Fluorine in pheromones: Synthesis of fluorinated 12-dodecanolides as emerald ash borer pheromone mimetics

Article abstract of DOI:10.1016/j.tet.2019.03.025

A series of five 12-dodecanolides have been synthesised containing CF₂ groups at C5, C6, C7, C8 and in one case, a double substitution at C5 & C8, as a strategy to bias the conformational space accessed by these macrocycles, and to assess if th

Full text of DOI:10.1016/j.tet.2019.03.025

Accepted Manuscript
Fluorine in pheromones: Synthesis of fluorinated 12-dodecanolides as emerald ash
borer pheromone mimetics
Qingzhi Zhang, Charlotte S. Teschers, Ricardo Callejo, Mingyan Yang, Mingan Wang,
Peter J. Silk, Krista Ryall, Lucas E. Roscoe, David B. Cordes, Alexandra M.Z. Slawin,
David O'Hagan
PII:
S0040-4020(19)30300-X
https://doi.org/10.1016/j.tet.2019.03.025
TET 30211
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 28 January 2019
Revised Date: 6 March 2019
Accepted Date: 12 March 2019
Please cite this article as: Zhang Q, Teschers CS, Callejo R, Yang M, Wang M, Silk PJ, Ryall K,
Roscoe LE, Cordes DB, Slawin AMZ, O'Hagan D, Fluorine in pheromones: Synthesis of fluorinated
12-dodecanolides as emerald ash borer pheromone mimetics, Tetrahedron (2019), doi: https://
doi.org/10.1016/j.tet.2019.03.025.
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ACCEPTED MANUSCRIPT
Fluorine in pheromones: Synthesis of fluorinated 12-dodecanolides as
Emerald Ash Borer pheromone mimetics

ACCEPTED MANUSCRIPT
Fluorine in pheromones: Synthesis of fluorinated 12-
dodecanolides as Emerald Ash Borer pheromone mimetics
Qingzhi Zhang,a Charlotte S. Teschers,a Ricardo Callejo,a Mingyan Yang,a,b
Mingan Wang,b Peter J. Silk,c Krista Ryall,c Lucas E. Roscoe,d David B
Cordes,a Alexandra M. Z. Slawin,a David O’Hagana*
a
School of Chemistry, University of St. Andrews, North Haugh, St. Andrews, Scotland KY16 9ST
Department of Applied Chemistry, College of Science, China Agricultural University, No.2 Yuanmingyuan
West Road, Haidian District, Beijing , P. R. China 100193
Canadian Forest Service, Insect Chemical Ecology, Atlantic Forestry Centre, 1350 Regent Street, P.O. Box
4000, Fredericton, New Brunswick, E3B 5P7
Canadian Forest Service, Great Lakes Forestry Centre, 1219 Queen Street East, Sault Ste Marie, Ontario
P6A 2E5.
b
c
d
ABSTRACT
A series of five 12-dodecanolides have been synthesised containing CF2 groups at C5, C6,
C7, C8 and in one case a double substitution at C5 & C8, as a strategy to bias the
conformational space accessed by these macrocycles, and to assess if the analogues may act
as mimetics for 12-decenolide pheromones associated with the Emerald Ash Borer.
Accordingly individual syntheses of 5,5-difluoro- 5, 6,6-difluoro- 6, 7,7-difluoro- 7, 8,8-
difluoro- 8 and 5,5,8,8-tetrafluoro- 9, 12-decanolides is outlined and X-ray structural data
was obtained for three (5, 8 and 9) of these compounds. The structures show clearly that the
CF2 groups occupy ‘corner’ locations in the macrocycle consistent with their ability to bias
accessible conformations. The fluorine containing 12-dodecanolides all generated an
electro-antennogram response in female beetles.
Keywords:
Insect pheromones
Emerald ash borer
Organofluorine chemistry
12-Decanolides
Electroantennogram (EAD) analyses
1. Introduction
Fluorine is rarely encountered in natural products [1] and there are no examples
known of insect pheromones containing fluorine; its occurrence in organic chemistry is
almost exclusively anthropogenic. In that context fluorine has been widely and successfully
employed to improve properties and efficacy in the design of pharmaceuticals products [2]
and it would seem reasonable by extension that the strategic incorporation of fluorine into
insect pheromone analogues may offer prospects as a design strategy for improving the
efficacy of pheromone analogues. Such practice has however been slow to gain traction, and
where fluorine has been explored in this context, outcomes have been mixed and
unpredictable [3]. Almost always the fluorine has directly replaced an aliphatic hydrogen
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and clear cut improvements are rare [3 - 8]. This has much to do with the pheromones
themselves already being optimal as they are highly evolved natural products and fluorine
not being a very good hydrogen mimetic from a steric and electronic perspective.
Differences in molecular volatility must also be anticipated with the molecular weight
increase. Undeterred we have explored a new approach incorporating the fluorine as a
means to limit the conformational flexibility of a macrocyclic pheromone and we report our
synthesis and preliminary evaluation of the efficacy of a series of analogues in this paper.
The emerald ash borer (EAB), Agrilus planipennis Fairmaire (Coleoptera: Buprestidae), is a
wood boring beetle native to East Asia, however it has become a serious invasive pest in
North America, causing extensive mortality to ash trees when it emerged on the continent in
2002 [9]. Currently it has spread to 31 States in the U.S. and across five Canadian Provinces.
Western Europe is also under threat with its recent emergence in Russia [10]. The plant
volatiles and pheromones such as 1 - 4 which stimulate the EAB have become relevant for
developing strategies for monitoring and control [11]. (3Z)-Dodecen-12-olide 2 was
identified as a key antennally-active compound produced primarily by females to attract
males [11,12]. Similarly, the non-natural stereoisomer (3E)-dodecen-12-olide 3, and the
saturated dodecanolactone 4, also showed similar activities towards male EAB [13].
Fluorine has advantages as a hydrogen mimetic for bioactives in that it is sterically compact,
and it does not enter into strong intermolecular interactions [14]. However the introduction
of fluorine is never neutral. Fluorine is significantly larger than hydrogen based on van der
Waals radii (F = 1.47Å versus H = 1.2Å) [15] and we have established that the -CF2- group
tends to dictate corner positions when it is incorporated into aliphatic rings, and particularly
in medium sized macrocyclic ring compounds [16]. This is a consequence of the larger size
of fluorine over hydrogen, avoiding transannular interactions relative to hydrogen, and also
the electronegativity of fluorine changing the hybridisation towards sp2 at the directly bound
carbon and widening the C-CF2-C angle, often close to sp2 hybridisation [16b]. We have
recently explored replacing one or two CH2 groups by CF2 in various macrocyclic lactones
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such that the stereoelectronic influence of the fluorines might limit conformational
flexibility and help provide some insight into favoured bioactive conformations of fragrance
lactone and ketones such as muscone [17a] and musk lactones [17b,c]. We now report the
synthesis of the CF2 containing 12-dodecanolides 5-9 (Figure 4), where the CF2 groups are
variously positioned around the lactone ring. The fluorines should place conformational
constraints into these molecules at different locations, as an alternative strategy to
introducing double bonds of defined geometry such as is found in 2 and 3. Compounds 5 - 9
underwent preliminary electroantennography (EAG) analyses, comparing the relative
sensitivity of the fluorinated lactones to female beetles.
2.
Result and Discussion
Synthesis: The synthesis of the 12-dodecanolide 6, was accomplished as illustrated in
Scheme 1. Full experimental details are given in the extensive Supplementary Information.
A key reaction involved DAST treatment of propargylic ketone 13 to generate
difluoromethylene 14, following previously developed protocols [18]. Orthogonal
deprotection allowed release of alcohol 15 which was oxidised to carboxylic acid 16.
Hydrogenation then released an alcohol at the other terminus of the chain, with concomitant
reduction of the acetylene to generate fatty acid 17, which was cyclised to generate 12-
dodecanolide 6. The routes to analogues 7 and 8 are illustrated in Scheme 2. Their syntheses
were accomplished in a similar manner to that described for target 6, but differed by
manipulating the chain lengths of the aldehydes and terminal acetylenes used to generate
propargylic alcohols 22 and 23. In order to access 12-dodecanolide 5, the protecting group
strategy was controlled by introducing a triisopropylsilyl ether (TIPS group) [19], such that
oxidation could be achieved at the opposite end of the chain with respect to the previous
syntheses.
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Scheme 1. Preparation of 6,6-difluorododecanolactone. Reagents and conditions: a) PCC, DCM, rt, 52%; b)
PMBO(CH2)3C≡CH, BuLi, THF, -78°C to rt, 87%; c) IBX, DMSO, rt, overnight, 80%; d) DAST, 50°C, 42%;
e) DDQ, wet DCM, rt, 23%; f) PhI(OAc)2, TEMPO, CH3CN/H2O, 44%; g) H2, 10% Pd/C, THF, 100%; h)
2,4,6-trichlorobenzoyl chloride, Et3N, THF, DMAP, toluene, rt, 44%.
OH
HO
OPMB
m
O
18 m = 5
19 m = 6
OPMB
m
a
OPMB
m
BnO
a
n
BnO
b
n
22 m = 5, n = 2
23 m = 6, n = 1
24 m = 5, n = 2
25 m = 6, n = 1
OPMB
O
m
20 m = 5
21 m = 6
O
F
F
F
F
F
F
d
OPMB
m
e
OH
c
OH
m
m
BnO
BnO
n
BnO
n
n
26 m = 5, n = 2
27 m = 6, n = 1
28 m = 5, n = 2
29 m = 6, n = 1
30 m = 5, n = 2
31 m = 6, n = 1
h
F
F
F
F
O
F
F
F
F
f
g
HO
or
OH
m
OTIPS
6
n+3
BnO
32 m = 5, n = 2
33 m = 6, n = 1
O
O
O
34
O
8
7
F
F
O
O
F
F
F
F
3
F
F
i
e
j
g
HO
HO
OTIPS
5
HO
OH
OTIPS
O
3
6
4
6
6
O
36
37
35
Scheme 2. Preparation of 7,7- , 8,8- and 5,5-difluorododecanolactone 7, 8, 5. Reagents and conditions: a) IBX,
DMSO, rt, 64% for 20, 83% for 21, 92% for 24, 78% for 25; b) BnO(CH2)3C≡CH or BnO(CH2)2C≡CH, BuLi,
THF, -78°C to rt, 60% for 22, 70% for 23; c) DAST, 50°C, 55% for 26 and 27; d) CAN, CH3CN, H2O, rt, 82%
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for 28, 81% for 29; e) PhI(OAc)2, TEMPO, CH3CN/H2O, 80% for both 30 and 31, 90% for 36; f) H2, 5% Pd/C,
THF, 71% for 32 and 57% for 33; g) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, DMAP, toluene, rt, 52% for
7, 63% for 8, 32% for 5; h) triisopropylsilyl chloride, imidazole, DCM, rt, 90%; i) H2, 10% Pd/C, THF, 76%; j)
TBAF, THF, 50°C, 79%.
The preparation of 5,5,8,8-tetrafluorolactone 9 proved to be the most demanding synthesis
certainly in terms of the length of the linear sequence and the route is illustrated in Scheme 3.
The difluoromethylene groups were introduced also by DAST reaction of a propargyl ketone
[18] in a sequential manner to generate the orthogonally protected diacetylene 47, with both
difluoromethylene groups installed. The p-methoxybenzyl group (PMB) was removed and
replaced by TIPS and then a key hydrogenation step, using palladium on carbon cleaved the
terminal benzyl ether with concomitant saturation of both acetylene bonds, to generate
aliphatic alcohol 50. An oxidation to carboxylic acid 51, ω-deprotection to alcohol 52 and
then cyclisation gave the desired macrolide 9.
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BnO
b
a
HO
O
OPMB
OPMB
OPMB
OPMB
38
39
40
OH
BnO
BnO
BnO
c
a
d
OPMB
41
O
F
F
42
44
BnO
a
OH
O
43
F
F
F
F
a
BnO
OH
a
BnO
O
e
F
F
OPMB
F
F
45
OPMB
46
BnO
BnO
d
F
F
F
F
c
F
F
F
F
F
OH
OPMB
47
48
BnO
F
F
F
g
f
HO
OTIPS
F
F
F
F
OTIPS
49
50
F
F
F
F
HO
i
h
OTIPS
HO
OH
F
F
O
F
F
O
52
51
j
F
F
F
F
O
9
O
Scheme 3. Preparation of 5,5,8,8-tetrafluorododecanolactone 9. Reagents and conditions: a) IBX, DMSO, rt,
75% for 39, 78% for 41, 72% for 44, 60% for 46; b) BnO(CH2)2C≡CH, BuLi, THF, -78°C to rt, 83%; c)
DAST, 50°C, 43% for 42, 75% for 47; d) CAN, CH3CN, H2O, rt, 96% for 43, 77% for 48; e)
PMBO(CH2)2C≡CH, BuLi, THF, -78°C to rt, 49%; f) triisopropylsilyl chloride, imidazole, DCM, rt, 97%; g)
H2, 10% Pd/C, THF, 2h, 47%; h) PhI(OAc)2, TEMPO, CH3CN/H2O, 64%; i) HF-pyridine, THF, 50%; j) 2,4,6-
trichlorobenzoyl chloride, Et3N, THF, DMAP, toluene, rt, 50%.
X-Ray structure analysis: Of the five compounds prepared in this study, 6 and 7 were
colourless oils, 5 and 8 were semi-solids at room temperature and notably 12-dodecanolide
9, with two CF2 groups, was a crystalline solid. In the event the three lactones 5, 8 and 9
proved amenable to X-ray analysis and the resultant structures are shown in Figure 1. It is
clear from these structures that in all cases the CF2 groups occupy corner locations, certainly
6

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in the solid state, consistent with our previous conclusions on thermodynamically favoured
location of the CF2 groups in rings. Compounds 5 and 9 have a common C(5)F2 group and
they adopt almost identical solid state conformations.
Fig. 1 Representations of the X-ray derived structure of 12-dodecanolides 5, 8 and 9. In all
cases the CF2 groups adopt corner locations in the solid state.
Bioactivity screening: Electroantennogram-detection (EAD) analyses [13] were conducted
to determine if one or more of the 12-dodecanolides were detectable to adult female A.
planipennis beetles. Ten adult insects (7-10 days old) were used in the study. All five 12-
dodecanolides 5-9 as well as a hexane (Sigma Aldrich, 99%) control and the female
pheromone, (3Z)-dodecen-12-olide 2 were used for each antenna. Concentrations of the 12-
fluorine containing dodecanolides 5-9 and pheromone 2 were about 4mM (1mg/ml) with the
stimulus source concentration for each compound at 3 ꢀg. The order in which the
compounds were applied to each antenna was randomly assorted for each antennal
preparation.
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Fig 2. Electroantennogram-detection (EAD) analyses of 12-dodecanolides 5-9 of the
antennae of female A. planipennis beetles against hexane and the pheromone, 3Z-lactone 2.
After Log transformation of multiple measurements followed by a one-way ANOVA
analysis, a post-hoc Tukey HSD test was then applied to compare pairs of compounds, to
identify which pair-wise comparisons gave significantly different responses. This analysis
demonstrated significant stimulatory differences for all of the fluorinated 12-decanolides
relative to the hexane control, with the most significant responses being detected for
decanolides 7, 8 and 9. Notably there was a significant difference between 12-decanolides 5
and 9 despite having similar solid state conformations, the latter having an additional CF2 at
C-8. This difference may indicate a poorer performance for the more conformationally
flexible decanolide 5.
3. Conclusion
In this study we have synthesised five 12-decanolides 5-9 each carrying CF2 groups at
different locations around the macrolide ring. These compounds are new analogues of the
pheromones of the Emerald Ash Borer, a significant pest in North American and Canadian
forests. Three of these compounds were amenable to X-ray structure analysis and reinforced
the hypothesis that the CF2 groups will adopt corner locations in aliphatic ring systems,
placing limitations on the accessible conformational space in each case. In the event all of
the compounds gave a positive EAD response with female EAB beetle antenna, with several
showing similar levels of stimulatory activity to the natural pheromone, (3Z)-dodecen-12-
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olide 2. Thus the fluorines do not have a significantly negative effect and indeed the
analogue 9 carrying four fluorines, with two conformationally biasing CF2 groups, recorded
a similar stimulatory response to pheromone 2. This analogue might have been expected to
suffer most detrimentally in the context of reduced volatility. The results provide some
support to the developing hypothesis that correctly biasing conformation, in this case with
CF2 group, can improve pheromone efficacy.
4. Experimental Section
General procedure for the last step of the synthesis of 12-decanolides 5-9. Triethylamine
(15.0 equiv.) and 2,4,6-trichlorobenzoyl chloride (10.0 equiv.) were added to a solution of
12-hydroxydodecanoic acid bearing CF2 group(s) (17, 32, 33, 37, 52) (1.0 equiv., 2 mM) in
dry THF at room temperature under an argon atmosphere. The reaction mixture was stirred
for 2 h and then the mixture was diluted with dry toluene (half volume of THF) and added
over 2 h using syringe pump to a solution of 4-DMAP (20 equiv., 70 mM) in dry toluene. The
reaction mixture was stirred at room temperature for 12 h and then quenched with sat. aq.
NaHCO3 solution and diluted with DCM. The organic layer was separated and the aqueous
was extracted into DCM. The combined organic layers were washed with brine, dried over
anhydrous MgSO4 and the solvent was removed under reduced pressure. Purification by
column chromatography using silica gel (hexanes/EtOAc 15:1) gave the lactones 5-9.
X-ray diffraction data for 5, 8 and 9 were collected at 173 K using a Rigaku MM-007HF
High Brilliance RA generator/confocal optics with XtaLAB P100 diffractometer [Cu Kα
radiation (λ = 1.54187 Å)]. Intensity data were collected using both ω and φ steps
accumulating area detector images spanning at least a hemisphere of reciprocal space. Data
for all compounds analysed were collected and processed (including correction for Lorentz,
polarization and absorption) using CrystalClear [20]. Structures were solved by direct
methods (SIR2011) [21] and refined by full-matrix least-squares against F2 (SHELXL-
2016/4) [22]. Non-hydrogen atoms were refined anisotropically, and hydrogen atoms were
refined using a riding model. All calculations were performed using the CrystalStructure [23]
interface. CCDC 1891108-1891110 contains the supplementary crystallographic data for this
paper. The data can be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/structures.
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1
5,5-Difluorododecanolactone (5). Colourless wax (32%). H NMR (400 MHz, CDCl3) δH
1.38-1.97 (m, 16H, 8 × CH2), 2.40-2.43 (m, 2H, CH2CO), 4.17-4.19 (m, 2H, CH2O); 13C
NMR (100 MHz, CDCl3) δC 19.1 (t, 3JCF = 5.7 Hz CH2,), 20.8 (t, CH2, 3JCF = 5.7 Hz), 24.6
(CH2), 25.9 (CH2), 26.5 (CH2), 27.2 (CH2), 33.3 (t, 2JCF = 25.2 Hz, CH2), 34.2 (t, 2JCF = 25.7
Hz, CH2), 65.5 (CH2O), 125.9 (t, 1JCF = 246.9 Hz, CF2), 172.8 (C=O); 19F{1H} NMR (377
MHz, CDCl3) δF -91.2 (s, CF2), 19F NMR (377 MHz, CDCl3) δF -91.2 (p, J = 15.0 Hz, CF2);
HRMS (ESI+) 257.1322 [M+Na]+, C12H20F2O2Na requires 257.1329.
X. Ray data; C12H20F2O2, M = 234.29, monoclinic, a = 12.188(3), b = 6.4319(10), c =
16.142(3) Å, β = 106.701(6) °, U = 1212.0(4) Å3, T = 173 K, space group P21/n (no. 14), Z =
4, 12204 reflections measured, 2185 unique (Rint = 0.0986), which were used in all
calculations. The final R1 [I > 2σ(I)] was 0.0550 and wR2 (all data) was 0.1402.
6,6-Difluorododecanolactone (6). Colourless oil (44%). 1H NMR (400 MHz, CDCl3) δH
1.37-1.55 (m, 8H, 4 × CH2), 1.66-1.77 (m, 4H, 2 × CH2), 1.82-1.97 (m, 4H, 2 × CH2CF2),
2.38-2.41 (m, 2H, CH2CO), 4.16-4.18 (m, 2H, CH2O); 13C NMR (100 MHz, CDCl3) δC 20.2
(t, 3JCF = 5.6 Hz, CH2), 22.0 (t, 3JCF = 5.6 Hz, CH2), 24.2 (CH2), 24.5 (CH2), 26.6 (CH2), 27.1
(CH2), 32.7 (t, 2JCF = 25.3 Hz, CH2), 33.8 (CH2), 34.3 (t, 2JCF = 25.7 Hz, CH2), 64.9 (CH2O),
126.4 (t, 1JCF = 239 Hz, CF2), 173.6 (C=O); 19F{1H} NMR (376 MHz, CDCl3) δF -90.5 (s,
CF2); 19F NMR (376 MHz, CDCl3) δF -90.5 (p, J = 15.2 Hz, CF2); HRMS (ESI+) 257.1322
[M+Na]+, C12H20F2O2Na requires 257.1324.
7,7-Difluorododecanolactone (7). Colourless oil (52%). 1H NMR (400 MHz, CDCl3) δH
1.42-1.59 (m, 8H, 4 × CH2), 1.71-1.77 (m, 4H, 2 × CH2), 1.84-1.97 (m, 4H, 2 × CH2CF2),
2.41-2.44 (m, 2H, CH2CO), 4.20-4.22 (m, 2H, CH2O); 13C NMR (100 MHz, CDCl3) δC 21.3
(t, 3JCF = 5.6 Hz, CH2), 21.8 (t, 3JCF = 5.6 Hz, CH2), 23.6 (CH2), 25.8 (CH2), 26.6 (CH2), 27.5
(CH2), 33.1 (t, 2JCF = 25.3 Hz, CH2), 34.1 (t, 2JCF = 25.7 Hz, CH2), 34.3 (CH2), 65.7 (CH2O),
126.6 (t, 1JCF = 240.2 Hz, CF2), 173.8 (C=O); 19F{1H} NMR (376 MHz, CDCl3) δF -89.3 (s,
CF2); 19F NMR (376 MHz, CDCl3) δF -89.3 (p, J = 15.2 Hz, CF2); HRMS (ESI+) 215.1447
[M-F]+, C12H20FO2 requires 215.1447.
8,8-Difluorododecanolactone (8). Colourless gum (63%). 1H NMR (400 MHz, CDCl3) δH
1.39-1.56 (m, 8H, 4 × CH2), 1.69-1.79 (m, 4H, 2 × CH2), 1.82-1.98 (m, 4H, 2 × CH2CF2),
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2.39-2.42 (m, 2H, CH2CO), 4.19-4.22 (m, 2H, CH2O); 13C NMR (100 MHz, CDCl3) δC 19.2
(t, 3JCF = 5.7 Hz, CH2), 20.3 (t, 3JCF = 5.5 Hz, CH2), 24.2 (CH2), 26.2 (CH2), 26.3 (CH2), 27.1
(CH2), 32.5 (t, 2JCF = 25.3 Hz, CH2), 34.3 (t, 2JCF = 25.7 Hz, CH2), 34.6 (CH2), 63.0 (CH2O),
126.4 (t, 1JCF = 240.2 Hz, CF2), 173.8 (C=O); 19F{1H} NMR (376 MHz, CDCl3) δF -90.8 (s,
CF2); 19F NMR (376 MHz, CDCl3) δF -90.8 (p, J = 15.2 Hz, CF2); HRMS (ESI+) 215.1439
[M-F]+, C12H20FO2 requires 215.1447.
X. Ray data; C12H20F2O2, M = 234.29, monoclinic, a = 11.2700(19), b = 8.3223(14), c =
12.952(2) Å, β = 96.450(4) °, U = 1207.1(3) Å3, T = 173 K, space group P21/n (no. 14), Z =
4, 11813 reflections measured, 2151 unique (Rint = 0.0730), which were used in all
calculations. The final R1 [I > 2σ(I)] was 0.0562 and wR2 (all data) was 0.1918.
5,5,8,8-Tetrafluorododecanolactone (9). Colourless solid (50%). 1H NMR (400 MHz,
CDCl3) δH 1.49-1.57 (m, 2H, CH2), 1.74-1.80 (m, 2H, CH2), 1.84-1.87 (m, 2H, CH2),1.90-
2.11 (m, 8H, 4 × CH2), 2.46 (t, 2H, 3JCF = 5.8 Hz, CH2CO), 4.22 (t, 2H, 3JCF = 5.4 Hz, CH2O);
δC 19.3 (t, 3JCF = 6.2 Hz, CH2), 19.7 (t, 3JCF = 5.5 Hz, CH2), 27.3 (CH2), 28.4 (tt, 3JCF = 5.5
Hz, 2JCF = 27.5 Hz, CH2), 28.8 (tt, 3JCF = 5.8 Hz, 2JCF = 27.1 Hz, CH2), 33.8 (t, 2JCF = 26.0
Hz, CH2), 34.0 (CH2), 33.99 (t, 2JCF = 25.6 Hz, CH2), 64.1 (CH2O), 125.0 (t, 1JCF = 241.2 Hz,
CF2), 125.1 (t, 1JCF = 241.2 Hz, CF2), 172.2 (C=O); {1H}19F (377 MHz, CDCl3) –92.7 (br s),
-92.5 (t, 5JF,F = 1.3 Hz); MS (ESI+) 293.11398 [M+Na]+, C12H18F4O2Na requires 293.1141.
M.pt 99-103oC.
X. Ray data; C12H18F4O2, M = 270.27, monoclinic, a = 12.2019(12), b = 6.5194(6), c =
16.2763(15) Å, β = 107.805(2) °, U = 1232.7(2) Å3, T = 173 K, space group P21/n (no. 14), Z
= 4, 12544 reflections measured, 2219 unique (Rint = 0.0542), which were used in all
calculations. The final R1 [I > 2σ(I)] was 0.0414 and wR2 (all data) was 0.1103.
The experimental procedures for the synthesis and analysis of the intermediates/precursors
can be obtained in the Supplementary Section (Appendix)
Acknowledgements
We thank the Engineering and Physical Sciences Research Council (EPSRC) for funding
and we are grateful to the EPSRC Mass Spectroscopy Service at the University of Swansea
for carrying out some of the accurate mass analysis of prepared compounds.
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Appendix Supplementary data
Supplementary data to this article can be found on line at ….
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