by GC–MS.
cQuantified using a nitrobenzene spike.
dRepresentative examples of NBS bromination for comparison with the “Br+” method; a complete table containing all NBS reactions is given in the supplementary
material.
eRegiochemistry of substitution could not be definitively determined.
Table 2. Results for phenol (and aniline) substituents.
Species in final reaction mixture (relative ratios by GC)
Halide source,
molar ratio
Time
(h)
Unreacted
substrate
1:1
product
2:1
product
Other
Identification
methodb
Entry
27
Substrate
Phenol
productsa
Br+, 1 equiv.
20
14%
38% o-bromo
39% p-bromo
0% o-bromo
10% p-bromo
99% 1-bromo
99% 1-bromo
36% 2-bromo
9% 2,4-dibromo
NMR/MS,GC
28
Phenol
Br+, 2 equiv.
20
82% 2,4-dibromo
8% Tribromoc
NMR/MS,GC
29
30
31
32
33
2-Naphthol
2-Naphthol
4-Nitrophenol
4-Nitrophenol
Aniline
Br+, 1 equiv.
Br+, 2 equiv.
Br+, 1 equiv.
Br+, 2 equiv.
Br+, 1 equiv.
20
20
20
20
20
Trace
31%
Trace
Trace
NMR/MS
NMR/MS
NMR/MS
NMR/MS
GCd
33% 2,6-dibromo
95% 2,6-dibromo
16% 2,4-dibromo
Multiple trace
9% tribromoc
10%
16% o-bromo
57% p-bromo
34
Aniline
Br+, 2 equiv.
20
91% 2,4-dibromo
GCd
aBecause the substrates are generally reagent grade, there are often trace byproducts in the gas chromatogram.
bGC, product identified using retention times of known materials; NMR, product identified by NMR; MS, product identified by GC–MS.
cGC–MS shows a tribromo species, but no attempt was made to separate this product to definitively characterize it.
dGC peaks assigned by analogy with reference 17; the identities were confirmed by NMR and MS analysis.
parable in selectivity and yields to typical NBS substitutions. Given
that the effectiveness of the two methods is similar, the “X+” method
is greener, with the significant advantages of environmentally be-
nign waste products and solvent.
Conclusions
In conclusion, we have demonstrated an efficient green
halogenation reaction for electron-rich heterocyclic rings. The con-
ditions lead to highly selective substitutions on sites ␣ to the heteroa-
tom. Dibromination of both ␣ positions, or monobromination when
the second ␣ position already contains a functional group, proceed
quantitatively. As expected,18,22 the results in Table 2 show that regi-
oselectivity for phenols was not as good as for thiophenes, with
significant amounts of both o- and p-substitution. Reactions are com-
Experimental section
Materials
The following materials were synthesized by literature meth-
ods: 4,28 4-Br,29 and 4-Br229; 3-methylthiophene-2-carbonitrile
Published by NRC Research Press

682
Can. J. Chem. Vol. 91, 2013
Scheme 2. Substrates and products in this study.
uct separated as a pale yellow oil, removed using a Pasteur pipette
(2.66 g, 36%). 1H NMR is identical to commercially available mate-
rial; no evidence of impurities present.
Isolation-scale synthesis of 5,5=-dibromo-2,2=-bithiophene (4-Br2)
In acetic acid (4.0 mL), bithiophene (0.32 g, 1.9 mmol) and am-
monium bromide (0.43 g, 4.4 mmol) were dissolved followed by
dropwise addition of 0.23 mL (2 mmol) of 30% hydrogen peroxide.
The mixture was stirred overnight (16 h). The acetic acid was re-
moved using a rotary evaporator and then 10 mL of water added to
dissolve the residual ammonium salts and peroxide. The solid
1
product was filtered to give 0.76 g of product (76%). H NMR is
identical to material synthesized by the literature route;29 no ev-
idence of starting materials, monobrominated product 4-Br, or
other impurities present.
Synthesis of 3-methylthiophene-2-carbonitrile
Although commercially available, we synthesized this com-
pound as follows. The acid chloride of 3-methylthiophene-2-
carboxylic acid was generated by refluxing the acid (2.01 g,
14.2 mmol) in SOCl2 (6 mL) for 10 min. The residual SOCl2 was
removed in vacuo and the chloride converted to the amide upon
addition of aqueous ammonium hydroxide (15 mL) and warming
(to 75 °C) for 30 min. The resultant solid was suction filtered,
washed copiously with water, and dried. Without further purifi-
cation, 0.51 g of this crude was dehydrated by heating to 50 °C for
1 h in POCl3 (8 mL). Quenching in water followed by extraction
into CH2Cl2 (dried using Na2SO4) and rotary evaporation gave a
brown oil. Purification by vacuum distillation (50 °C at 10−3 atm)
gave a colourless oil (0.20 g, 12% from acid). Spectral data match
the literature.30 1H NMR (CDCl3, 500 MHz): 7.47 (d, J = 5 Hz, 1H),
6.95 (d, J = 5 Hz, 1H), 2.46 (s, 3H). IR (film): 3108 (m), 2926 (m), 2215
(s), 1448 (m), 1404 (m), 1264 (w), 1174 (w), 1086 (w), 1014 (w), 939 (w),
839 (w), 734 (m) cm−1.
Table 3. Calculation of EcoScale penalty points.
Parameter
NBS “X+” Notes
1. Yield
na na Yields similar by GC
2. Price of reaction
components
3. Safety
0
5
0
0
All components <$10/mmol
product
Toxic byproduct
Succinimide vs. ammonium
acetate
Toxic solvent
Flammable solvent
4. Technical setup
5
5
0
0
0
1
Tetrahydrofuran vs. acetic acid
Tetrahydrofuran vs. acetic acid
“X+” reaction requires dropwise
addition of H2O2
5. Temperature/time
1
1
Room temperature reaction,
1 h < reaction time < 24 h
Both solvents have boiling point
temperature <150 °C,
Characterization
6. Workup/purification
0
0
As shown in Tables 1 and 2, the following products were char-
acterized by comparing the GC retention times of the reaction
products with the retention times of commercial or indepen-
dently synthesized products: 1-Br, 1-Br2, 1-I, 1-I2, 4-Br, 4-Br2, and
o- and p-bromophenol. Peaks for 2- and 4-bromoaniline and 2,4-
dibromoaniline were assigned according to the literature
method.18 The following products were assigned by isolating the
products from the reaction mixture and comparing with litera-
ture NMR spectra: 1-BrI,31 2-Br,32 2-Br2,33 4-I,34 4-I2,34 5-Br,35 and
1-bromo-2-naphthol.36 The following compounds are commer-
cially available and were assigned based on the NMR spectra in the
Sigma-Aldrich online spectral database: 3-Br and 2,6-dibromo-4-
nitrophenol. For the unisolable 2-bromo-4-nitrophenol (a mate-
rial that can be isolated by another method37), the product was
assigned based on the mass spec and the fact that the dibromin-
ated product contained 2,6-disubstitution and therefore must
have gone through this monosubstituted structure. Finally, the
regiochemistry of 3-Br2 was never definitively determined (and
was never more than a minor product anyway).
everything else will
be the same
Total
16
2
was synthesized by the method given below. All other materials
were obtained commercially (>95% purity) and used as received.
General procedure for green halogenation reactions
Substrate (2.0 mmol) and ammonium halide (NH4Br or NH4I,
2.2 mmol for monohalogenation, 4.4 mmol for dihalogenation)
were stirred in glacial acetic acid (4 mL) for 5 min, after which 30%
hydrogen peroxide solution (0.23 mL for monohalogenation,
0.46 mL for dihalogenation) was added dropwise. The mixture was
stirred for the time given in Tables 1 and 2 (4−20 h), then the
mixture quenched with sodium bicarbonate solution and ex-
tracted into CH2Cl2. This organic layer was injected into the
GC−FID to give the relative yields summarized in the tables or
rotary evaporated to isolate the product for NMR analysis. GC−FID
yields are the area under a given peak as a percentage of the sum
of peak areas for all peaks. They are uncorrected for differences in
detector response for different species except where noted.
Supplementary data
Supplementary data are available with the article through the
journal Web site at http://nrcresearchpress.com/doi/suppl/10.1139/
cjc-2013-0058. Supplementary data include full characterization
data for all compounds, copies of 1H NMR spectra, data for the NBS
reactions, and details on the calculations for the green scales.
Isolation-scale synthesis of 2,5-dibromothiophene (1-Br2)
In acetic acid (60 mL), 2-bromothiophene (4.90 g, 30 mmol) and
ammonium bromide (3.23 g, 33 mmol) were dissolved followed by
dropwise addition of 4.48 mL (40 mmol) of 30% hydrogen perox-
ide. The mixture was stirred overnight (16 h). The acetic acid was
removed using a rotary evaporator and then 20 mL of water added
to dissolve the residual ammonium salts and peroxide. The prod-
Acknowledgements
Funding was provided by Lakehead University and NSERC Can-
ada (through a Discovery Grant to CG and an Undergraduate Sum-
mer Research Award to DND).
Published by NRC Research Press

D’Aleo et al.
683
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