TEFDDOLs (α,α,α',α '-tetrakis(perfluoroaryl/alkyl)- 2,2'-dimethyl-1,3-dioxolane-4,5-dimethanols): Highly fluorinated chiral H-bond donors and Bronsted acids with distinct H-bonding patterns and supramolecular architectures

Article abstract of DOI:10.1021/jo301609g

The synthesis of six enantiopure α,α,α',α'- tetrakis(perfluoroalkyl/aryl)-2,2′-dimethyl-1,3-dioxolane-4,5-dimethanols (TEFDDOLs), by addition of perfluorinated organolithium reagents or Ruppert's reagent (TMS-CF₃) to isopropylidene tartaric dic

Full text of DOI:10.1021/jo301609g

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Article
TEFDDOLs (alpha,alpha,alpha',alpha'-Tetrakisperfluoroaryl/
alkyl-2,2'-dimethyl-1,3-dioxolan-4,5-dimethanols): Highly
Fluorinated Chiral H-Bond Donors and Bronsted-Acids with
Distinct H-Bonding Patterns and Supramolecular Achitectures.
Albrecht Berkessel, Sonja S. Vormittag, Nils E. Schlörer, and Jörg-M. Neudörfl
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 02 Oct 2012
Downloaded from http://pubs.acs.org on October 4, 2012
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TEFDDOLs (α,α,α’,α’-Tetrakisperfluoroaryl/alkyl-2,2’-dimethyl-1,3-
dioxolan-4,5-dimethanols): Highly Fluorinated Chiral H-Bond Donors and
Brønsted-Acids with Distinct H-Bonding Patterns and Supramolecular
Achitectures.
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Albrecht Berkessel,* Sonja S. Vormittag, Nils E. Schlörer, and Jörg-M. Neudörfl
†Department of Chemistry (Organic Chemistry), University of Cologne, Greinstr. 4, 50939
Cologne, Germany; Fax: (+49) 221-4705102
*E-mail: berkessel@uni-koeln.de
Table of Contents Graphic
__________________________________________________________________
Abstract
The synthesis of six enantiopure α,α,α’,α’-tetrakisperfluoroalkyl/aryl-2,2’-dimethyl-1-3-
dioxolan-4,5-dimethanols (TEFDDOLs), by addition of perfluorinated organolithium reagents
or Ruppert's reagent (TMS-CF3) to iso-propylidene tartaric dichloride, is reported. X-Ray
crystal structures of the TEFDDOLs alone or in complexes with H-bond acceptors such as
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water or DABCO revealed that this new class of highly fluorinated chiral 1,4-diols forms
distinct intra- and intermolecular H-bond patterns. Intramolecular OH-OH bonding accounts
for the relatively high acidity of the perfluoroalkyl TEFDDOLs [pKa in DMSO: tetrakis-CF3: 5.7;
tetrakis-C2F5: 2.4]. For the tetrakis-perfluorophenyl TEFDDOL, a quite unusual "pseudo-anti"
conformation of the diol, with no intramolecular (and no intermolecular) OH-OH bonds was
found both in the crystal and in solution (DOSY- and NOESY-NMR). The latter conformation
results from a total of four intramolecular OH-Faryl hydrogen bonds overriding OH-OH
bonding. Due to their H-bonding properties, the TEFDDOLs are promising new building
blocks for supramolecular and potentially catalytic applications.
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__________________________________________________________________________
1.
Introduction
Over recent years, selective hydrogen bonding has been recognized as one of the most
important principles in (asymmetric) organocatalysis.1 The most broadly applicable hydrogen
bond donor motifs are (thio)ureas 1,2 more recently squareamides 2,3 and TADDOLs4 3
(Figure 1). Whereas (thio)ureas and squaramides are typically able to donate two H-bonds to
Figure 1. Typical H-bond donor patterns of (thio)ureas 1, squaramides 2 and TADDOLs 3.
TADDOL: α,α,α’,α’-tetraaryl-2,2-dimethyl-1,3-dioxolane-4,5-dimethanol; A: H-bond acceptor.
a suitable acceptor, TADDOLs - with only few exceptions - typically form one intramolecular
and one intermolecular hydrogen bond.5 As a consequence, the intermolecular H-bond donor
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ability of TADDOLs is enhanced, a situation resembling Yamamoto's concept of "Brønsted
acid assisted Brønsted acids" (BBAs).6
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On the other hand, fluorinated alcohols such as 1,1,1,3,3,3-hexafluoro-2-propanol
("hexafluoro-iso-propanol", HFIP, 4, Figure 2) have served in numerous instances as solvents
with remarkable properties.7 For example, their high solvation power, together with low
nucleophilicity, allowed the generation and observation of reactive cationic or radical-cationic
species.8 Additionally, fluorination accounts for their increased acidity, relative to non-
fluorinated analogs.7 Not surprisingly, they are good H-bond donors and poor acceptors.
Fluorinated alcohols as solvents furthermore promote the epoxidation of olefins and the
sulfoxidation of thioethers.9 A recent study of ours established accelerations (of epoxidation)
up to 100.000-fold, relative to conventional solvents such as 1,4-dioxane.10
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Altogether, we settled on compound 5a (Figure 2) as a fluoroalcohol (here: HFIP)–
TADDOL hybrid. In analogy to the TADDOLs, we dubbed the α,α,α’,α’-tetrakis(perfluoroalkyl/
aryl)-2,2-dimethyl-1,3-dioxolane-4,5-dimethanols 5 "TEFDDOLs". In this article, we describe
(i) the synthesis of the hitherto unknown tetrakis-perfluoroalkyl-TEFDDOLs [CF3 (5a), C2F5
(5b), n-C3F7 (5c), n-C4F9 (5d), n-C6F13 (5e); Figure 2], (ii) a largely improved synthesis of the
tetrakis-pentafluorphenyl-TEFDDOL 5f, (iii) X-ray crystal structures of all TEFDDOLs made,
and of H-bonded aggregates thereof with H-bond acceptors such as water and amines, and
(iv) NMR studies (DOSY) showing that the dimerization of TEFDDOLs by H-bonding (as
observed in the crystal) persists in solution. It is furthermore shown by NOESY-NMR that the
quite unusual "pseudo-anti" conformation found for 5f in the crystal persists in solution. pKa-
values for the TEFDDOLs 5a, 5b and 5f have been reported from this laboratory earlier,11
revealing inter alia the remarkably high acidity of the "parent" tetrakis-CF3-TEFDDOL 5a [pKa
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(DMSO) = 5.7], and in particular of its C2F5- homologue 5b [pKa (DMSO) = 2.4]. These data
suggest that TEFDDOLs may not only be suitable as hydrogen bond donors, but may just as
well have potential as chiral Brønsted acid organocatalysts.12
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Figure 2. Top: TEFDDOL 5a as a covalent and chiral analogue of a supramolecular HFIP (4)
dimer; A: H-bond acceptor. Bottom: TEFDDOLs 5a-f reported in this article.
Similar to the synthesis of the TADDOLs 3 by Seebach et al.,5a we envisaged the
addition of perfluoroalkyl lithium reagents13 to activated forms (ester, acid chloride) of iso-
propylidene tartaric acid as the most straightforward approach to the TEFDDOLs 5b-f. An
exception is the tetrakis-trifluoromethyl-TEFDDOL 5a, as it is known that trifluoromethyl
lithium is too unstable to serve as a CF3-nucleophile.13 In this particular case, Ruppert's
reagent (CF3-TMS, 6) was considered as an alternative CF3-donor.14 Before our study, the
only TEFDDOL known in the literature was the tetrakis-pentafluorophenyl-TADDOL 5f
(Figure 2), reported by Hafner et al.15 In our hands, however, the procedure by Hafner et al.
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(employing tartaric ester) gave at best yields < 10 %. As described in detail below, a quite
satisfactory yield of 70 % resulted upon switching to the acid chloride as electrophile and in
situ-quenching.16
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2. Results and Discussion
2.1 Syntheses. For the tartaric acid electrophiles, we found in extensive optimization studies
(not reported) that (R,R)-iso-propylidene tartaric acid dichloride 7 invariable gave superior
yields of TEFDDOLs compared to e.g. tartaric esters. This starting material 7 was prepared
from (R,R)-iso-propylidene tartaric disodium salt according to Klotz et al.17 Upon sublimation,
material suitable for X-ray crystallography was obtained. The X-ray crystal structure of 7 is
shown in Figure 3.
Figure 3. X-Ray crystal structure of (R,R)-iso-propylidene tartaric acid dichloride (7).
O
Cl
O
O
H3C
H3C
Cl
7
O
2.1.1 Synthesis of the TEFDDOL 5a using Ruppert's reagent (6). When the acid chloride
7 was treated with increasing amounts of Ruppert's reagent 6 and tetramethylammonium
fluoride18 at -50 °C in DME, significant conversion was observed beginning from ca. 4 equiv.
of reagent and fluoride used. A trifluoromethylation product 8 was isolated in 33 % yield after
aqueous workup which, however, turned out not to be the desired TEFDDOL 5a. As
evidenced by NMR and in particular by X-ray crystallography, the "semi-trifluoromethylated"
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tartaric acid 8 was formed under these conditions (Scheme 1, top). To our delight, increasing
the amount of TMS-CF3 (6) to ca. 7 equiv. resulted in the formation of the TEFDDOL 5a
which could be isolated in 20 % yield (Scheme 1, bottom).
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Scheme 1. Trifluoromethylation of iso-propylidene tartaric acid dichloride (7), using Ruppert’s
reagent (6).
CF3
OH
F3C
O
H3C
H3C
4 eq. TMS-CF3 (6), 4 eq. [Me4N]F
DME, -50 oC to r.t., 12 h
O
O
O
CO2H
Cl
Cl
8, 33 %
O
O
H3C
H3C
CF3
OH
F3C
O
7
H3C
H3C
7 eq. TMS-CF3 (6), 7 eq. [Me4N]F
DME, -50 oC to r.t., 12 h
O
F3C
OH
CF3
5a, 20 %
The X-ray crystal structures of the tartaric acid bis-trifluoromethyl derivative 8 and of the
tetrakis-trifluoromethyl TEFDDOL 5a are shown in Figure 4. The water-free crystals needed
for the X-ray structural analysis of pure 5a were obtained by sublimation under vacuum in a
sealed tube, and through a layer of 4 Å molecular sieves (see section II.3 below for the
structure of the 2:1 complex of 5a with water).
Figure 4. X-Ray crystal structures of the tartaric acid bis-trifluoromethyl derivative 8 and of
the tetrakis-trifluoromethyl TEFDDOL 5a.
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8
5a
The crystal packing of the bis-trifluoromethyl carboxylic acid 8 revealed numerous
hydrogen bonding interactions (Figure 5) which result in the aggregation of three molecules
of 8 to form repeating "triplets". The most prominent interaction is a hydrogen bond between
the OH-group of the carboxylic acid and one oxygen atom of the dioxolane ring of a
neighboring molecule. A third molecule of 8 is involved in the sense that the hydroxyl group
of its fluoroalcohol moiety is hydrogen bonded to the carbonyl oxygen atom of the first
molecule (Figure 5).
Figure 5. Crystal packing diagram of the bis-trifluoromethyl carboxylic acid 8.
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As may have been expected, the preparation of the tetrakis-CF3-TEFDDOL 5a was not
successful when halogen-lithium exchange on CF3I was tried for the generation of the CF3-
nucleophile. No trifluoromethylation of iso-propylidene tartaric acid dichloride (7) could be
observed. The latter result is not surprising as it is well known that even at low temperatures,
trifluoromethyl lithium or the corresponding Grignard reagent are unstable and decompose
instantaneously to difluorocarbene by elimination of the metal fluoride.13
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2.1.2 Synthesis of the TEFDDOLs 5b-f using perfluorinated organolithium reagents. In
our optimized procedure, iso-propylidene tartaric acid dichloride (7) and the perfluorinated
alkyl/aryl iodide or bromide (ca. 7 equiv.) were dissolved together in diethyl ether at -78 °C.
Methyl lithium (5 equiv.), stabilized by lithium bromide, was then added in one portion. After 1
h, aqueous work-up followed by chromatographic purification afforded the desired products
with yields ranging from 15-70 % (Scheme 2).
Scheme 2. Synthesis of the TEFDDOLs 5b-f starting from iso-propylidene tartaric acid
dichloride 7.
O
R
R
5b: R = C2F5, 55 %
5c
5d: R = n-C4F9, 26 %
5e: R = n-C6F13, 15 %
5f: R = C6F5, 70 %
Cl
Cl
OH
OH
O
O
O
O
H3C
H3C
RF-I/Br, CH3Li•LiBr
ether, -78 oC, 1 h
: R = n-C3F7, 25 %
H3C
H3C
R
R
7
O
Halogen-lithium exchange is sufficiently fast to be performed in the presence of the
electrophile 7 - no side reactions of methyl lithium with tartaric acid dichloride 7 have been
observed. With regard to the yields of TEFDDOLs 5b-f, the in situ-quenching method
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described above proved superior to the sequential formation of the perfluoroalkyl lithium
intermediates, followed by addition of the acid chloride 7. By the same token, the acid
chloride 7 proved superior to other tartaric acid derived electrophiles, such as esters. As
summarized in Scheme 2, we sucessfully introduced pentafluorophenyl-, pentafluoroethyl-,
heptafluoro-n-propyl-, nonafluoro-n-butyl- and tridecafluoro-n-hexyl-groups using lithium-
halogen exchange. As expected, CF3I did not afford any of the CF3-TEFDDOL 5a under the
conditions described above. However, as mentioned above (2.1.1), this "parent" TEFDDOL
was accessible using Ruppert's reagent (CF3-TMS, 6) as the trifluoromethyl source.
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2.2 Solid State Structures.
2.2.1 X-Ray crystal structures of the TEFDDOLs 5a-f: intramolecular hydrogen bonding
in 5a-e, but not in 5f. All TEFDDOLs 5a-f were characterized by x-ray crystallography. The
molecular structures of 5b-f are shown in Figure 6. Note that all perfluoroalkyl TEFDDOLs
5b-e show - just as the parent system 5a (Figure 4) - the expected intramolecular OH-OH
hydrogen bonding. In line with this, the "pseudo-torsion angle" O-Ccarbinol-Ccarbinol-O is low and
in the range of ca. 20-30o. As the sole exception, the tetrakis-pentafluorophenyl TEFDDOL 5f
adopts a completely different conformation in the crystal: There is no intramolecular (and no
intermolecular) OH-OH bonding. Instead, each one of the two hydroxyl groups forms a
bifurcated hydrogen bond to two "ortho" fluorine atoms on the phenyl rings. A "pseudo-anti"
arrangement of the two hydroxyl groups results, with a "pseudo-torsion angle" O-Ccarbinol
-
Ccarbinol-O of 170.7 (2)o. The H-F distances are in the range of 2.23 - 2.29 Å. These values
coincide very well with the H-F bond length of 2.23 Å observed earlier in intramolecularly H-F
bonded 2-fluorophenyldiphenylmethanol.19
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Figure 6. Crystal structures of TEFDDOLs 5b-f. Disorder of OH H-atoms is not shown. The
C2F5-groups of 5b are disordered, and only one orientation is shown.
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5b
5c
5d
5e
5f
Note that in the area of TADDOLs, of the 161 crystal structures deposited in the
CCDC-file, only two show the “pseudo-anti” arrangement of the two hydroxyl groups.20 In
both of these cases, the TADDOL incorporates a diphenyl-dioxolane (i.e. a benzophenone
acetal). Thus, 5f is the only case of a dimethyl-dioxolane (i.e. acetone acetal) showing
“pseudo-anti” conformation. In the case of the two TADDOLs, the "pseudo-anti" conformation
is enforced by non-bonding interactions involving the acetalic phenyl groups. In other words,
steric hindrance overrides the attractive intramolecular OH-OH bonding. In the case of the
tetrakis-pentafluorophenyl TEFDDOL 5f, a total of four intramolecular OH-F bonds override
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one OH-OH bond. Note that the "pseudo-anti" conformation of TEFDDOL 5f persists in
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solution (see section 2.3 below), thus it is clearly not an effect of crystal packing.
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2.2.2 X-Ray crystal structures of the TEFDDOLs 5a-f: modes of intermolecular
hydrogen bonding. To our delight, the X-ray crystal structure of the tetrakis-trifluoromethyl
TEFDDOL 5a monomer (Figure 7), which could be obtained in water-free form by sublimation
through molecular sieves (4Å), revealed a hydrogen bond network reminiscent of that found
for HFIP (4) itself.10 Most importantly, the OH-groups of 5a form an endless, zig-zag-
patterned ribbon. In this endless sequence of intra- and intermolecular hydrogen bonds, the
Figure 7. Layered crystal packing of intra- and intermolecular hydrogen bonded TEFDDOL
5a.
intramolecular O-H-O bonds have an O-O-distance of 2.752 Å (average over the three
independent molecules in the unit cell), wheras the intermolecular ones are on the average
3.079 Å in length. Furthermore, it is interesting to note that the crystal shows a "trifle"-type
separation of the polar OH-regime, mantled by "fluorous" layers which are made up by the
closely interacting CF3-groups. These fluorous layers are again followed by a medium-
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polarity hydrocarbon layer, consisting of the oxygen atoms and the methyl groups of 5a's
acetal substructure (Figure 7).
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The crystal structures of tetrakis-pentafluoroethyl TEFDDOL 5b and its homologue 5c
revealed a different mode of intermolecular hydrogen bonding interaction. As shown in Figure
8, these TEFDDOLs are characterized by hydrogen bonded dimers. Dimerization is brought
about by intermolecular hydrogen O-H-O bonding, typically 2.745 Å in length, in addition to
the typical intramolecular O-H-O-bonding (2.695 Å on the average). Most likely, the
increasing size of the perfluoroalkyl groups (C2F5, and C3F7 vs. CF3) prohibits the formation
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Figure 8. Cyclic hydrogen bond networks observed for the tetrakis-pentafluoroethyl (5b), the
tetrakis-heptafluoro-n-propyl-TEFDDOL (5c), the tetrakis-nonafluoro-n-butyl (5d), and the
tetrakis-tridekafluoro-n-hexyl-TEFDDOL (5e). Disorder of OH H-atoms is not shown. The
C2F5-groups of 5b are disordered, and only one orientation is shown.
5b
5c
5d
5e
of endless H-bonded aggregates (as in 5a, Figure 7), and accounts for the observed change
in packing. The higher TEFDDOL homologues 5d and 5e form dimers with an analogous
hydrogen bonding pattern (Figure 8). Note that in the area of fluorinated mono-alcohols,
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similar oligomers, with analogous 8-membered cyclic hydrogen bond networks, are observed
e.g. for racemic 1-phenyl-2,2,2-trifluoro-ethanol.10,20
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The crystal structure of the tetrakis-pentafluorophenyl-TEFDDOL 5f revealed a
completely different aggregation mode of the individual molecules. Unlike all other
TEFDDOLs, and almost all TADDOLs which have an intramolecular O-H-O-hydrogen bond,
this is not the case for the TEFDDOL 5f. Instead, its hydroxyl groups are involved in both
intra- and intermolecular O-H-F bonding (Figure 9).
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Figure 9. Intra- and intermolecular OH-F hydrogen bonding in tetrakis-pentafluorophenyl-
TEFDDOL 5f.
As mentioned before, each one of TEFDDOL 5f's hydroxyl group forms a bifurcated
hydrogen bond to two "ortho" fluorine atoms on the phenyl rings (Figure 9, marked in red). In
the crystal, a third - now intermolecular - interaction exists between the hydroxyl groups' H-
atom and a "meta" fluorine atom of a neighboring TEFDDOL molecule (Figure 9, marked in
blue). For the intermolecular OH-F bonds, the H-F distances were found to be in the range of
2.33-2.46 Å - significantly below the sum of the van der Waals radii of the two atoms (267
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pm). Clearly, also the lengths of the intramolecular OH-F bonds in TEFDDOL 5f (2.23-2.29 Å,
see above) fall significantly below this value.
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An earlier analysis of hydrogen bonding involving "organic" fluorine as acceptor (1997
by Dunitz and Taylor, based mainly on crystal structures) came to the conclusion that this
type of interaction occurs only scarcely.21 A very recent (2012) discussion of the topic by
Schneider, including spectroscopy, association equilibria in solution, and computational
studies, points to a much more widespread occurence and importance of hydrogen bonding
to fluorine.22 We feel that TEFDDOL 5f is a good example for the importance of OH-F
bonding, both with regard to molecular conformation and aggregation.
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2.2.3 X-Ray crystal structures of the TEFDDOLs 5a-f in the presence of Lewis-bases:
complexes with hydrogen bond acceptors.
Water as the second component: We also obtained crystallographic data of
TEFDDOL 5a as a 2:1 complex with water (Figure 10). In this hydrate, again an
intramolecular hydrogen bond between the two hydroxyl groups of each TEFDDOL monomer
is visible. Two TEFDDOL monomers dimerize, similar to the aggregation mode seen in
water-free TEFDDOL 5a (Figure 7). The terminal “activated” hydroxyl group of the dimer then
forms an intermolecular hydrogen bond to water, which itself donates another intermolecular
hydrogen bond to one of the oxygen atoms of the dioxolane ring of a TEFDDOL from the next
TEFDDOL-dimer. Overall, an endless hydrogen bonded [5a2-H2O]n-aggregate results (Figure
10). The crystal structure of the 2:1-complex of the tetrakis-pentafluoroethyl TEFDDOL 5b
with water revealed a rather similar hydrogen bonding pattern, giving rise to an endless [5b2-
H2O]n-aggregate (Figure 11).
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Figure 10. 2:1-Complex of TEFDDOL 5a with H2O.
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Figure 11. 2:1-Complex of TEFDDOL 5b with H2O.
Amines (DABCO and piperidine) as the second component: In the cases of the
pentafluoroethyl-TEFDDOL 5b and the pentafluorophenyl-TEFDDOL 5f, we have also
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prepared and characterized complexes with amine bases, in particular with piperidine and
DABCO (1,4-diazabicyclo[2.2.2]octane).
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The crystal structure of the complex of 5b with DABCO is shown in Figure 12. The
composition of this material can be described as a [TEFDDOL-H+•DABCO+H+•TEFDDOL]-
salt. As it should be the case, the tertiary diamine [pKa(DMSO) = 8.93, 2.97]23 is mono-
protonated by one of two tetrakis-pentafluoroethyl TEFDDOL (5b) molecules. Once again,
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Figure 12. 2:1-Complex of TEFDDOL 5b with DABCO.
intramolecular H-bonds exist between the hydroxyl groups of the two TEFDDOL units [dO1O2
= 2.466(6) Å, dO3O4 = 2.655(8) Å]. It is evident from these bond lengths that one of the two
TEFDDOL molecules is deprotonated, i.e. has transferred the “exocyclic” proton to the
amine. In Figure 12, the deprotonated TEFDDOL unit is the “left” one, harbouring O1 and O2.
The “right” TEFDDOL molecule appears to just form a strong hydrogen bond to the second
N-atom of DABCO. Overall, two intermolecular hydrogen bonds exist between the N-atoms of
DABCO and the “activated” hydroxyl groups of the two TEFDDOL molecules [dN1O2=2.686(6)
Å, dN2O3=2.585(7) Å].
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With DABCO as the proton acceptor, also the less acidic tetrakis-pentafluorophenyl-
TEFDDOL 5f forms a salt (Figure 13). In the 2:3-complex of C6F5-TEFDDOL 5f with DABCO,
we see two independent H-bridged ion pairs of DABCO+H+• 5f-H+ (left and right in Figure
13). The relatively short O-O distances within the TEFDDOL moieties are indicative of the
deprotonated state [dO1O2 = 2.562(3) Å, dO3O4 = 2.622(4) Å]. It is interesting to note that in the
deprotonated state, the TEFDDOL 5f adopts the conformation typical for all other
TEFDDOLS, i.e. showing an intramolecular OH-O-hydrogen bond. In other words, single OH
hydrogen bonding to the anionic carbinolate oxygen atom overrides two bifurcated OH-F
hydrogen bonds. A third DABCO molecule occupies a central position as a non-hydrogen
bonded guest molecule.
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Figure 13. 2:3-Complex of TEFDDOL 5f with DABCO.
Not surprisingly, in the complex of the tetrakis-pentafluorophenyl-TEFDDOL 5f with
the more basic piperidine [pKa(DMSO) = 10.85]24, the TEFDDOL is deprotonated as well
(Figure 14). In this 2:1-complex, a cyclic hydrogen bond network is completed by
incorporation of a second piperidine molecule. In this arrangement, the TEFDDOLs OH-O
distance is short [dO1O2 = 2.457(3) Å], indicative of deprotonation of the TEFDDOL moiety.
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Figure 14. 1:2-Complex of the tetrakis-pentafluorophenyl-TEFDDOL 5f with piperidine
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(hydrogen atoms in the N-H-N-bridge are disordered).
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2.3 TEFDDOL-structures in solution.
The conformational and aggregational behaviour of the tetrakis-C2F5-TEFDDOL 5b and of
the tetrakis-C6F5-TEFDDOL 5f (Figure 15) in solution was investigated by NOE- and by
DOSY-spectroscopy, respectively (1H, 19F).
2.3.1 TEFDDOL-conformations in solution – NOE experiments.
For the tetrakis-C2F5-TEFDDOL 5b, the "pseudo-syn" orientation of the intramolecularly
hydrogen-bonded hydroxyl functions (see Figures 6,8) could be also confirmed for the
solution structure of 5b (Figure 16). In the homonuclear F,F NOESY spectrum, the two non-
equivalent pentafluoroethyl groups can be assigned, while the H,F HOESY experiment
served to distinguish between the two thinkable conformers for the signal set observed. In
particular, the very strong cross peaks between H4/5 and F2B’’ - or H4/5 and F1B'' – (see
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Figure 15. Numbering scheme for TEFDDOLs 5b and 5f investigated by NMR spectroscopy.
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2A"
2B''
F
F
F
F
F
F
F
1A''F
1B''
1B''
1A"
F
F
1'''
O
H3C
1'
1'
OH
OH
CF2
1
5
4
2
3
H3C
O
F2C
1"'
CF3 CF3
5b
5f
Figure 15 for atom numbering) are not expected for a conformation where the two OH
functionalities are pointing in opposite directions from the plane of the five-membered ring
(“pseudo-anti”). On the contrary, no cross peak is observed between H4/5 and F1A'' and only
a very weak NOE between H4/5 and F1A'', which cannot be accounted for by a “pseudo-anti”
conformer. Likewise, the non-existence of a cross peak for H1''' and F2B'' together with the
strong NOE for H1''' and F2A'' can only be explained with a “pseudo-syn” arrangement of the
hydroxyl groups with respect to each other.
Figure 16. NOEs observed for the TEFDDOL 5b. For reasons of clarity, the second 5b
molecule present in the dimeric aggregate is not shown. See Supporting Information for the
original NOESY spectra.
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For the tetrakis-C6F5-TEFDDOL 5f - as also indicated by diffusion measurements (see
below) - a monomeric structure is supported by NOE data as well. Homo- and heteronuclear
NOE experiment were performed. In particular, the two-dimensional H,F HOESY spectra
show that in solution, like in the solid state (compare Figure 6), a “pseudo-anti” arrangement
of the two OH-groups is preferred (Figure 17). In other words, also in CDCl3 solution, the
molecule's conformation is dominated by intramolecular OH-F bonding. Distance evaluation
for possible “pseudo-syn” and “pseudo-anti” conformers, with the first one forming a possible
dimer, and comparison with NOE data led to the assignment given in the Experimental
Section. A very strong NOE between H4/5 and F2B''/F6B'', which is attributed to the NOE
between each of the two identical stacked C6F5 unit’s interaction with the methine group, and
also the strong NOE’s between the hydroxyl protons and F2A''/F6A’' and F2B''/F6B'', as well as
H1''' and F2A''/F6A'' are in favor of this interpretation. At the same time, missing NOE contacts
between H1''' and F4B'' or F3B''/F5B'', respectively, clearly would be in contradiction with a
“pseudo-syn” form and therefore further support our conclusions.
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Figure 17. NOEs observed for the TEFDDOL 5f. See Supporting Information for the original
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2.3.2 Supramolecular structures in solution – DOSY experiments.
For the tetrakis-pentafluoroethyl TEFDDOL 5b, diffusion measurements were
recorded for a series of different concentrations, ranging from 0.8 mM to 12.5 mM (in CDCl3).
As can be seen from the plot of diffusion coefficients vs. concentration (Figure 18), at diol
concentrations below 0.01 M, an increase in diffusion coefficient - which is equivalent to a
larger fraction of monomeric species - can be observed. As has been suggested earlier,
changes in hydrodynamic radii upon build-up or breaking of H-bonds can be gauged by using
TMS as an internal diffusion reference.25 By comparison of experimentally determined
diffusion coefficients and the relative change in hydrodynamic radius, the value of D/DTMS of
ca. 0.5 for the concentrations of 12.5 mM and above, vs. D/DTMS of 0.73 for the most diluted
solution under investigation, and a corresponding change of the hydrodynamic radius, ΔrH, by
ca. 1.4, were obtained. This result can be interpreted by the TEFDDOL 5b existing in an
aggregation state close to monomer in solutions of ca. 0.8 mM in concentration, or below.
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Note that this value was determined in chloroform as solvent which is at the most of very low
hydrogen bond accepting capacity. We interpret the aggregation state being populated at
higher concentrations as the H-bonded dimer found in the crystal structure of TEFDDOL 5b
(Figure 8).
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Figure 18. TEFDDOL 5b: diffusion coefficient in CDCl3 as a function of concentration. TMS
was used as standard. See Supporting Information.
A similar set of diffusion experiments was carried for the tetrakis-pentafluorophenyl-
TEFFDOL 5f. In contrast to the changes observed for increasingly diluted solutions of the
TEFDDOL 5b, when recording diffusion experiments with 5f, almost no changes in diffusion
coefficient were visible throughout the investigated range of concentrations (Figure 19). At
the same time, the absolute values of diffusion coefficients match the ones expected for the
monomeric TEFDDOL 5f in chloroform solution. In other words, the tetrakis-
pentafluorophenyl-TEFDDOL 5f does not show any tendency towards aggregation in
chloroform solution up to at least 12.5 mM concentration. This result indicates that the third
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and intermolecular OH-F hydrogen bond found in the crystal structure of 5f (Figure 9, H-
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bonds indicated in blue) is weak and does not persist in solution.
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Figure 19. TEFDDOL 5f: diffusion coefficient in CDCl3 as a function of concentration. TMS
was used as standard. See Supporting Information.
2.4. Miscellaneous.
2.4.1 The attempted synthesis of the meso-TEFDDOL 9. Under the same reaction
condition as described above (2.1.2), we have tried to synthesize an achiral counterpart of
the tetrakis-pentafluoroethyl TEFDDOL 2b, namely the meso-TEFDDOL 9 (Figure 20). For
Figure 20. Formulae of the desired meso-TEFDDOL 9 and of iso-propylidene meso-tartaric
anhydride 10.
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the preparation of the required meso-tartaric dichloride, we applied the procedure by Klotz et
al. for the synthesis of the chiral tartaric dichloride 7.17 However, treatment of the meso-
tartaric disodium salt with thionyl chloride furnished the anhydride 10, which was employed
for further experimentation.
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As described under 2.1.2, pentafluoroethyl iodide and the anhydride 10 were dissolved
in diethylether at -78°C, and methyl lithium, stabilized with lithium bromide was added. Under
these conditions, no indication for the formation of the desired meso-TEFDDOL 9 was
obtained. Instead, the product rac-11 with only two pentafluoroethyl groups was isolated
(Scheme 3).
Scheme 3. Synthesis of compound rac-11 starting from iso-propylidene protected anhydride
10.
The X-ray crystal structure of rac-11 is shown in Figure 21. In the crystal, the
enantiomers of rac-11 form heterochiral hydrogen-bonded dimers ("horizontal" hydrogen
bonds in Figure 21). The latter dimers aggregate, again by hydrogen bonding ("vertical" H-
bonds in Figure 21), to endless ribbons.
Figure 21. X-Ray crystal structure of compound rac-11: molecular structure (top);
intermolecular hydrogen bonding pattern (bottom).
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The formation of the unexpected product rac-11 from the meso-tartaric anhydride 10
can be explained as summarized in Scheme 4. Initial exo-attack of pentafluoroethyllithum on
the bicyclic anhydride 10 affords the alcoholate rac-12. A second exo-attack on the remaining
carbonyl group furnishes the diolate meso-13. As the final step, trans-acetalization – most
likely during acidic workup - in meso-13 affords rac-11. The latter process is facilitated by the
cis-orientation of the hydroxyl groups involved.
Scheme 4. Suggested mechanism for the formation of the diol rac-11.
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LiO
LiO
LiO
C2F5
C2F5
O
O
H3C
H3C
H3C
H3C
C2F5Li
C2F5Li
O
10
O
O
O
C2F5
O
12*)
13
H2O, H+
HO
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OH
HO
H
C2F5
*)racemic
mixture
C2F5
H+
O
O
O
H3C
H3C
H
O
O
C2F5
O
C2F5
H3C
11*)
HO
CH3
2.4.2. pKa-Values of the TEFDDOLs 5a,b,f. We recently disclosed the pKa values of the
TEFDDOLs 5a, 5b and 5f in DMSO.11 It was found that the tetrakis-perfluoralkyl-TEFDDOLs
5a and 5b are rather acidic [pKa (5a) = 5.7; pKa (5b) = 2.4], wheras the tetrakis-
pentafluorophenyl-TEFDDOL 5f has a pKa value of ca. 11. Clearly, intramolecular hydrogen
bonding accounts for the increased acidity of the tetrakis-perfluoroalkyldiols 5a and 5b
relative to their “monomer” 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP, pKa = 17.211). In the
case of the tetrakis-pentafluorophenyl-TEFDDOL 5f, the pKa of ca. 11 is basically identical to
that of the “monomer” decafluorohenzhydrol (ca.11).11 In other words, the hydroxyl groups of
5f act independently - consistent with TEFDDOL 5f's preferred "pseudo-anti"-conformation,
both in the crystal (Figures 6 and 9) and in solution (Figure 17).
3.
Conclusions
(i) We have established a versatile one-step synthesis for a novel class of chiral and
highly fluorinated diols, the TEFDDOLs (α,α,α’,α’-tetrakisperfluoroaryl/alkyl-5,5’-dimethyl-1-3-
dioxolan-4,5-dimethanols).
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(ii) All perfluororalkyl-TEFDDOLs (5a-e) show intramolecular HO-HO hydrogen
bonding, both in the solid state and in solution ("pseudo-syn" orientation of the H-bonded OH
groups). As a result, the perfluoroalkyl TEFDDOLs show acidity significantly higher than the
parent fluorinated mono-alcohols. pKa-Values as low as 2.4 were measured, which make the
TEFDDOLs promising candidates for applications in asymmetric organocatalysis.
(iii) In the tetrakis-pentafluorophenyl-TEFDDOL 5f, the overall conformation is dictated
by bifurcated intramolecular hydrogen bonding between the molecule's OH groups and the
"ortho" fluorine atoms of the C6F5-rings. This interaction overrides the molecules's intrinsic
potential for intramolecular HO-HO hydrogen bonding, and a "pseudo-anti" arrangement of
the OH groups results. As a consequence of the non-cooperativity of its OH-groups, the
tetrakis-pentafluorophenyl-TEFDDOL 5f does not show enhanced acidity relative to its mono-
alcohol decafluorobenzhydrol.
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(iv) In the solid state, the pure perfluororalkyl-TEFDDOLs 5a-e form aggregates
(dimers to infinite ribbons) by intermolecular hydrogen bonding. Furthermore, these
aggregates are characterized by a strict layering of the perfluoroalkyl groups, the highly polar
OH-groups, and the dioxolane residues of medium polarity.
(v) An analogous layering is observed for the tetrakis-pentafluorophenyl-TEFDDOL 5f.
Intermolecular bonding, however, is effected by weak OH-F interactions, and not by HO-HO
bonds.
(vi) In chloroform solution, the conformational features found in the crystal for both the
perfluoroalkyl- and perfluorophenyl-TEFDDOLs 5b and 5f persist. The monomeric tetrakis-
perfluoroethyl-TEFDDOL 5b is in equilibrium with a dimer which prevails at higher
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concentrations. In contrast, the tetrakis-perfluoropheny-TEFDDOL 5f shows no tendency
towards aggregation.
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(vii) In the presence of Lewis-bases (water, amines), all TEFDDOLs form well-defined
aggregates in the solid state. The TEFDDOL's diol substructure acts as "monodentate"
hydrogen bond donor.
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(viii) In the presence of sufficiently basic partners (amines), the TEFDDOLs may
become deprotonated and can form crystalline ammonium salts. For the tetrakis-
pentafluorophenyl-TEFDDOL 5f, deprotonation is accompanied by a dramatic change in
conformation: in its anion, OH-F hydrogen bonding is overridden, and a conformation with an
intramolecular OH-O hydrogen bond results (i.e. the conformation typical for all tetrakis-
perfluoroalkyl-TEFDDOLs).
Future studies in our laboratory will be devoted to potential applications of this new
class of chiral fluorodiols, in particular with regard to their potential as chiral Brønsted acids,
or building blocks for chiral ligands.
4.
Experimental Section
4.1. General Information. All reactions were carried out under argon atmosphere and in
flame-dried glassware, using standard Schlenk techniques. Reagents were purchased from
standard suppliers and were used without further purification. Solvents were dried according
to general procedures.26 TLC spots were visualized by fluorescent indicator or by cerium-
molybdenum-spray reagent. Flash chromatography was performed on silica gel. Gas
chromatography (GC): Helium was used as a carrier gas, and HP-5 MS or Optima 5 Accent
(Macherey-Nagel) 30 m x 0.25 mm capillary columns. GC-data are given as follows: type of
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the column, GC-method in the following formula: initial temperature [min] → ramp [°C/min] →
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final temperature [min].
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Nuclear magnetic resonance (NMR): H and C chemical shifts (δ) are given in ppm
relative to the solvent reference as an internal standard. Assignments are supported by H,H
COSY, H,C HMQC and H,C HMBC spectra. Gradient-selected F,F COSY, F,C HMBC and
H,F HOESY27 spectra were recorded using an inverse H,F TBI probe, equipped with a pulsed
gradient unit capable of producing magnetic field pulse gradients in the z-direction of 56
G•cm-1. Data are reported as follows: chemical shift [multiplicity (s for singlet, d for dublet, t
for triplet, q for quartet, sept for septet, m for multiplet), coupling constant [Hz], integration,
assignment]. For the attribution of scalar couplings, 19F NMR spectra were simulated with
SpinWorks 3.1.7 (Copyright 2010, K. Marat, University of Manitoba) using NUMRIT
algorithms.28 For the numbering scheme of 19F NMR assignments, see Figure 15.
High-resolution mass spectrometry (HR-MS): High-resolution mass spectra were
recorded in ESI mode, using a quadrupole ion trap (EB-Q-trap).
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Fourier transform infrared spectroscopy (FT-IR): Absorption bands are given in wave
numbers ( , cm-1). Intensities of the bands are given as follows: ‘s’ for strong peaks, ‘m’ for
peaks with a medium intensity and ‘w’ for weak bands. Broad absorptions are marked with
supplement ‘br’.
Melting points (m.p.) are uncorrected.
X-ray crystal structure analysis: Structures were solved using SHELXS97, and refined
with SHELXL97.
For optical rotations, concentrations c are given in g/100 ml.
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