Efficient syntheses of climate relevant isoprene nitrates and (1R,5S)-(-)-myrtenol nitrate

Article abstract of DOI:10.3762/bjoc.12.103

Here we report the chemoselective synthesis of several important, climate relevant isoprene nitrates using silver nitrate to mediate a 'halide for nitrate' substitution. Employing readily available starting materials, reagents and Horner-Wadsworth-Emmons chemistry the synthesis of easily separable, synthetically versatile 'key building blocks' (E)- and (Z)-3-methyl-4-chlorobut-2-en-1-ol as well as (E)- and (Z)-1-((2-methyl-4-bromobut-2-enyloxy)methyl)-4-methoxybenzene has been achieved using cheap, 'off the shelf' materials. Exploiting their reactivity we have studied their ability to undergo an 'allylic halide for allylic nitrate' substitution reaction which we demonstrate generates (E)- and (Z)-3-methyl-4-hydroxybut-2-enyl nitrate, and (E)- and (Z)-2-methyl-4-hydroxybut-2-enyl nitrates ('isoprene nitrates') in 66-80% overall yields. Using NOESY experiments the elucidation of the carbon-carbon double bond configuration within the purified isoprene nitrates has been established. Further exemplifying our 'halide for nitrate' substitution chemistry we outline the straightforward transformation of (1R,2S)-(-)-myrtenol bromide into the previously unknown monoterpene nitrate (1R,2S)-(-)-myrtenol nitrate.

Full text of DOI:10.3762/bjoc.12.103

Efficient syntheses of climate relevant isoprene nitrates and
(1R,5S)-(−)-myrtenol nitrate
Sean P. Bew*1, Glyn D. Hiatt-Gipson1, Graham P. Mills2 and Claire E. Reeves2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 1081–1095.
1School of Chemistry, University of East Anglia, Norwich Research
Park, Norwich, NR4 7TJ, UK and 2Centre for Ocean and Atmospheric
Science, School of Environmental Sciences, University of East Anglia,
Norwich Research Park, Norwich, NR4 7TJ, UK
doi:10.3762/bjoc.12.103
Received: 20 October 2015
Accepted: 12 April 2016
Published: 27 May 2016
Email:
Sean P. Bew* - s.bew@uea.ac.uk
Associate Editor: B. Stoltz
* Corresponding author
© 2016 Bew et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
atmospheric chemistry; exchange reaction; halide; isoprene nitrate;
monoterpene
Abstract
Here we report the chemoselective synthesis of several important, climate relevant isoprene nitrates using silver nitrate to mediate a
’halide for nitrate’ substitution. Employing readily available starting materials, reagents and Horner–Wadsworth–Emmons chem-
istry the synthesis of easily separable, synthetically versatile ‘key building blocks’ (E)- and (Z)-3-methyl-4-chlorobut-2-en-1-ol as
well as (E)- and (Z)-1-((2-methyl-4-bromobut-2-enyloxy)methyl)-4-methoxybenzene has been achieved using cheap, ’off the shelf’
materials. Exploiting their reactivity we have studied their ability to undergo an ‘allylic halide for allylic nitrate’ substitution reac-
tion which we demonstrate generates (E)- and (Z)-3-methyl-4-hydroxybut-2-enyl nitrate, and (E)- and (Z)-2-methyl-4-hydroxybut-
2-enyl nitrates (‘isoprene nitrates’) in 66–80% overall yields. Using NOESY experiments the elucidation of the carbon–carbon
double bond configuration within the purified isoprene nitrates has been established. Further exemplifying our ‘halide for nitrate’
substitution chemistry we outline the straightforward transformation of (1R,2S)-(−)-myrtenol bromide into the previously unknown
monoterpene nitrate (1R,2S)-(−)-myrtenol nitrate.
Introduction
Understanding the chemistry of the biosphere and its interac- Plants emit into the biosphere a substantial amount (0.5–2%) of
tion with the atmosphere is fundamental to Earth System their assimilated carbon as small organic molecules. In this
science. Such is the importance of this topic a whole issue of context isoprene is one of the most important compounds
Chemical Reviews was dedicated to the ‘Role of Chemistry in emitted [2], however, many other different types of biogenic
the Earth’s Climate’ [1].
volatile organic compounds (BVOCs) are also generated and re-
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leased. These include monoterpenes, e.g., 1,8-cineole, borneol, pattern on the alkene affords a higher α or branching ratio. A
β-phellandrene, 2-carene, camphene, sabinene and citral; further interesting observation was identified when deuterated
sesquiterpenes, e.g., α-copaene, β-cubebene, α-cedrene, alkenes were employed, in these examples α increased by a
β-selinene, α-farnesene, β-gurjunene, β-muurolene and allo- factor of ~1.5 [10].
aromadendrene, as well as simple alkanes, alkenes, alcohols,
esters, aldehydes, ketones and carboxylic acids [3].
Within the atmosphere a wide range of struturally diverse IPNs
have been identified. However, the formation of IPN mixtures
The quantities of BVOCs released far exceed non-methane has led to uncertainty in quantifying the true effect of isoprene
hydrocarbon emissions derived from anthropogenic activity on the NOx cycle and subsequent O3 enhancement. Shepson et
(~90 Tg C yr−1 where 1 Tg = 1 × 106 tons) [4]. Indeed, al- al. sought to deconvolute this process replicating the atmos-
though early estimates of isoprene emissions were as high as pheric synthesis of IPN using a photochemical reaction chamber
1200 Tg C yr−1 [5] these have, in recent years, been revised to determine IPN yield from isoprene photooxidation and high
down to 600 Tg C yr−1 [6]. Be this as it may, a comprehensive NO concentration. They compared their results with field obser-
understanding of the atmospheric chemistry and kinetics associ- vations, collected during the Southern oxidant and Aerosol
ated with isoprene and its derivatives is largely based on chemi- Study (SOAS) campaign conducted in 2013, and model simula-
cal theory and modeling with very little verified measurements. tions. These studies identified NO as the limiting factor in IPN
Therefore, the impact of isoprene on air quality and climate production [11].
change remains highly uncertain.
Schwantes et al. reported a comprehensive study that focused
Isoprene or 2-methylbuta-1,3-diene is a volatile C5-organic on the oxidation of isoprene with a nitrate radical. Using a
compound generated by plants to help protect them against variety of detection methods, e.g., CIMS and GC-FID they
’attack’ from bacteria, fungi and parasites. Isoprene also helps identified the nitrate radical preferentially reacted at the C1 po-
to protect against abiotic ’stress’ induced by excessive fluctua- sition of isoprene. The resulting intermediate subsequently
tions in temperature, by drought, exposure to radiation as well reacted with oxygen affording a suite of nitroxyalkylperoxy
as by contact with herbicides and insecticides [7]. Isoprene radicals. Worthy of note and a fundamental reason for initiating
reacts readily with O3, HO• and •NO3 with the resulting inter- the UEA study was the fact that Schwantes et al. make refer-
mediates subsequently reacting with NOX, i.e., nitric oxide and ence to the fact that “synthetic standards are not available, the
nitrogen dioxide in a process that generates mixtures of CIMS sensitivities for most of the isoprene nitrates formed in
isoprene nitrates (IPNs), O3 and secondary organic aerosols this work are not known“ [12].
(SOA) [8]. Thus, the formation of IPN mixtures plays a key role
in O3 synthesis and it is this aspect of their chemistry that deter- Organic nitrates are important in locations where biogenic
mines how much NOX is lost or recycled [9].
hydrocarbon emissions mix with anthropogenic NOx sources. It
is generally accepted that transport models should include
Taking all of this into account it is clear that isoprene and representation of organic aerosols derived from the reaction of
isoprene nitrates are important. However, what is still not fully monoterpenes with nitrate radicals. With this in mind Pye et al.
understood is the role of individual IPNs (Scheme 1) on atmos- recently developed a system to study the formation and subse-
pheric chemistry [1-3]. Evidently, to comprehensively investi- quent aerosol-phase partitioning of organic nitrates derived
gate the role of individual IPNs within climate chemistry it is from both isoprene and monoterpenes. Their studies indicated
important that any synthetic protocol employed to generate the concentrations of organic aerosol and gas-phase organic
IPNs affords either individual C=C stereoisomers or generates nitrates increased when particulate organic nitrates underwent
readily separable stereoisomers of the IPNs. Thus although the rapid pseudohydrolysis; a process that generates corrosive nitric
lack of synthetic standards has hindered a comprehensive acid and non-volatile SOA [13].
understanding of IPN climate chemistry, there has been
progress in a number of laboratory, field and theoretical studies Similar to the isoprene studies by Pye et al. the role of organic
that have focused on probing their formation, kinetics, yields nitrates derived from terpenes is starting to gain traction. Rinde-
and decomposition. By way of example, Teng et al. investigat- laub et al. undertook a photochemical reaction chamber
ed the branching ratio (α) when C2–C8 alkenes (including study that focused on the hydroxyl radical oxidation of α-pinene
isoprene) react with HO• in the presence of oxygen. In this under high NOx conditions. α-Pinene is an important
process the generated β-hydroxyperoxy radicals subsequently contributor to SOA with annual emissions estimated to be
react with NO affording β-hydroxy nitrates. The results from 66 Tg C yr−1. In their study using nitric oxide (NO) the yield of
the Teng laboratory established that increasing the substitution α-pinene derived organic nitrate was determined to be 26 ± 7%,
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interestingly the concentration of organic nitrates was found to In the atmosphere isoprene (1) has a half-life of ~1−2 hours
be highly dependent on the relative humidity and seed aerosol [16]. It reacts readily with HO• and O2 generating alkoxy
acidity. Worthy of note this report also highlighted that “unfor- radical (RO•) intermediates (not shown) as well as hydroperoxy
tunately, standards are unavailable for the expected organic radicals (ROO•) such as rac-2 and rac-3 (Scheme 1). The for-
nitrate products (derived from α-pinene)“ this, again, reinforces mation and reaction of these reactive intermediates with NO
the need for chemical synthesis studies on the formation of generates O3 and mixtures of IPNs, i.e., rac-7–(E)-10
climate relevant organic nitrates [14].
(Scheme 1). Contributing to the complexity of the climate
chemistry associated with 1 is its oxidation to ketones, e.g., 11
Even though the atmospheric synthesis of structure diverse and rac-6 and aldehydes, e.g., rac-5, rac-12 and (E)-4.
C5-IPNs, i.e., 4–10 is thought to be efficient, i.e., up to
15% yield [15] what is not currently fully understood is the A comprehensive survey of the literature revealed three general
mechanism or kinetics of IPN formation, the percentages of synthesis routes to IPNs. In summary, Shepson et al. [17]
individual IPNs generated or how they are synthesised and the reacted isoprene epoxide with concentrated nitric acid
products of their decomposition. Answering these important (Scheme 2, path A); Kames et al. outlined the O-nitration of
questions requires the combined expertise of synthetic and simple alcohols using dinitrogen pentoxide [18] (Scheme 2,
atmospheric chemists using the former to generate authentic path B); Cohen et al. reported the application of bismuth(III)
samples of IPNs which can be ’handed over’ to the atmos- nitrate for isoprene epoxide ring-opening/trapping with nitrate
pheric chemists for subsequent testing.
[19] (Scheme 2, path C).
A comprehensive and systematic approach to bespoke IPN syn- The 2010 report by Shepson et al. (path A) exploited chemistry
thesis has yet to be undertaken. Here we outline preliminary originally described by Nichols et al. who, employing nitric
results towards the development of a series of efficient synthe- acid as a convenient and cheap Brønsted acid, transformed a
tic routes to IPNs that should allow atmospheric chemists to range of epoxides [20] into the corresponding nitrato alcohols.
undertake physicochemical analysis of important climate related Shepson substituted ethylene oxide for commercially available
IPNs.
isoprene epoxide and generated eight stereo- and structurally
Scheme 1: Simplified overview outlining how a small number of different IPNs are synthesised and are able to undergo transformations within the
atmosphere.
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Scheme 2: Protocols for the synthesis of O-nitrated alcohols using (±)-isoprene epoxide and 2° alcohols as starting materials.
isomeric IPNs. Within this mixture 3° nitrate rac-7, 1° nitrate specialist gas manifold linked up to a pirani-gauge, capacitance-
rac-8, (E)-13 and (Z)-14 (path A, Scheme 2) were generated pressure transducers and an ozone generator. Additionally once
and separated in the following ratios 31.5:2.43:2.14:1. From a generated the dinitrogen pentoxide requires purification via
purely practical point of view the addition of ’fuming’ nitric sublimation and low temperature recrystallization under a con-
acid to isoprene epoxide is relatively straightforward. However, tinuous stream of ozone and oxygen. Not only is this a time-
several drawbacks to using this protocol are immediately consuming process it also requires considerable experimental
evident. Not least the fact that dispensing strongly oxidizing expertise. Furthermore, although using dinitrogen pentoxide is
’fuming’ (i.e., >90%) nitric acid onto reactive isoprene epoxide suited to the small-scale synthesis of volatile O-nitrate esters,
affords the distinct possibility that a dangerous exothermic such as rac-15, its application to the synthesis of high-boiling
‘runaway’ reaction could take place (cautionary note: experi- diols is more difficult due to their low-vapour pressures.
mental section labelled this reaction “highly exothermic”) or
indeed an explosion if heated (cautionary note: experimental Recently Cohen et al. synthesised mixtures of IPNs via the reac-
reports 2-nitratoethanol underwent a “violent explosion, tion of (±)-isoprene epoxide with pre-ground bismuth(III)
possibly detonation”). Furthermore, although the reaction nitrate [19]. Using a preliminary ’flash’ purification (silica gel)
afforded gram quantities of the IPN mixture the separation and afforded an improved, but still impure, mixture of (E)-13, (Z)-
purification of this into rac-7, rac-8, (E)-13 and (Z)-14 was 14 and 2° O-nitrate ester rac-16. Subsequent purification via an-
restricted to 100 μL aliquots. Furthermore this did not afford the alytical HPLC afforded small quantities of pure (E)-13, (Z)-14
individual products in high purity. Consequently an additional and rac-16 in an overall yield of approximately 10% and in
analytical HPLC purification was required for each ’semi-pure’ 7.3:2.7:1 ratio’s respectively (path C, Scheme 2).
fraction using a substantially smaller 20 μL column. In
summary, this route was time consuming, labour intensive and The goal of our research program was the development of a
expensive affording only small quantities of IPNs.
‘suite of protocols’ that afford specific IPNs using straightfor-
ward, reliable chemistry. Worthy of note, we also considered
In 1993 Kames et al. [18] described the reaction of dinitrogen the development of efficient synthesis routes to small organic
pentoxide with seventeen low molecular weight alcohols. They nitrates to have broader benefits to the general synthesis
demonstrated that dinitrogen pentoxide reacted readily with, for community. By way of example, currently there are very few
example, 1-propanol, 1-hexanol, rac-2-pentanol, 1-octanol and protocols that afford multi-functional allylic nitrates. This, it
that rac-2-butanol afforded rac-2-butyl nitrate (rac-15, path B, would seem, has hindered their exploitation in the development
Scheme 2) although no yields were provided. Unfortunately this of new synthetic methodology. Furthermore and in a slightly
protocol requires the pre-synthesis of dinitrogen pentoxide from different context there is significant interest in the pharmaceuti-
nitric oxide and 5% ozone in oxygen. Evidently the handling cal sector in generating structure and function diverse O-nitrate
and reaction of different gases as well as the synthesis of dini- esters for use as in vivo NO-donors. In this context particular
trogen pentoxide necessitates access to or the construction of a emphasis has been placed on developing O-nitrate esters as bio-
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logically active agents that act on acetylcholinesterase (AChE), ward combination of nitric and sulfuric acid was unsuited to the
amyloid-βx-42 (Aβ42) aggregation, cyclooxygenase-II (COX2), efficient synthesis of IPNs.
serotonin reuptake and specific GAG inhibitors [21-23].
Results and Discussion
Initiating our research we wanted to generate O-nitrate esters
based on rac-8, (Z)-9, (E)-10 (Scheme 1), (E)-13, (Z)-14, and
rac-16 (Scheme 2). Exploring the potential of isoprene as a
starting material we considered it to have several advantages: it
is cheap, commercially available, easily handled and has the
prerequisite C5-skeleton that ensures it is a highly desirable and
amenable starting material for its chemical transformation into
IPNs. Subjecting isoprene (10 mmol) to a racemic Sharpless
dihydroxylation [24] afforded the inseparable (flash chromatog-
raphy) (±)-3-methylbut-3-ene-1,2-diol (rac-17) and (±)-2-
Scheme 3: Attempted synthesis of O-nitrate ester rac-19 and rac-20
synthesis.
methylbut-3-ene-1,2-diol (rac-18) in a 3:2 ratio and unopti-
mized 67% yield (Scheme 3). Investigating O-nitrate ester for-
mation the rac-17/rac-18 mixture was dissolved in dichloro-
methane, acetonitrile, or ether at 0 °C or −78 °C. To each was Although generating a mixture of rac-17 and rac-18 was
added nitric acid (16 M) and concentrated sulfuric acid (18 M), broadly acceptable due to their ease of synthesis, our inability to
a biphasic organic/inorganic reaction mixture formed [25]. effectively separate the diols or execute a regioselective 1° or 2°
Unfortunately after work-up all of these reactions afforded com- mono-O-nitration was not. Eliminating the former problem
plex mixtures. Thus although the 1H NMR and mass spectrome- Hodgson et al. [26] reported rac-17 could be generated from
try indicated the desired mono-O-nitrate rac-19 and rac-20 had cheap, commercially available 2,5-dihydrofuran which, after
formed (Scheme 3) and it seemed that the corresponding di-O- epoxidation with meta-chloroperbenzoic acid (mCPBA),
nitrate esters (not shown) had also formed; all attempts at flash afforded epoxide 21 in a 65% yield. Subsequent reaction of 21
chromatographic separation and purification met with failure; a with methyllithium (2.5 equiv, −78 °C, THF) in an alkylative
fact that hindered our ability to confidently analyse and identify double ring-opening process afforded, exclusively, (±)-3-
individual components. In summary, the seemingly straightfor- methylbut-3-ene-1,2-diol (rac-17) in a 54% yield (Scheme 4).
Scheme 4: Olah et al. O-nitrated alcohol syntheses of 23–33 using N-nitro-2,4-6-trimethylpyridinium tetrafluoroborate (22).
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The next step required the mild regioselective O-nitration of (rac-3-penten-2-ol) were O-nitrated using in situ generated 22
rac-17. Olah et al. reported that nitronium tetrafluoroborate (Scheme 5).
reacts with 2,4,6-trimethylpyridine in acetonitrile at −10 °C
affording N-nitro-2,4,6-trimethylpyridinium tetrafluoroborate Treating 34 and 35, independently, to the Olah O-nitration
(22) [27]. Disappointingly, subjecting rac-17 to O-nitration conditions (MeCN, 0 °C and 1.5 equiv of in situ generated 22)
with in situ generated 22 resulted, as judged by 1H NMR, in a the desired mono-O-nitrated adduct 38 was afforded in a quanti-
very poor yield (<10%) of a mixture of O-nitrate esters that, tative yield in only two hours. On the contrary C=C bond con-
potentially, also included the desired rac-16. Indeed, although taining 3-methylbut-3-ene-1-ol (35) reacted with 22 (1.5 equiv)
we explored alternative reaction times, temperatures, solvents affording (1H NMR) a complex mixture that contained a small
and stoichiometry’s of 22 our attempts at generating rac-16 amount of 39 (Scheme 5). Similar to 34, butanol (36) afforded a
were disappointing. Furthermore, employing short or quantitative yield of n-butyl nitrate (40) in two hours.
longer reaction times at −78 °C afforded low yields of complex Carbon–carbon double bond containing rac-(E)-pent-3-en-2-ol
mixtures that proved, essentially, inseparable by flash (37) generated a complex mixture (determined via 1H NMR) of,
chromatography.
again, largely unidentifiable compounds. Albeit our compare
and contrast study was limited to only a handful of simple sub-
Upon closer inspection of the Olah report we were intrigued by strates it did generate convincing evidence that synthesising
the fact that of the eleven alcohols employed none of the corre- C=C containing IPNs using 22 was problematic. A potential
sponding O-nitrate esters, i.e., 23–33 (Scheme 4) contained a reason for the inability of 22 to cleanly generate 39 or 41 was
non-conjugated ‘isolated’ C=C bond, typical of an allylic associated with the propensity of nitronium salts to mediate
alcohol, i.e., rac-17 (Scheme 4). Intrigued by the possibility it alkene polymerization [28]. An alternative further plausible ex-
was the C=C bond of rac-17 that was contributing, in a nega- planation for failure to isolate the C=C derived O-nitrates
tive sense, to a poor reaction outcome a ‘compare and contrast focuses on a report by Scheinbaum and Dines who established
study’ using paired-up alcohols, i.e., 34 (4-hydroxy-2- that alkenes in the presence of acetonitrile and 22 undergo a
butanone)/35 (3-methyl-3-buten-1-ol) and 36 (butan-1-ol)/37 Ritter reaction affording vicinal nitro acetamido species [29].
Scheme 5: O-nitration study using 22 and the alcohols 34–37.
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Silver nitrate reacts with alkyl, benzyl or acyl halides affording via comparison of our data with that in the literature [28]. Thus
the corresponding alkyl [30], benzyl [31,32] or acyl nitrates in the 1H NMR the downfield shift of the -CH2Cl group from
[33]. By way of example and relevant to the work reported here 4.15 ppm to 4.94 ppm was associated with the installation of
Ogawa et al. [34] transformed bromoacetone to 2-oxopropyl NO3 affording the -CH2ONO2 group. With this positive result
nitrate (component of climate mediated IPN decomposition in hand application of the halide to nitrate transformation within
[35]) using silver nitrate in acetonitrile. Initiating the synthesis the context of IPN synthesis was initiated. Interestingly, al-
of ‘test substrate’ 43 we reacted silver nitrate in acetonitrile though silver nitrate has been widely employed for the synthe-
with the cheap, commercial and readily available chloroacetone sis of structure and function diverse benzyl nitrates; the
in place of the less accessible and considerably more expensive analogous reaction affording allylic nitrates using allylic
bromoacetone. After 16 hours at 40 °C the <15% yield of 43 halide starting materials has, surprisingly, been reported only
was disappointing; it seemed the enhanced reactivity associated once [37].
with bromoacetone was a requirement for an efficient ‘bromide
to nitrate’ substitution. Changing tactics we opted to generate The lack of prior art associated with the synthesis of (E)-2-
the more reactive iodoacetone in situ from chloroacetone (42) methyl-4-bromobut-2-en-1-ol validated the importance of this
and a stoichiometric quantity of tetra-n-butylammonium iodide seemingly valuable starting material and useful building block.
(TBAI). Gratifyingly the iodoacetone reacted readily with silver Indeed it is not commercially available and has been reported in
nitrate at 60 °C affording 43 (Scheme 6) as a yellow oil in an the patent literature only once. Following the procedure of
unoptimized 69% yield. Unfortunately the unstable and reac- Gurumurthy et al. [38] isoprene was reacted with N-bromosuc-
tive properties of 43 meant purification was not straightforward cinimide (NBS, 44) in water at 8–10 °C for 2 h. The reaction
[36]. However installation of the nitrate group was confirmed afforded a mixture of two allylic bromides and two allylic alco-
hols in a combined 42% yield, these were tentatively assigned
as (E)-45, (Z)-46, rac-47 and rac-48 (route A, Scheme 7). All
attempts at separating this mixture using flash column chroma-
tography were unsuccessful. Repeating this reaction but with
N-chlorosuccinimide (NCS, route B, [39]) or alternatively using
iodine and silver(I) oxide (route C, [40]) we considered the pos-
sibility that the resulting allylic chlorides or iodides may be
Scheme 6: Silver nitrate mediated synthesis of 2-oxopropyl nitrate 43.
more amenable to separation. Utilizing a procedure reported by
Scheme 7: Application of isoprene for the synthesis of precursors to IPNs and synthesis via ‘halide for nitrate exchange’ of rac-7, rac-8, (E)-13 and
(Z)-14.
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Koo et al. [39] isoprene and NCS were stirred in aqueous DMF vent removal and analysis via 1H NMR indicated the IPNs had
at ambient temperature for 4 hours. 1H NMR analysis indicated formed. Subjecting the mixture to flash column chromatogra-
that (E)-49, (Z)-50, rac-51 and rac-52 had formed. Disappoint- phy and, similar to previous reports, it was not possible to sepa-
ingly our attempts at isolating and purifying the individual com- rate (E)-13, (Z)-14, rac-7 or rac-8 and it was therefore not
ponents were only partially successful. Thus although rac-51 possible to determine, unambiguously, if all of the above had
and rac-52 could be separated, (E)-49 and (Z)-50 could not.
been formed. Nevertheless physicochemical analysis of the
‘purified’ mixture (54% yield) indicated the O-nitrate esters
Disappointed with this outcome we opted to react isoprene with were present with distinctive FTIR absorption peaks located at
a combination of iodine and silver(I) oxide in aqueous aceto- 1635 and 1278 cm−1. Furthermore changes in the 1H NMR
nitrile. Our intention was to generate a mixture of, hopefully, chemical shifts compared to the starting materials as well as
separable allylic alcohols and allylic iodides. Interestingly this GC–MS analysis (negative ion mode) corroborated the
alternative protocol afforded only two of the possible four prod- O-nitrate ester groups were present.
ucts. Thus terminal alkene derived 1-iodo-2-methylbut-3-en-2-
ol (rac-53) and 2-iodo-2-methylbut-3-en-1-ol (rac-54) were Although the use of silver nitrate had been validated in our
afforded in a 9:1 ratio, respectively, and a pleasing 72% yield ‘test’ reaction, the use of isoprene as a starting material was
(route C, Scheme 7). Analysis via 1H NMR afforded no evi- clearly not as convenient as first envisaged. Its application was
dence for the formation of (E)- or (Z)-2-methyl-4-iodo-2-but-2- restricted by its propensity to generate difficult to separate
en-1-ol. Needless to say the formation of rac-53 and rac-54 was structure and stereoisomeric mixtures of allylic bromides and
of little benefit as their separation proved impractical via flash alcohols, e.g., (E)-45–rac-48. We contemplated using Wittig or
column chromatography.
Horner–Wadsworth–Emmons (HWE) chemistry to construct
(E)-alkyl 3-methyl-4-chlorobut-2-enoates which [41-43]
As noted (Scheme 2) the efficient separation of (E)-13 and (Z)- possessing a chemically differentiated C=C bond (appended at
14 was not possible without recourse to analytical HPLC [9]. one end with a chloromethylene and the opposing end an ester)
Nevertheless we considered it important to validate our pro- should allow the chemoselective reduction of the ester to the
posed ‘halide for nitrate’ substitution by undertaking a ‘test’ corresponding 1° alcohol. This we predicted would allow,
reaction using silver nitrate and the allylic bromide/allylic depending on the starting material employed, the synthesis of
alcohol mixture (E)-45–rac-48. Dissolving this in acetonitrile either (E)-3-methyl-4-chlorobut-2-en-1-ol ((E)-60) or (Z)-3-
the reactants were protected from light by wrapping the flask in methyl-4-chlorobut-2-en-1-ol ((Z)-61, Scheme 8). Reacting tri-
aluminium foil and one equivalent of silver nitrate was added. phenylphosphine with 1-((2-bromoethoxy)methyl)-4-methoxy-
The reaction was stirred for 5 hours at ambient temperature benzene (55) generated non-stabilized phosphonium ylide (2-(4-
after which the reaction was complete, a simple filtration re- methoxybenzyloxy)ethyl)triphenylphosphonium bromide (56),
moved the silver bromide that had generated. Subsequent sol- we envisaged its subsequent deprotonation and addition to
Scheme 8: Synthesis of (E)-3-methyl-4-chlorobut-2-en-1-ol ((E)-60) and (Z)-3-methyl-4-chlorobut-2-en-1-ol ((Z)-61).
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chloroacetone would afford (E)-1-((2-methyl-4-chlorobut-2- silver nitrate added. After stirring for 16 hours at ambient tem-
enyloxy)methyl)-4-methoxybenzene (57). Inclusion of the perature a sample was removed for 1H NMR analysis. This in-
PMB-ether was beneficial due to the ease with which it can be dicated approximately 15% of (E)-60 had been consumed.
cleaved using readily available reagents, e.g., DDQ or CAN and Enhancing the sluggish reactivity of (E)-60 a catalytic amount
mild conditions [44]. The synthesis of the previously unknown of sodium iodide (10 mol %) was added (presumably gener-
56 [45] was high yielding, i.e., 87% yield (Scheme 8). Howev- ating in situ the corresponding allylic iodide). After stirring for
er despite numerous attempts employing different bases [46], a further 16 hours, the majority of (E)-60 had reacted as judged
e.g., NaH, LHMDS, t-BuOK, as well as reaction temperatures, by TLC and 1H NMR analysis. Removing the sodium chloride
e.g., 0 °C and −78 °C and solvents, e.g., THF and ether all our via a simple filtration was more advantageous than the previ-
efforts at generating 57 failed, affording instead highly ously employed organic soluble and more expensive TBAI
coloured, complex mixtures (1H NMR) that were difficult to (Scheme 6). Straightforward flash-column purification afforded
purify. Whilst researching alternative organophosphorous medi- (E)-10 in an unoptimized 60% yield and with physicochemical
ated C=C bond forming reactions that incorporated chloroace- properties similar to those reported [9].
tone the synthesis of 3-methyl-4-chlorocrotonic ethyl ester via a
Horner–Wadsworth–Emmons reaction caught our attention Confident our silver nitrate mediated halide substitution
[47]. Changing tack and in a slightly modified procedure to that protocol was robust, attention switched to incorporating (Z)-3-
originally reported by Fujiwara et al. triethyl phosphonoacetate methyl-4-chlorobut-2-en-1-ol ((Z)-61). Employing a sodium
was deprotonated (NaH) and the resulting stabilised ylide (not iodide enhanced reaction (10 mol %) using 16 mmol of (E)-61
shown) reacted by slow addition of chloroacetone in THF. It afforded 1.4 g of (Z)-2-methyl-4-hydroxybut-2-enyl nitrate ((Z)-
was important in establishing high yields of (E)-58 and (Z)-59 9) in an unoptimized 60% yield. Comparing the 1H NMR data
to use a syringe pump. This helped to minimise the number and associated with (E)-10 and (Z)-9 revealed they were, as ex-
amounts of side-products formed via, presumably, the enolate pected, broadly similar (see Supporting Information File 1).
of chloroacetone which likely undergoes rapid secondary reac- However, subtle chemical shift differences were evident, most
tions. Subsequent work-up and purification afforded stereoiso- notably with those associated with the CH3 attached to the C=C
mers (E)-58 and (Z)-59 in a 2:1 ratio, respectively, and bond, i.e., 1.75 ppm ((E)-10) and 1.84 ppm ((E)-9); similarly
combined, unoptimized, 71% yield.
the CH2ONO2 groups were located at 4.84 ppm for (E)-10 and
4.97 ppm for (Z)-9. Substantiating our tentative carbon–carbon
Separation of the stereoisomers via flash column chromatogra- double bond stereochemical assignment for (Z)-9 and (E)-10
phy was straightforward. Pure (E)-58 and (Z)-59 were afforded was important. Homonuclear two-dimensional NOE spectrosco-
with physicochemical properties essentially identical to those py (NOESY) was used to explore the C=C double bond config-
reported [48]. Taking (E)-58 and (Z)-59 forward their reduction uration. (E)-10 displayed two NOE interactions between the
to (E)-60 and (Z)-61 using DIBAL-H (−78 °C) was uncompli- alkene proton and the methylene groups of the adjacent
cated. The corresponding (E)- and (Z)-allylic alcohols were -CH2OH and -CH2ONO2 (see ‘double-headed arrows’,
afforded in 87% and 81% yields, respectively. The physico- Scheme 9). In (Z)-9 the alkene proton had an NOE interaction
chemical properties of (E)-60 were essentially identical to those with the adjacent CH3 (see red arrow, Scheme 9) and the meth-
reported [49]. The potential for (E)-3-methyl-4-chlorobut-2-en- ylene of the -CH2ONO2 group likewise had an observable inter-
1-ol ((E)-60) to react with silver nitrate generating (E)-10 action with the CH3 (see purple arrow). However, unlike (E)-10
(Scheme 1) was investigated. Dissolving it in acetonitrile, the no interaction was observed between the alkene proton and the
flask was wrapped in aluminium foil and one equivalent of methylene of the -CH2OH group. Importantly, the lack of an
Scheme 9: Using NOESY interactions to establish the conformations of the C=C bonds within (E)-10 and (Z)-9.
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Beilstein J. Org. Chem. 2016, 12, 1081–1095.
interaction between the (E)-C=C bound hydrogen on 10 and the Our preliminary ‘halide for nitrate’ results using silver nitrate
‘(E)-CH3‘ group afforded good evidence that 10 was indeed a and allylic chlorides (E)-60 and (Z)-61 were positive and firmly
(E)-configured C=C bond.
established this route as a straightforward method of generating
stereochemically pure IPNs (E)-10 and (Z)-9. It was important
Furthermore comparison of our 1H NMR spectra with the one to complete this preliminary study synthesizing (E)-11 and (Z)-
reported by Lee et al. [19] for structural isomer (E)-4-hydroxy- 12 (Scheme 10), both of which are structural isomers of (E)-10
3-methylbut-2-enyl nitrate ((E-)13, Scheme 2) displayed a and (Z)-9 (Scheme 9). Employing our HWE approach 1-(4-me-
subtle chemical shift difference centred on the methyl group at- thoxybenzyloxy)propan-2-one (63) was easily generated via a
tached to the C=C bond. By way of example, (E)-13 displayed two-step protocol (overall 63% yield) that started with the
the methyl at 1.75(7) ppm whilst we observed the methyl group etherification of sodium para-methoxybenzyl alcolate with
in (E)-10 as a sharp singlet at 1.69 ppm, perhaps more impor- propargyl bromide [50]. The terminal alkyne on 62 was effi-
tantly the alkene proton of silver nitrate generated (E)-10 was ciently transformed into a ketone via an oxymercuration reac-
identified as a triplet (J = 5.8 Hz) at 5.73 ppm compared with tion using a combination of mercury(I) chloride (0.06 mol %)
5.64 ppm (J = 7.2 Hz) for (E)-13. We attempted to further and sulfuric acid (0.35 mol %) in water following the proce-
substantiate our assignment by undertaking a structure search dure of Boger et al. [51]. 63 was afforded in an unoptimized
on SciFinder for (E)-10 comparing the 1H NMR data available 78% yield. Employing the conditions outlined in Scheme 10 63
with ours. However, although 5 papers report (E)-10 none, reacted with the stabilized ylide generated from the deproton-
unfortunately, had any 1H NMR data.
ation of triethyl phosphoacetate with sodium hydride. A sepa-
rable mixture of (E)-64 and (Z)-65 (1.35:1) was afforded in an
A SciFinder search for (Z)-9 afforded 3 references, similar to overall 61% yield from 62.
(E)-10, none reported any 1H NMR data that could be used as
reference spectra. In addition to (E)-13 Lee et al. described [19] DIBAL-H readily reduced the ethyl ester on (E)-64 and (Z)-65
the synthesis and 1H NMR of (Z)-14 the structural isomer of (−78 °C, toluene) affording 1° alcohols (E)-66 and (Z)-67 in
(Z)-9. Comparing their physicochemical data sets similar but 97% and 95% yields, respectively. Increasing the electrophilic
subtle differences were evident. Thus the alkene proton in (Z)- nature of the desired allylic halides (viz. use of allylic chloride
14 was observed as a triplet (J = 7.6 Hz) at 5.45(7) ppm whilst and 10 mol % sodium iodide in Scheme 9) we opted to trans-
in our synthesised (Z)-9 the similarly positioned proton was also form 1° alcohols (E)-66 and (Z)-67 into their corresponding
observed as a triplet but with a smaller coupling constant, e.g., allylic bromides (not shown). This was straightforward and effi-
J = 6.4 Hz located at 5.82 ppm.
cient using phosphorus tribromide in ether at 0 °C. The desired
Scheme 10: Synthesis of isoprene nitrates (E)-11 and (Z)-12 from ketone 63.
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Beilstein J. Org. Chem. 2016, 12, 1081–1095.
(Z)- and (E)-allylic bromides were generated in 95% and The low cost ($1 per gram), ease of use and convenient
97% yields, respectively. Although the allylic bromides were handling associated with silver nitrate coupled with its straight-
readily purified (flash column chromatography) their subse- forward ability to generate (Z)-9–(Z)-12 convinced us to explore
quent reaction with silver nitrate had to be undertaken quickly the synthesis of rac-7, rac-8 (Scheme 1) and rac-16
and, ideally, straight away because of their propensity to de- (Scheme 2). Employing ketone 63 as a readily available ‘core’
composition. Gratifyingly, reacting (E)-1-((2-methyl-4-bromo- starting material its reaction with vinylmagnesium bromide
but-2-enyloxy)methyl)-4-methoxybenzene and (Z)-1-((2- afforded racemic 3° allylic alcohol rac-68 in an 88% yield.
methyl-4-bromobut-2-enyloxy)methyl)-4-methoxybenzene with Subsequent hydroxy group protection using tert-butyl-
silver nitrate in acetonitrile afforded (E)-4-(4-methoxybenzyl- dimethylsilyl chloride and imidazole afforded orthogonally pro-
oxy)-3-methylbut-2-enyl nitrate (70% yield) and (Z)-4-(4-me- tected O-TBDMS/PMB ether rac-69 in a moderate 53% yield.
thoxybenzyloxy)-3-methylbut-2-enyl nitrate (68% yield) as Needless to say the moderate yield was not problematic as rac-
stable, colourless oils. Mild oxidative cleavage of the PMB 68 and rac-69 were readily separable, allowing rac-68 to be
groups using DDQ in wet DCM generated the desired 1° allylic recycled (based on recovered starting material the yield was
alcohol (E)-3-methyl-4-hydroxybut-2-enyl nitrate ((E)-11) and almost quantitative). Oxidative O-PMB deprotection of rac-69
(Z)-3-methyl-4-hydroxybut-2-enyl nitrate ((Z)-12) in 62% and using DDQ in biphasic dichloromethane/water generated
53% yields, respectively (Scheme 10). Analysing the configura- 1° alcohol (±)-2-(tert-butyldimethylsilyloxy)-2-methylbut-3-en-
tion of the C=C bond in (E)-11 and (Z)-12 via NOESY con- 1-ol (70) in a 78% yield (Scheme 11).
firmed, similar to (E)-10 and (Z)-9, the C=C bonds were, as ex-
pected, in the (E)- and (Z)-configurations for 11 and 12 respec- Attempted conversion of the 1° alcohol on rac-70 into the cor-
tively. Further confirmation of these assignments was sought. responding 1° alkyl bromide failed to generate the desired prod-
Referencing our data with that reported by Lee et al. [19] we uct, instead an intractable tar was formed. Changing our ap-
were delighted that (E)-11 and (Z)-12 displayed, within experi- proach Anzini et al. [22] demonstrated tetra-n-butylammonium
mental error, identical 1H NMR spectra. Of note we observed nitrate [17] to be a source of nitrate that was capable of effi-
the isomerization of (Z)-12 to (E)-11 to be rapid (1–2 hours), a ciently mediating an SN2 ‘1° mesylate for nitrate’ substitution,
fact that contrasted quite sharply with the rate of isomerization i.e., 72 to 73 (Scheme 12).
for (Z)-9 to (E)-10 which was, comparatively, quite slow
(~24 hours). Presumably the increased rate of isomerization for Generating the 1° mesylate of rac-70 using methanesulfonyl
(Z)-12 to (E)-11 was associated with relief of the allylic strain chloride and pyridine afforded rac-71 in a 77% yield after
between the (Z)-configured, polar -CH2OH and -CH2ONO2 16 hours at ambient temperature. Unfortunately subjecting it to
groups that reside on the same side of the C=C bond a ‘mesylate for nitrate’ substitution akin to our previously suc-
(Scheme 10).
cessful ‘halide for nitrate’ substitution, cf. (E)-60 to (E)-10
Scheme 11: Attempted synthesis of rac-8 from O-mesylate rac-71.
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Beilstein J. Org. Chem. 2016, 12, 1081–1095.
Scheme 12: Synthesis of O-nitrate 73 from O-mesylate 72.
(Scheme 9) using silver nitrate did not work and starting materi- reaction byproducts had to be undertaken swiftly because of its
al rac-71 was returned in a quantitative yield. Furthermore, we relatively rapid decomposition (10–15 minutes). Negating this,
did consider employing the elevated reaction conditions a quick flash column was undertaken and the resulting ~75%
(110 °C) reported by Anzini et al. but were not confident that pure product was taken on ‘as is’. Employing silver nitrate in
the O-TBDMS protected O-nitrate ester rac-8 if formed would our standard reaction conditions afforded a novel compound
be stable [8]. For this reason we explored transforming rac-71 presumed to be (±)-3-methyl-1-(nitrooxy)but-3-en-2-yl acetate
into O-TBDMS protected rac-8 at ambient temperature using (rac-77) in an unoptimized 70% yield. The final stage of the
silver nitrate in acetonitrile. Unfortunately in contrast to synthesis was the hydrolysis of the O-acetate ester using mild,
previous successful ‘halide for nitrate’ transformations no reac- slightly basic reaction conditions. Thus using potassium
tion was observed with mesylate rac-71 even after extended carbonate in methanol a new alcohol was afforded in an excel-
reaction times. Repeating the reaction but substituting the silver lent 94% yield. Seeking structure confirmation a search on
salt for tetra-n-butylammonium nitrate TLC analysis did indi- SciFinder confirmed rac-19 had been previously reported.
cate, after 24 hours, a small percentage (i.e., ~10%) of rac-8 However inspection of these manuscripts and, more important-
had formed with the remainder comprising rac-71. However ly, their electronic supporting information’s established that no
using flash column chromatography to separate rac-71 from 1H or 13C NMR data associated with rac-19 was available.
the, presumed, 1° nitrate ester was not possible.
It was during these studies that we noticed the 1H NMR data,
Circumventing the lack of reactivity displayed by rac-71 the in reported by Lee et al., for 1° alcohol rac-16 was, within experi-
situ synthesis of a ‘naked’ nitrate containing species, i.e., mental error, identical to the 1H NMR observed for the
[K(18-crown-6)NO3] and its application to mesylate displace- supposed 2° alcohol rac-19 (Scheme 13). It seemed that during
ment was attempted. Premixing potassium nitrate and our attempted synthesis of rac-16 we had in fact generated rac-
18-crown-6 we envisaged would sequester the potassium cation 19. Accounting for this we propose that activation of the
[52] and generate a [K(18-crown-6)NO3] complex. Using aceto- 1° alkyl bromide with silver nitrate generates an electrophilic
nitrile as solvent one equivalent of [K(18-crown-6)NO3] was species similar to rac-78 which in the presence of the proximal
stirred with rac-71. Disappointingly, although a new compound O-acetate generates a 5-membered electrophilic acyloxonium
was generated it accounted for only a small percentage of the species based on rac-79/rac-81. The formation of such species
reaction mixture. The majority of rac-71 had not reacted and from simpler non C=C containing starting materials has been
due to purification issues this route to O-nitrate ester synthesis reported and established (1H NMR) by Gopius et al. [52]. Ac-
was abandoned.
counting for the exclusive formation of O-acetate rac-83 the
trapping of the more stable 2° allyl carbocation intermediate 82
Disappointed with the lack of reactivity displayed by rac-71 we (generated via ring-opening of rac-81) with nitrate is preferable
opted instead to tackle the synthesis of (±)-2-hydroxy-3- to the formation of the higher energy/more unstable 1° carbo-
methylbut-3-enyl nitrate (rac-19). Starting from 3-methyl-2- cation 80 (generated via ring-opening of rac-79, Scheme 13).
buten-1-ol its conversion, on a multigram scale, to (±)-3- Subsequent formation of rac-83 allows its hydrolysis with
(bromomethyl)-2,2-dimethyloxirane (rac-74) was straightfor- potassium carbonate in methanol to generate the observed
ward. Heating rac-74 with a mixture of acetic anhydride and rac-16.
para-toluenesulfonic acid (PTSA, 1 equiv) afforded via,
presumably, protonated rac-75 ring-opened and O-acylated (±)- Isoprene and monoterpenes account for a large percentage of
1-bromo-3-methylbut-3-en-2-yl acetate (rac-76) in a 58% yield. the total emissions that are not non-methane VOCs. Further-
Isolation, solvent removal and purification of rac-76 from the more although monoterpene emissions (127 Tg C yr−1) are sig-
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Beilstein J. Org. Chem. 2016, 12, 1081–1095.
Scheme 13: Attempted synthesis of 2° alcohol containing 1° nitrate ester rac-19 and the unexpected synthesis of (±)-1-hydroxy-3-methylbut-3-en-2-yl
nitrate, rac-16.
nificant lower than isoprene [6] (viz. 600 Tg C yr−1) they are Exploiting our methodology further its diversity and applica-
nonetheless gaining in significance and are now considered to tion to monoterpene derived O-nitrate ester synthesis was
be important contributors to climate chemistry [53]. By way of undertaken using (1R,5S)-(−)-myrtenol (84) which was quickly
example although α-pinene is slightly less reactive to the and efficiently converted into the corresponding optically active
hydroxyl radical (HO•) than isoprene it does, conversely, have a 1° alkyl bromide 85 which, due to its instability, was used ‘as
higher reactivity to O3 and nitrate radicals (•NO3) making its is’ [55]. Employing our standard silver nitrate conditions
atmospheric oxidation significant with respect to regional (1R,5S)-(−)-85 was efficiently transformed into optically active
tropospheric O3 and NOX concentrations. The oxidation O-nitrate ester (1R,5S)-(−)-86 in an unoptimized 80% yield
products derived from monoterpenes have been demonstrated to (Scheme 14). The importance of this preliminary result resides
be important in generating atmospheric based secondary in the increased awareness of the role that monoterpene and
organic aerosols (SOA’s) that have a significant impact on sesquiterpene nitrates have in climate chemistry. Research,
global radiation [54].
however, on their role is, similar to IPNs, severely limited by
Scheme 14: Synthesis of monoterpene derived (1R,5S)-(−)-myrtenol nitrate 86.
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Beilstein J. Org. Chem. 2016, 12, 1081–1095.
6. Gunther, A.; Karl, T.; Harley, P.; Wiedinmyer, C.; Palmer, P. I.;
Geron, C. Atmos. Chem. Phys. 2006, 6, 3181–3210.
doi:10.5194/acp-6-3181-2006
the dearth of convenient protocols capable of generating struc-
ture and function diverse monoterpene and sesquiterpene
nitrates.
7. Vickers, C. E.; Gershenzon, J.; Lerdau, M. T.; Loreto, F.
Nat. Chem. Biol. 2009, 5, 283–291. doi:10.1038/nchembio.158
8. Werner, G.; Kastler, J.; Looser, R.; Ballschmiter, K.
Angew. Chem., Int. Ed. 1999, 38, 1634–1637.
Finally, the kinetics and measurement of the IPNs generated
within this study and their relationship to aspects of atmos-
pheric chemistry have been reported [56].
doi:10.1002/(SICI)1521-3773(19990601)38:11<1634::AID-ANIE1634>3
.0.CO;2-C
9. Emmerson, K. M.; Evans, M. J. Atmos. Chem. Phys. 2009, 9,
1831–1845. doi:10.5194/acp-9-1831-2009
Conclusion
Isoprene, monoterpene and sesquiterpene nitrates are gaining
recognition for their significant roles in climate chemistry how-
ever an efficient route to their synthesis has yet to be developed.
Here we report an efficient silver nitrate mediated synthesis
procedure that is broadly applicable to the production of sought-
after ‘isoprene nitrates’. The general applicability of this proce-
dure has also been confirmed via its application to the first syn-
thesis of a monoterpene nitrate derived from (1R,5S)-(−)-
myrtenol. In the former examples our protocol proceeds via the
application of Horner–Wadsworth–Emmons Chemistry that
generates readily functionalized motifs that undergo an all but
previously non-existent, allylic ‘halide for nitrate’ substitution
reaction. A consequence of the broader importance of organic
nitrates we envisage our ‘halide for nitrate’ synthesis transfor-
mation will be of considerable interest to, not only atmospheric
chemists, but also the wider synthetic and medicinal chemistry
communities.
10.Teng, A. P.; Crounse, J. D.; Lee, L.; St. Clair, J. M.; Cohen, R. C.;
Wennberg, P. O. Atmos. Chem. Phys. 2015, 15, 4297–4316.
doi:10.5194/acp-15-4297-2015
11.Xiong, F.; McAvey, K. M.; Pratt, K. A.; Groff, C. J.; Hostetler, M. A.;
Lipton, M. A.; Starn, T. K.; Seeley, J. V.; Bertman, S. B.; Teng, A. P.;
Crounse, J. D.; Nguyen, T. B.; Wennberg, P. O.; Misztal, P. K.;
Goldstein, A. H.; Guenther, A. B.; Koss, A. R.; Olson, K. F.;
de Gouw, J. A.; Baumann, K.; Edgerton, E. S.; Feiner, P. A.; Zhang, L.;
Miller, D. O.; Brune, W. H.; Shepson, P. B. Atmos. Chem. Phys. 2015,
15, 17843–17886. doi:10.5194/acpd-15-17843-2015
12.Schwantes, R. H.; Teng, A. P.; Nguyen, T. B.; Coggon, M. M.;
Crounse, J. D.; St. Clair, J. M.; Zhang, X.; Schilling, K. A.;
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13.Pye, H. O. T.; Luecken, D. J.; Xu, L.; Boyd, C. M.; Ng, N. L.;
Baker, K. R.; Ayres, B. R.; Bash, J. O.; Baumann, K.; Carter, W. P. L.;
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Experimental.
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