The difluoromethylene (CF2) group in aliphatic chains: Synthesis and conformational preference of palmitic acids and nonadecane containing CF2 groups

Article abstract of DOI:10.3762/bjoc.10.4

The syntheses of palmitic acids and a nonadecane are reported with CF ₂ groups located 1,3 or 1,4 to each other along the aliphatic chain. Specifically 8,8,10,10- and 8,8,11,11-tetrafluorohexadecanoic acids (6b and 6c) are prepared as well as the singly modified analogue 8,8-difluorohexadecanoic acid (6a). Also 8,8,11,11-tetrafluorononadecane (27) is prepared as a pure hydrocarbon containing a 1,4-di-CF₂ motif. The modified palmitic acids are characterized by differential scanning calorimetry (DSC) to determine melting points and phase behaviour relative to palmitic acid (62.5 °C). It emerges that 6c, with the CF₂ groups placed 1,4- to each other, has a significantly higher melting point (89.9 °C) when compared to the other analogues and palmitic acid itself. It is a crystalline compound and the structure reveals an extended anti-zig-zag chain. Similarly 8,8,11,11- tetrafluorononadecane (27) adopts an extended anti-zig-zag structure. This is rationalized by dipolar relaxation between the two CF₂ groups placed 1,4 to each other in the extended anti-zig-zag chain and suggests a design modification for long chain aliphatics which can introduce conformational stability.

Full text of DOI:10.3762/bjoc.10.4

The difluoromethylene (CF2) group in aliphatic
chains: Synthesis and conformational preference
of palmitic acids and nonadecane
containing CF2 groups
Yi Wang, Ricardo Callejo, Alexandra M. Z. Slawin and David O’Hagan*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 18–25.
EaStCHEM School of Chemistry, University of St. Andrews, St.
Andrews, Fife KY16 9ST, UK
doi:10.3762/bjoc.10.4
Received: 28 August 2013
Accepted: 22 November 2013
Published: 06 January 2014
Email:
David O’Hagan* - do1@st-andrews.ac.uk
* Corresponding author
This article is part of the Thematic Series "Organo-fluorine chemistry III".
Associate Editor: V. M. Dong
Keywords:
difluoromethylene; fatty acids; fluorination; organic fluorine chemistry;
organo-fluorine; palmitic acid
© 2014 Wang et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The syntheses of palmitic acids and a nonadecane are reported with CF2 groups located 1,3 or 1,4 to each other along the aliphatic
chain. Specifically 8,8,10,10- and 8,8,11,11-tetrafluorohexadecanoic acids (6b and 6c) are prepared as well as the singly modified
analogue 8,8-difluorohexadecanoic acid (6a). Also 8,8,11,11-tetrafluorononadecane (27) is prepared as a pure hydrocarbon
containing a 1,4-di-CF2 motif. The modified palmitic acids are characterized by differential scanning calorimetry (DSC) to deter-
mine melting points and phase behaviour relative to palmitic acid (62.5 °C). It emerges that 6c, with the CF2 groups placed 1,4- to
each other, has a significantly higher melting point (89.9 °C) when compared to the other analogues and palmitic acid itself. It is a
crystalline compound and the structure reveals an extended anti-zig-zag chain. Similarly 8,8,11,11-tetrafluorononadecane (27)
adopts an extended anti-zig-zag structure. This is rationalized by dipolar relaxation between the two CF2 groups placed 1,4 to each
other in the extended anti-zig-zag chain and suggests a design modification for long chain aliphatics which can introduce con-
formational stability.
Introduction
The selective replacement of hydrogen by fluorine is widely influences [5]. The difluoromethylene (CF2) functionality has
practised in bio-organic and medicinal chemistry [1-4]. It is received considerably less attention as a functional group for
generally perceived that fluorine exerts only a moderate steric modifying the properties of organic molecules, relative to –F
influence relative to hydrogen in organic compounds, but that and –CF3 groups. However we have recently become interested
the electronegativity of fluorine can have significant electronic in the CF2 group, and in particular have noticed that the replace-
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Beilstein J. Org. Chem. 2014, 10, 18–25.
ment of the two hydrogen atoms of a methylene by two fluo- In another study we have prepared cyclododecanes 3–5 with
rine atoms leads to widening of the C–CF2–C angle (~118°) and regiospecific placement of two CF2 groups around the ring [6]
a narrowing of the F–C–F angle (104°) relative to tetrahederal (Figure 2). X-ray structures reveal that the CF2 groups only ever
geometry [6,7]. This deviation of classical sp3, towards sp2 occupy corner locations. This is a result of several factors
hybridisation, imparts certain properties to the CF2 group in that including C–CF2–C angle widening, which relaxes 1,4-torsional
it can accommodate angle strain. For example CF2 compounds strain across corner positions, lengthening the contact distance
display an apparent Thorpe–Ingold effect relative to CH2 in ring between those H(1)···H(4) interactions relative to those with
closing metathesis reactions (RCM) to cycloheptene [8]. Com- CH2 at the corner. Also if the CF2 locates at an edge this would
parison of the rates of reaction with different substituents at the require that a C–F bond project into the middle of the ring. The
C-5 position of the diene precursors 1a–d, revealed that the CF2 larger steric influence of the fluorine, projecting into the tightly
substituent in 1c was as effective as the dicarboxylate 1a or packed arrangement of endo orientated hydrogen atoms, raises
ketal 1b in promoting RCM (Figure 1). This is attributed to the energy of such conformations. For cyclododecane, placing
C–CF2–C angle widening, which absorbs angle strain in the the CF2 groups 1,4 (3) or 1,7 (4) to each other, stabilizes the
resultant cycloheptene 2c.
[3.3.3.3] square like conformation of the ring. However if the
Figure 1: The CF2 group in 1c accelerates RCM reactions relative to CHF (1d) and CH2 (1e) and with a similar rate to classical or Thorpe–Ingold
substituents such as the ketal 1a and dicarboxylate ester 1b [8].
Figure 2: X-ray structures of a) 1,1,4,4- (3) b) 1,1,7,7- (4) and c) 1,1,6,6- (5) tetrafluorocyclododecanes. The CF2 groups locate at the corners, even
for 5 which gives rise to a distorted ring conformation [6,7].
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Beilstein J. Org. Chem. 2014, 10, 18–25.
CF2 groups are placed 1,6 to each other as in 5, this introduces any electronic influence. Two additional analogues 6b and 6c
considerable distortion of the ring conformation as shown in were prepared, each with two CF2 groups, located 1,3 and 1,4
Figure 2, because the CF2 avoids an edge location, which would from each other respectively. These targets were designed to
place a fluorine atom endo and unfavourably into the centre of explore the significance on properties and chain stability of
the ring.
co-locating the CF2 groups at different distances from each
other.
As part of an on-going interest in the behaviour and influence of
the CF2 group we have now explored the effect of locating two
Results and Discussion
CF2 groups along an extended aliphatic chain. Long chain fatty Synthesis of the palmitic acids 6a–c
acids present tractable model systems as they are solid ma- As a general strategy palmitic acids 6a–c were prepared by aryl
terials and their physical properties are well described [9]. In oxidation of long chain pentadecabenzenes [10,11]. The intro-
this study we selected the three palmitic acid analogues 6a–c duction of the CF2 groups was carried out by treatment of the
shown in Figure 3, as targets for synthesis and comparative appropriate precursor ketone with diethylaminosulfur trifluo-
analysis.
ride (DAST) [12,13]. The synthesis of palmitic acid 6a is illus-
trated in Scheme 1. At the outset aldehyde 8 was condensed
with the acetylide of 1-octyne to afford propargylic alcohol 9,
an alcohol which was readily oxidized to ketone 10. Treatment
with DAST afforded difluoromethyleneacetylene 11 in good
yield. The fluorination of propargylic ketones, to generate diflu-
oromethyleneacetylenes, is methodology developed by Grée et
al. [14-18] and it proved to be very reliable in our hands. An
efficient hydrogenation generated the C-8 substituted difluo-
romethylenepentadecabenzene 12. Finally biphasic ruthenium
tetroxide-catalyzed aryl oxidation gave the palmitic acid 6a in
24% overall yield as illustrated in Scheme 1 [10,11].
Figure 3: Synthesis targets: Palmitic acid analogues 6a–c.
For palmitic acid 6b, it was required to introduce the CF2
groups 1,3 to each other. This was achieved by sequential
Palmitic acid 6a containing a single CF2 group at C-8 was preparation of appropriate precursor ketones as illustrated in
prepared as a control compound. The location for CF2 substitu- Scheme 2. For the first CF2 group ketone 14 was treated with
tion in the middle of the aliphatic chain was selected as it is DAST. Conversion to the CF2 group occurred in modest (45%)
sufficiently remote from the carboxylic acid head group to have yield. Generally aliphatic ketones are less efficiently converted
Scheme 1: Synthesis route to 8,8-difluorohexadecanoic acid (6a).
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Beilstein J. Org. Chem. 2014, 10, 18–25.
Scheme 2: The synthesis of palmitic acid analogues 6b and 6c.
to CF2 groups with DAST in comparison to propargylic 18, generated the second fluorination substrate of the synthesis.
ketones. Progression of the resultant CF2 containing olefin 15 DAST treatment gave pentadecabenzene 19, which was again
by epoxidation, chain extension and then oxidation, to ketone oxidised by RuO3 to the corresponding palmitic acid 6b.
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Beilstein J. Org. Chem. 2014, 10, 18–25.
Palmitic acid 6c was prepared again relying on the method- natural palmitic acid (62.5 °C), Thus a single CF2 substitution,
ology developed by Grée et al. [14-17] for introduction of the certainly at this location, has very little influence on the melting
CF2 groups. Thus treatment of ketone 21 with DAST resulted in point. For palmitic acid 6b, with the two CF2-groups placed 1,3
an efficient conversion to difluoromethyleneacetylene 22. This to each other, the melting point (69 °C) is also similar to
terminal acetylene is amenable to acetylide formation on treat- palmitic acid, but the phase behaviour is more complex as evi-
ment with BuLi [19,20] and condensation with hexaldehyde denced by the broad DSC profiles. This palmitic acid 6b was
gave propargylic alcohol 23. The lithium methylenedifluo- amorphous in nature and was not a crystalline solid, unlike the
roacetylide (RCF2C≡CLi) reaction to form a C–C bond, other two analogues 6a and 6c which formed crystals
provides a particularly useful synthon to access this 1,4-di-CF2 (Figure 4).
motif. Oxidation and then treatment of the resultant ketone 24,
with DAST generated the tetrafluoroacetylene 25. Complete The tetrafluorinated palmitic acid 6c, with the CF2 groups
hydrogenation of the triple bond proved efficient and the resul- located 1,4 from each other displays a sharp and significantly
tant tetrafluoropentadecabenzene 26 was readily oxidized to higher melting point (89.9 °C) than the other two palmitic acids
palmitic acid 6c as illustrated in Scheme 2. This completed the 6a and 6b.
syntheses of the palmitic acid analogues 6a–c.
Palmitic acids 6a and 6c were crystalline solids and single
Differential scanning calorimetry (DSC) data was then crystal X-ray diffraction data were obtained for these com-
measured for all three of the palmitic acid samples 6a–c over a pounds. As described above analogue 6b was amorphous in
temperature range of −150 to 400 °C. In this way accurate nature and despite considerable effort a single crystal could not
melting point values were obtained. The melting point of C-8 be obtained for 6b. The resultant structures for 6a and 6c are
difluorinated palmitic acid 6a (62.9 °C) was very similar to the shown in Figure 5 and Figure 6 respectively. In each case two
Figure 4: DSC traces for the three palmitic acid analogues 6a–c.
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Beilstein J. Org. Chem. 2014, 10, 18–25.
Figure 5: The X-ray crystal structures of 8,8-difluorohexadecanoic acid (6a).
Figure 6: The X-ray structure of 8,8,11,11-tetrafluorohexadecanoic acid (6c).
molecules as they appear within the unit cell are presented in It occurred to us that the interactions of the carboxylate groups
the image, allowing a view from above and to the side of the in palmitic acid 6c, may be dictating overall stability and con-
extended chain. The closest CF···HC contacts are 2.88 Å in 6a formation of the alkyl chain in the solid state. Thus it appeared
and 2.85 Å in 6c, much longer than any meaningful organic appropriate to prepare a true hydrocarbon chain to further
fluorine hydrogen bond [21]. The C–CF2–C angle in 6a investigate the conformational preference of the 1,4-di-CF2
(Figure 5) is 117° and as expected, wider than the other motif. Accordingly we selected to prepare tetrafluorononade-
C–CH2–C angles which are typically ~112.5°. For 6c (Figure 6) cane 27. This is a long chain hydrocarbon with the 1,4-di-CF2
the C–CF2–C angles are 115.6° (at C-8) and 116.3° (at C-11) motif placed centrally. The synthetic route to 27 is illustrated in
also consistently wider that the aliphatic C–CH2–C angles. The Scheme 3. The strategy for incorporating the two CF2 groups
significantly higher melting point and good crystallinity of 6c followed that used for the preparation of palmitic acid 6c. In
can be attributed to the relative orientation of the two CF2 this case propargylic ketone 30 was treated with DAST to
groups. They are pointing perfectly anti-parallel to each other generate difluoroacetylene 31. The resultant acetylene could
such that their dipoles cancel out in the extended anti-zig-zag then be deprotonated for conjugation to aldehyde 32. Oxidation
chain conformation. We are currently exploring if this is a and then fluorination of ketone 34 with DAST, introduced the
special situation whereby CF2 groups positioned 1,4 from each second CF2 group and generated tetrafluoroacetylene 35.
other can add conformational stability to aliphatic chains in Finally hydrogenation of the central acetylene group gave the
other systems.
saturated tetrafluorononadecane 27. This compound proved to
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Beilstein J. Org. Chem. 2014, 10, 18–25.
Scheme 3: Synthesis route to the tetrafluorinated alkane 27.
be a crystalline solid (mp 35–37 °C) with a melting point very other. The CF2 groups of 6b, 6c and 27 were introduced
similar to nonadecane (32–35 °C). A suitable crystal was sequentially from appropriate precursor ketones, using DAST.
subject to X-ray structure analysis and the resultant structure is In particular, the methodology of Grée et al., enabled the effi-
shown in Figure 7. It is clear that the alkyl chain of 27 is cient introduction of CF2 groups from propargylic ketones in
extended in a similar conformation to that found in palmitic the syntheses of 6a, 6c and 27. A useful C–C bond forming
acid 6c and we conclude that this is the preferred conformation reaction involved a lithium methylenedifluoroacetylide
of this motif in a hydrocarbon chain.
(RCF2C≡CLi) condensation with an aldehyde, offers an effi-
cient strategy for the preparation of the 1,4-di-CF2 motif after
suitable functional group manipulations.
Conclusion
In conclusion, we have synthesised three palmitic acid
analogues 6a–c carrying regiospecifically located CF2 groups. The non-crystalline nature of 6b presumably arises due to chain
The tetrafluorononadecane 27 was also prepared as an example disorder from linear 1,3-repulsions between the fluorines, so the
of a true hydrocarbon. Relatively efficient synthesis protocols preferred conformation of this motif could not be determined in
were devised for placing the CF2 groups 1,3 and 1,4 to each this study. The melting point of palmitic acid 6c (89.9 °C) was
Figure 7: The X-ray structure of 8,8,11,11-tetrafluorononadecane (27).
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Beilstein J. Org. Chem. 2014, 10, 18–25.
Figure 8: Conformational interconversion of 1,4-di-CF2 motif.
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