Tandem application of C-C bond-forming reactions with reductive ozonolysis

Article abstract of DOI:10.1021/jo3015775

Several variants of reductive ozonolysis, defined here as the in situ generation of aldehydes or ketones during ozonolytic cleavage of alkenes, are demonstrated to work effectively in tandem with a number of C-C bond-forming reactions. For reactions involving basic nucleophiles (1,2- addition of Grignard reagents, Wittig or Horner-Emmons olefinations, and directed aldol reactions of lithium enolates), the one-pot process offers a rapid and high-yielding alternative to traditional two-step protocols.

Full text of DOI:10.1021/jo3015775

Article
pubs.acs.org/joc
Tandem Application of C−C Bond-Forming Reactions with Reductive
Ozonolysis
Rachel Willand-Charnley and Patrick H. Dussault*
Department of Chemistry, University of Nebraska−Lincoln, Lincoln, Nebraska 68588-0304, United States
S
* Supporting Information
ABSTRACT: Several variants of reductive ozonolysis, defined
here as the in situ generation of aldehydes or ketones during
ozonolytic cleavage of alkenes, are demonstrated to work
effectively in tandem with a number of C−C bond-forming
reactions. For reactions involving basic nucleophiles (1,2-
addition of Grignard reagents, Wittig or Horner−Emmons
olefinations, and directed aldol reactions of lithium enolates),
the one-pot process offers a rapid and high-yielding alternative
to traditional two-step protocols.
Scheme 1. Overview of Alkene Ozonolysis (Traditional)
INTRODUCTION
■
Methods for generation of new carbon−carbon bonds from
carbonyl electrophiles are among the most fundamental of
synthetic transformations. The aldehyde and ketone starting
materials are frequently generated via cleavage of alkenes with
ozone. As a method for oxidative carbonyl generation,
ozonolysis has many attractive features: compatibility with
either protic or aprotic media, useful selectivity for cleavage of
alkenes in the presence of other functional groups, the need for
only oxygen and electricity as inputs, and the absence of metal-
containing byproducts.1 However, on the negative side, the
intermediate ozonides or hydroperoxyacetals are often capable
of dangerously exothermic self-accelerating decomposition
reactions.2 The potential hazards related to accumulation of
energetic intermediates have limited large-scale application of
ozonolysis3 and motivated the development of flow-based or
modular reactor systems.4 We have recently reported several
methods for “reductive” ozonolysis that directly generate
carbonyl products, avoiding formation of isolable peroxides.5a−c
We now report the successful application of reductive
ozonolyses in tandem with a number of the most common
methods for carbon−carbon bond-forming reactions.
To understand the potential value of one-pot application of
reductive ozonolysis and C−C bond-forming reactions, it is
useful to look at a traditional ozonolysis pathway (Scheme
1).1a,6 Cycloaddition of an alkene with ozone generates a 1,2,3-
trioxolane, or “primary ozonide”,7 which undergoes cyclo-
reversion even at low temperatures to generate a carbonyl and a
short-lived carbonyl O-oxide.6,8 Reaction in aprotic media
favors cycloaddition with a dipolarophile, frequently the
cogenerated aldehyde, to furnish 1,2,4-trioxolanes (ozonides).9
Alternatively, nucleophilic trapping by unhindered alcohols
generates hydroperoxyacetals.10,11 Ozonides and hydroperox-
yacetals are most often decomposed to aldehydes or ketones by
reduction,12 although alternative workups are known on the
basis of base-promoted fragmentations.13 Reduction can be
accomplished with many reagents, but three are used most
frequently.1a,12 Me2S is a mild and chemoselective reagent
which can be used in excess and generates DMSO as a
byproduct. However, as became obvious in the course of this
work, the reaction of Me2S with ozonides is often slow, so slow
in the case of hindered ozonides as to result in potentially
hazardous situations.14 Zn/HOAc rapidly reduces most
peroxides, but the acidic conditions are incompatible with
many substrates. Ph3P reduces all hydroperoxyacetals and most
ozonides, but the formation of stoichiometric phosphine oxide
can complicate product isolation.15
Reductive Ozonolysis. We have recently described three
protocols for reductive ozonolysis. The first (Scheme 2, path a)
involves an operationally simple protocol, ozonolysis in wet
acetonitrile or wet acetone.5b In this case, attack of solubilized
water on the carbonyl oxide generates a tetrahedral
Special Issue: Robert Ireland Memorial Issue
Received: July 24, 2012
© XXXX American Chemical Society
A
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Scheme 2. Overview of Reductive Ozonolyses
Table 1. One-Pot Reductive Ozonolysis and Horner−
Emmons Reaction
a
Key: (A) O3, NMMO (3 equiv), CH2Cl2, 0 °C; then Wittig ylide (1.1
equiv) in THF. B) O3, pyridine (3 equiv), CH2Cl2, −78 °C; then
Wittig ylide.
Table 2. One-Pot Ozonolysis and Wittig Olefination
intermediate that decomposes to furnish the carbonyl
product(s) and hydrogen peroxide. The second (Scheme 2,
path b) involves ozonolysis in the presence of N-methyl-
morpholine N-oxide (NMMO) or related N-oxides.5a Nucle-
ophilic trapping of the carbonyl oxide generates unstable
zwitterionic acetals, which fragment to generate the target
carbonyl, O2, and a molecule of amine.16 Finally, we recently
described a general and high-yielding protocol for direct
conversion of alkenes to aldehydes and ketones based upon
ozonolysis in the presence of added pyridine.5c This trans-
formation (Scheme 2, path c) appears to involve an
unprecedented pyridine-promoted dimerization and fragmenta-
tion of carbonyl oxides. Of particular relevance to the current
studies, the N-oxide and pyridine-promoted protocols are
conducted under anhydrous conditions and generate by-
products (amines, N-oxides, or pyridine) not expected to
interfere with transformations based upon carbon nucleophiles.
a
Key: (A) O3, NMMO (3 equiv), CH2Cl2, 0 °C; then Wittig ylide (1.1
equiv) in THF; (B) O3, pyridine (3 equiv), CH2Cl2, −78 °C; then
Wittig ylide.
secondary or tertiary alcohols were obtained using only a slight
excess (1.1 equiv) of the alkyl- or arylmagnesium reagent.
Aldol Reactions. Addition of the lithium enolate of
cyclohexanone to the crude reaction mixtures resulting from
the pyridine- or NMMO-promoted reductive ozonolyses
furnished good yields of 3-hydroxy ketones as ∼3:1 mixtures
of anti/syn diastereomers (Table 4). The yields and sense of
RESULTS
■
We investigated in situ ozonolytic generation of aldehydes and
ketones in conjunction with several widely used methods for
carbon−carbon bond formation: 1,2-organometallic additions,
Wittig and Horner−Emmons olefinations, aldol reactions, and
allylations. Because the majority of these transformations
involve the use of water-sensitive reagents, we focused our
efforts on the reductive protocols based upon N-oxides
(Scheme 2b) and pyridine (Scheme 2c).
Table 3. One-Pot Ozonolysis and Organometallic Addition
Horner−Emmons Olefinations. As illustrated in Table 1,
addition of lithiated triethyl phosphonoacetate to the crude
reaction mixtures resulting from reductive ozonolysis provided
very good yields of α,β-unsaturated esters. Similar yields were
available through a traditional multistep route involving Me2S
(3−5 equiv) reduction of the intermediate ozonide (vida infra);
however, the reduction step required up to 24 h for removal of
ozonide.
Wittig Olefination. Wittig olefination with nonstabilized
ylides also paired effectively with reductive ozonolysis (Table
2). In the case of the N-oxide protocol, we found it most
effective to conduct the subsequent Wittig reaction at 0 °C or
above to avoid precipitation of reagents.
Organometallic Addition. Direct addition of organo-
metallics to solutions of ozonolysis-derived aldehydes was
investigated with Grignard reagents (Table 3). Good yields of
a
Key: (A) O3, NMMO, CH2Cl2, 0 °C; add RMgX in ether; (B) O3,
pyridine, CH2Cl2, 0 °C; then RMgX.
B
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Table 4. One-Pot Ozonolysis and Aldol Reaction
DISCUSSION
■
Ozonolysis has been previously investigated as a one-pot
reaction in tandem with a number of reductive transformations,
including borohydride reduction,18 reductive amination,19
hydrogenation,20 and Clemmensen reduction.21 Oxidation of
ozonolysis products with H2O2 has been employed for the
synthesis of carboxylic acids,22,23 and chromic acid oxidation
has been used to digest ozonides.24
However, the record related to C−C bond formation is
much thinner. Building upon an efficient synthesis of aldehydes
via base-promoted fragmentation of terminal ozonides,13 Hon’s
laboratory demonstrated the ability to convert the same
ozonides directly to unsaturated esters upon reaction with
stabilized Wittig ylides.25 The combination of SnCl2 and ethyl
diazoacetate has been shown to achieve the direct conversion of
ozonolysis-derived peroxides to 3-ketoesters.26 Cyclic oxoni-
triles have been prepared by pairing the ozonolysis of
unsaturated nitriles with a subsequent intramolecular aldol
reaction.27 Ozonides are also known to react directly with
organometallic reagents.28 However, this methodology requires
handling of a peroxide intermediate and the use of excess
organometallic (to cleave the O−O bond and then react with
the liberated carbonyl).29
Reductive ozonolyses, which achieve the direct conversion of
alkenes to ketones or aldehydes, were anticipated to partner
well with methods for carbon−carbon bond formation. In
particular, the pyridine or amine N-oxide promoters were not
expected to interfere with reactions involving basic nucleo-
philes. This assumption was supported by our results, which
found no significant change in stoichiometry or yield relative to
a traditional two-step procedure for reactions with phosphonate
anions, Wittig ylides, Grignard reagents, or lithium enolates.
Curiously, although the ozonolysis of terminal alkenes
generates formaldehyde as a byproduct,1a,6,8 we did not observe
products of one-carbon homologation, even in the presence of
PhMgBr, a reagent for which the derived alcohol would have
been easily observed and isolated. The failure to trap
formaldehyde, which is a definite plus in terms of avoiding
unnecessary consumption of reagent, presumably reflects loss
of this highly volatile byproduct under reaction conditions. In
contrast, application of a one-pot ozonolysis/Horner−Emmons
protocol to a cyclic alkene furnished a good yield of the product
derived from a ketoaldehyde (eq 1).
a
Key: (A) O3, NMMO, CH2Cl2, 0 °C; lithium enolate of
cyclohexanone; (B) same except O3, pyridine, CH2Cl2, 0 °C.
stereoselection were very similar to results previously reported
for analogous reactions of isolated aldehydes (see the
Experimental Section). In contrast, attempts to perform the
corresponding Lewis acid catalyzed Mukaiyama aldol reactions
with a trimethylsilyl enol ether were unsuccessful (not shown);
in fact, addition of enol ethers and TiCl4 to pyridine-containing
solutions resulted in the formation of a viscous, dark material.
Allylations. Lewis acid catalyzed allylations were inves-
tigated in tandem with both the N-oxide and the pyridine
protocols (Table 5).17 Treatment of the products of either
Table 5. One-Pot Ozonolysis and Lewis Acid-Mediated
Allylation
a
Key: (A) O3, NMMO, CH2Cl2, 0 °C; then TiCl4, allylSiMe3; (B)
same, but O3, pyridine, CH2Cl2, −78 °C; (C) O3, pyridine, CH2Cl2,
−78 °C; then BF3·OEt2, allylSiMe3; (D) Same except O3, NMMO,
CH2Cl2, 0 °C.
In contrast, Mukaiyama aldol reactions failed completely
under the tandem conditions, while Hosomi−Sakurai allyla-
tions were successful only in the presence of a significant excess
of Lewis acid. These results are not completely surprising;
pyridine and NMMO are strong Lewis bases, and we found no
examples of previous pairings of ozonolysis with Lewis-acid
promoted allylation chemistry.30 Based upon our results, we
cannot recommend the tandem application of reductive
ozonolysis in sequences employing strong Lewis acids.
Although we did not explore enamine-based aldol or Michael
chemistry, the conditions of the pyridine-mediated reductive
ozonolyses are likely to pair well with these increasingly popular
approaches for carbon−carbon bond formation.
protocol with allylsilane and BF3·OEt2 (excess) furnished
homoallyl alcohols in good yield. In contrast, TiCl4-promoted
allylation was unsuccessful when applied in tandem with
pyridine-promoted reductive ozonolysis and could be applied in
tandem with the NMMO protocol only if the Lewis acid was
used in excess relative to the N-oxide. Attempted allylations in
the presence of more oxophilic Lewis acids such as Yb(OTf)3
and TMSOTf were unsuccessful.
C
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reaction was allowed to stir for 1 h, whereupon the CH2Cl2 solution of
the carbonyl product of ozonolysis (nominally 3 mmol based upon
alkene starting material) was added dropwise. The reaction mixture
was then allowed to warm to room temperature and stirred for an
additional 2.5 h. The reaction was quenched with saturated NH4Cl (4
mL) and the mixture extracted with 30 mL of ether (3×). The
combined organic layers were washed with brine and extracted. The
aqueous washes were back extracted with a small amount of ether
(3×), the combined organic layers were dried with sodium sulfate, and
the residue obtained upon concentration was purified via flash
chromatography with EA/Hex to furnish the desired product.
Tandem Application of Reductive Ozonolysis and Grignard
Reactions. A solution of CH2Cl2 and carbonyl product (nominally 3
mmol), prepared from an alkene via ozonolysis as already discussed,5a,c
was recooled to 0 °C, whereupon a stoichiometric amount of phenyl-
or methylmagnesium bromide (3 mmol, 1 equiv, nominally 1 M in
THF) was added. The reaction was monitored by TLC and, when
complete, was quenched by dropwise addition of water followed by a
few drops of 6 M aq HCl. The mixture was diluted with a volume of
saturated aq NH4Cl, and the separated aqueous layer was extracted
thee times with CH2Cl2. The remainder of the workup was performed
as for the Horner−Emmons sequence described above.
Tandem Application of Reductive Ozonolysis and Allylation
Reactions. To a room temperature CH2Cl2 solution of the carbonyl
product (nominally 3 mmol), prepared from an alkene via ozonolysis
as already discussed,5a,c was dropwise added TiCl4 (6 mmol, neat).
After approximately 10 min, allyltrimethylsilane (2 mmol) was added
dropwise and the reaction mixture was allowed to stir for 45 min. The
reaction was quenched with deionized water. The organic layer was
extracted with 30 mL of ether (3×). The combined organic layers were
dried and concentrated as described previously followed by drying,
concentration, and purification by procedures similar to those
described above.
A comparison with traditional methodology reveals practical
advantages of the new approach. Application of a traditional
ozonolysis/Horner−Emmons reaction sequence (ozonolysis;
Me2S reduction; Horner−Emmons olefination) to 3-butenyl-
benzene (eq 2) furnishes ethyl 5-phenyl-2-pentenoate in a yield
only slightly lower than for the one-pot approach (see Table 1)
but requires 24 h or more for complete consumption of the
ozonide by Me2S (6−8 equiv) compared with minutes in the
one-pot procedures.
In conclusion, the application of convenient and high-
yielding approaches for reductive ozonolysis in tandem with a
number of widely used methods for C−C bond-forming
reactions is shown to result in streamlined synthetic sequences.
It is hoped that the methodology will be as widely applied as an
analogous strategy partnering C−C bond-forming reactions
with Swern oxidations.31
Notes on Safety. Although the procedures described above
typically preclude formation of significant amounts of ozonides
and other peroxides, experimenters are urged to verify the
absence of significant amounts of peroxides before concentrat-
ing crude reaction mixtures.32 Ozonolyses should always be
conducted with an awareness of the potential for spontaneous
and exothermic decompositions.2
Tandem Application of Reductive Ozonolysis and Wittig
Olefination. A CH2Cl2 solution of carbonyl product (nominally 3
mmol) was prepared from an alkene via ozonolysis as discussed
above.5a,c A stoichiometric (3 mmol; 1 equiv relative to nominal
amount of carbonyl) amount of pentyltriphenylphosphonium bromide
was placed in a flame-dried 50 mL RBF capped with a septa. The
atmosphere was removed under vacuum and backfilled with N2. The
salt was dissolved in THF (10−15 mL) and the solution cooled to 0
°C. The mixture was allowed to stir for 10 min, whereupon a solution
of n-BuLi (3 mmol, nominally 2.3 M in Hex) was added dropwise. The
reaction was allowed to stir for 0.5 h, after which the solution of
aldehyde was added dropwise. The reaction, when complete (∼0.5−1
h, TLC) was quenched by dropwise addition of water and the resulting
mixture extracted with 30 mL of ether. The organic layer was washed
successively with aqueous sodium bicarbonate, water, and bleach. The
aqueous washes were back-extracted three times with a small amount
of ether. The combined organic layers were dried and concentrated as
described previously followed by drying, concentration, and
purification by procedures similar to those described above.
EXPERIMENTAL SECTION
■
All reagents and solvents were used as supplied commercially, except
CH2Cl2 (distilled from CaH2), THF (distilled from Na/benzophe-
none) and pyridine (stored over activated 4 Å sieves). All reactions
were conducted under an atmosphere of N2 except where noted. NMR
spectra were acquired in CDCl3; chemical shifts are reported in ppm
1
referenced to the solvent peaks of CDCl3 (7.26 ppm for H and 77.1
( 0.1) ppm for 13C). The sample was analyzed by GC/MS (30 m DB-
5MS column with a 1:200 injector split and 1 mL/min flow of He gas,
analysis on an ion trap scanning in EI mode over 50−650 m/z range,
with the ion source set at 200 °C). IR was acquired via ATR as neat
films on a ZrSe crystal with selected absorbances reported in cm−1.
Silica gel was used for flash column chromatography. Thin-layer
chromatography (TLC) was performed on 0.25 mm hard-layer silica G
plates containing a fluorescent indicator. Developed TLC plates were
visualized with a hand-held UV lamp or by charring after staining with
1% ceric sulfate/10% ammonium molybdate in 10% H2SO4.
Reductive Ozonolysis in the Presence of Pyridine. The alkene
(internal or terminal) substrate (1−3 mmol) and dry pyridine (3−9
mmol) were dissolved in dry CH2Cl2 (15−20 mL) in a flame-dried
flask under N2. The solution was cooled to −78 °C, at which point a
stream of O3/O2 (delivering ∼1 mmol/min of O3) was introduced
through a disposable pipet for a period proportional to the amount of
alkene. Once consumption of alkene was complete, the reaction was
sparged with O2 and then N2. The resulting solution was added
dropwise (syringe or cannula) to the next reaction mixture.
Reductive Ozonolysis in the Presence of N-Methylmorpho-
line N-Oxide (NMMO). The alkene (internal or terminal) substrate
(1−3 mmol) and NMMO (3−5 equiv relative to alkene) were
dissolved in dry CH2Cl2 (15−20 mL) in a flame-dried flask under N2.
The solution was cooled to 0 °C, after which ozonolysis carried out as
described in the previous procedure, as was application of the reaction
mixture to the following reaction.
Tandem Application of Reductive Ozonolysis with Aldol
Reactions. The aldehyde (nominally 3 mmol) was prepared from an
alkene via ozonolysis as already discussed.5a,c To a stirring 0 °C
solution of diisopropylamine (3 mmol) in 7 mL of THF in a flame-
dried RBF was added n-butyllithium (3 mmol, as a nominally 2.3 M
solution in hexane). After 15 min, a solution of cyclohexanone (3
mmol) in THF (2 mL) was added. The reaction was cooled to −78
°C, and the CH2Cl2 solution of the aldehyde product was added. After
15 min, the aldehyde was completely consumed (TLC), and the
reaction was quenched with 1 M HCl (1−2 equiv). The solution
(emulsion) was extracted with 30 mL of ether, and the organic layer
was washed successively with aqueous sodium bicarbonate, water, and
aqueous sodium chloride. The aqueous washes were back-extracted
with a small amount of ether (3×). The combined organic layers were
dried and concentrated as described previously followed by drying,
concentration, and purification by procedures similar to those
described above. The syn/anti ratios (∼1:3 in all cases) were assigned
Tandem Application of Reductive Ozonolysis and Horner−
Emmons Olefination. To a −78 °C solution of triethyl
phosphonoacetate (4 mmol) in THF (20 mL) was dropwise added
n-butyllithium (5 mmol, as a nominally 2.3 M solution in hexane). The
33−37
1
by comparison of the H NMR spectra with literature reports.
D
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Article
Products Prepared via Tandem Ozonolysis. The following
were prepared according to the experimental procedures described. All
compounds afforded spectral data identical to values described in the
literature.
ACKNOWLEDGMENTS
■
The research was conducted with funding from the NSF
(CHE-1057982) in facilities remodeled with support from the
NIH (RR016544).
(E)-Ethyl 11-acetoxyundec-2-enoate (via Horner−Emmons
reaction): colorless oil; Rf = 0.5 (10% EA/hex); 1H (400 MHz,
CDCl3) δ 6.98 (1H, dt, 7.0, 15.7), 5.82 (1H, dt, 1.5, 15.6), 4.21 (2H, q,
7.1), 4.07 (2H,t, 6.7), 2.19 (2H, dq, ∼1, 6.7), 2.06 (3H, s), 1.63 (2H,
p, 6.7), 1.47 (2H, p, 6.9), 1.30 (11H, t, 7.1); 13C (100.6 MHz, CDCl3)
δ 171.4, 166.8, 149.4, 121.3, 64.6, 60.1, 32.2, 29.2, 29.1, 29.0, 28.6,
28.0, 25.9, 21.0, 14.3; IR 2929, 2856, 1717 cm−1; HRMS (ESI,
MeOH/H2O, NaOAc), calcd for C15H26NaO4 (M + Na)+ 293.1729,
found 293.1722 (−2.0 ppm).
DEDICATION
Dedicated to the memory of Robert E. Ireland.
■
REFERENCES
■
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(E)-Ethyl 5-phenylpent-2-enoate (via Horner−Emmons reaction):
Rf = 0.7 in (10% EA/hex).38
(E)-Ethyl 4-acetoxybut-2-enoate (via Horner−Emmons reaction):
Rf = 0.4 in (10% EA/hex).39
(E)-Ethyl 7-oxooct-2-enoate (via Horner−Emmons reaction): Rf =
0.7 in (10% EA/hex).40
(Z)-Tridec-5-ene (via Wittig reaction): Rf = 0.92 (10% EA/hex).41
(Z)-Tetradec-5-ene (via Wittig reaction): Rf = 0.70 (10% EA/
hex).41
(Z)-Oct-3-en-1-ylbenzene (via Wittig reaction): Rf = 0.75 (10%
EA/hex).42
2-(1-Hydroxy-3-phenylpropyl)cyclohexanone (via aldol reaction):
Rf = 0.22 (10% EA/hex), isolated as an approximately 3:1 mixture of
anti and syn isomers, determined by comparison on NMR spectra with
literature reports. The stereochemical outcome is very similar to that
reported for corresponding reactions of 3-phenylpropanal.33
2-(1-Hydroxynonyl)cyclohexanone (via aldol reaction): Rf = 0.38
(10% EA/hex), isolated as an approximately 3:1 mixture of anti and
syn isomers, determined by comparison on NMR spectra against
literature reports. The stereochemical outcome is very similar to that
reported for corresponding reactions of analogous aldehydes.34
2-(1-Hydroxyoctyl)cyclohexanone (via aldol reaction): Rf = 0.40
(10% EA/hex).35
Decan-2-ol (via Grignard reaction): Rf = 0.20 (10% EA/hex).43
1-Phenyldecan-1-ol (via Grignard reaction): Rf = 0.26 in (10% EA/
hex).44
2-Phenylnopinol (via Grignard reaction): Rf = 0.20 (10% EA/
hex).45
4-tert-Butyl-1-methylcyclohexanol (via Grignard reaction): Rf =
0.20 (10% EA/hex).46
1,3-Diphenylpropan-1-ol (via Grignard reaction): Rf = 0.22 (10%
EA/hex).47
(12) Kropf, H. In Houben-Weyl Methoden Der Organische Chemie;
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67, 7561.
(15) See, for example: Årstad, E.; Barrett, A. G. M.; Hopkins, B. T.;
1-Phenyloctan-1-ol (via Grignard reaction): Rf = 0.33 (10% EA/
hex).46
1-Phenylhex-5-en-3-ol (via allylation reaction): Rf = 0.8 (10% EA/
hex).48
Dodec-1-en-4-ol (via allylation reaction): Rf = 0.36 (10% EA/
hex).49
Undec-1-en-4-ol (via allylation reaction): Rf = 0.34 (10% EA/
hex).50
Koebberling, J. Org. Lett. 2002, 4, 1975.
ASSOCIATED CONTENT
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units, see ref 3.
■
S
* Supporting Information
1H NMR of known molecules prepared as described above and
characterization (1H, 13C, IR and HRMS) for ethyl 11-acetoxy-
2-undecenoate. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: pdussault1@unl.edu.
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Notes
The authors declare no competing financial interest.
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