Preparation of dialkylamino-substituted benzenes and naphthalenes by nucleophilic replacement of fluorine in the corresponding perfluoroaromatic compounds

Article abstract of DOI:10.1515/znb-2006-0519

The reactions between hexafluorobenzene (HFB) and octafluoronaphthalene (OFN) with secondary aliphatic amines (pyrrolidine, dimethylamine and piperidine) and lithium amides (pyrrolidide, dimethylamide and piperidide) have been investigated both experiment

Full text of DOI:10.1515/znb-2006-0519

Preparation of Dialkylamino-Substituted Benzenes and Naphthalenes
by Nucleophilic Replacement of Fluorine in the Corresponding
Perfluoroaromatic Compounds
Vladimir I. Sorokina, Valery A. Ozeryanskiia, Gennady S. Borodkinb,
Anatoly V. Chernyshevb, Max Muirc, and Jon Bakerc,d
a Department of Organic Chemistry, Rostov State University, 344090, Zorge street 7, Rostov-on-Don,
Russia
b Institute of Physical and Organic Chemistry, 344090, Stachki ave. 194/2, Rostov-on-Don, Russia
c Parallel Quantum Solutions, 2013 Green Acres Road, Suite A, Fayetteville, Arkansas 72703, U.S.A.
d Department of Chemistry, University of Arkansas, Fayetteville, Arkansas 72701, U.S.A.
Reprint requests to Dr. V. I. Sorokin. E-mail: vsorokin@aaanet.ru
Z. Naturforsch. 61b, 615 – 625 (2006); received December 13, 2005
The reactions between hexafluorobenzene (HFB) and octafluoronaphthalene (OFN) with sec-
ondary aliphatic amines (pyrrolidine, dimethylamine and piperidine) and lithium amides (pyrrolidide,
dimethylamide and piperidide) have been investigated both experimentally and (in part) theoretically.
With amines HFB, depending on the selected conditions, gives either di-substituted products or a
complex mixture of di-, tri- and tetrasubstituted compounds. Under similar conditions OFN produces
almost exclusively the 2,3,6,7-tetrasubstituted compound. Interaction of HFB with the more nucle-
ophilic lithium amides results in the replacement of four fluorines giving 1,2,4,5-tetrasubstituted di-
fluorobenzenes, while OFN under similar conditions with lithium pyrrolidide produces an inseparable
mixture of 1,2,4,5,6,8-hexa- and 1,2,3,4,5,6,8-hepta-substituted derivatives. With lithium dimethy-
lamide, it is possible to substitute six (in dioxane) or seven (in THF) fluorines in OFN. Lithium
piperidide in all employed solvents reacts with OFN to give only the 1,2,4,5,6,8-hexasubstituted
derivative. Theoretical calculations indicate that with lithium dimethylamide the third fluorine is sub-
stituted at position 1, whereas with dimethylamine it is position 3. The basicities of selected hexa-
and heptakis(dialkylamino)naphthalenes have been measured; they are all stronger bases than 1,8-
bis(dimethylamino)naphthalene, although by less than expected.
Key words: Hexafluorobenzene, Octafluoronaphthalene, Nucleophilic Substitution,
Dialkylamino-Substituted Arenes, Basicity
Introduction
Although a great many papers have been published
in this field, much remains to be done. For exam-
ple, there is only limited data available concerning
nucleophilic substitution by secondary amines. It is
generally known that with HFB in excess secondary
amine, 1,4-disubstitution typically take place [4, 5],
whereas with OFN 2,6-disubstitution occurs [6]. With
N-lithium amides, Koppang has shown that interac-
tion of HFB with different lithium anilides allows
preparation of mono-, 1,2- or 1,4-di- and 1,2,4,5-
tetrasubstituted derivatives, depending on the condi-
tions [7, 8]. We are aware of only one report on the
replacement of more than one fluorine in OFN; re-
action with lithium amides gave an inseparable mix-
ture of 2,6- and 2,7-dialkylaminosubstituted deriva-
tives (with relative abundance 2 : 1) [9]. Attempts to
prepare more highly substituted products have appar-
It is possible to replace hydrogen by fluorine in a
wide range of hydrocarbons without major structural
changes [1]. The resulting fluorocarbon systems usu-
ally show high thermal stability and have volatilities
similar to those of the corresponding hydrocarbon. Be-
cause fluorine is so electronegative there are of course
major differences in the chemistry of hydro- and flu-
orocarbons; in particular whereas aromatic hydrocar-
bons (e. g., benzene) tend to undergo electrophilic sub-
stitution (with hydrogen formally leaving as a proton)
the reactions of aromatic perfluorocarbons are domi-
nated by nucleophilic substitution. Perfluoroaromatic
compounds readily undergo nucleophilic replacement
of fluorines, often giving rise to highly substituted
derivatives [2, 3].
c
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V. I. Sorokin et al. · Polykis(dialkylamino)arenes by Nucleophilic Fluorine Replacement
Amine
R
T, ◦C
Reaction mass composition, %
5
6
5
2
9
2
8
0
7
1
0
7
1
5
0
8
0
69
0
66
0
9
0
12
0
14
0
Dimethylamine N(CH3)2
Dimethylamine N(CH3)2
95
190
95
94
16
84
15
87
42
Pyrrolidine
Pyrrolidine
Piperidine
Piperidine
pyrrolidin-1-yl
pyrrolidin-1-yl 190
piperidin-1-yl
piperidin-1-yl
95
190
53
5
Scheme 1.
ently not been reported. However, such polyamines, Action of neutral amines on HFB and OFN
especially those able to form intramolecular hydrogen
◦
Standard reaction conditions include: 95 C, 1,3-
dimethylimidazolidin-2-one [dimethyl(ethylene)urea,
DMEU] as solvent and a 4-fold excess of amine. At
lower temperatures, as well as lower amine concentra-
tions, monosubstitution is the main reaction pathway.
Selection of the reaction conditions was based on pre-
liminary experiments in which several dipolar aprotic
solvents [including dimethylformamide (DMF), hex-
amethylphosphoric triamide (HMPTA) and dimethyl
sulphoxide (DMSO)] were tested. In particular, DMF
was rejected at an early stage of this work due
to its decomposition, even at low temperatures, to
form dimethylamine, which competes with the start-
ing amine in nucleophilic substitution. HMPTA was
rejected mainly because of its carcinogenicity and dif-
ficulties removing this solvent from the reaction prod-
ucts. DMSO would seem to be a good alternative for
the more expensive DMEU, but its main disadvantage
is thermal lability at elevated temperatures and slightly
lower yields in comparison with DMEU.
bonds (IHB) of types 1 and 2, continue to attract in-
terest as non-nucleophilic basic catalysts for organic
transformations, models for studying IHB, and simu-
lators of proton transfer reaction in living cells [10].
Furthermore, their defluorinated analogues (for exam-
ple types 3 and 4 below) – due to the ease of one-
electron oxidation, and the stability of the resulting
radical-cations – find application both in the synthesis
of magnetic and conductive materials [11] and as color
developing agents in the manufacture of photographic
materials [12].
Previously, the Russian authors have published in
part results on nucleophilic substitution in OFN using
secondary amines [13] and secondary lithium amides
[14]; in this paper all collected data are presented and
analyzed, and supplemented with the reactions of HFB
under the same conditions.
HFB under standard conditions even after 24 h
produces mainly 1,4-disubstituted products of type 5
(Scheme 1), along with minor amounts of 1,3- (6) and
1,2- (7) isomers. The product composition and struc-
tures were determined by a combination of GC/MS,
and 1H and 19F NMR. Thus, for example, compounds
6 show the following characteristic 19F NMR signals:
an unresolved multiplet at about δ = −140 ppm (2-F),
a doublet at −159 ppm (4,6-F, 3J = 21 Hz) and a
triplet of doublets at −169 ppm (5-F, 3J = 21 Hz,
5J = 2 Hz). These 19F signals resemble those observed
earlier for products obtained by nucleophilic substitu-
tion in pentafluoroanilines [4].
Results and Discussion
In the present work, dimethylamine, pyrrolidine,
piperidine and their N-lithium derivatives, generated
in situ from the corresponding amines via treatment
with n-buthyl lithium, have been selected as the nitro-
gen nucleophiles. They differ from each other in both
nucleophilicity and steric requirements and allow us to
Extending the reaction time for up to 7 days had
model most reaction situations and predict the behav- no effect on the substitution pattern, and only with
ior of other amines. pyrrolidine were trace amounts of trisubstituted prod-
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617
Amine
R
Time, days
Reaction mass composition, %
14
2
0
0.3
0
3
15
75
0
79.5
0
16
23
100
20.2
100
15
Dimethylamine N(CH3)2
Dimethylamine N(CH3)2
3
7
3
7
3
7
Pyrrolidine
Pyrrolidine
Piperidine
Piperidine
pyrrolidin-1-yl
pyrrolidin-1-yl
piperidin-1-yl
piperidin-1-yl
82
63
0
37
Scheme 2 .
5
ucts 8 formed; the corresponding 19F NMR spectrum Jperi = 68 Hz, J = 17 Hz), a doublet of doublets at
5
contains three signals: a doublet near δ = −137 ppm
−135 ppm (1-F, Jperi = 67 Hz, J = 16 Hz), a dou-
blet at −148 ppm (7-F, 3J = 16 Hz) and a doublet
of multiplets at −152 (8-F, Jperi = 67 Hz). The fluo-
rines in compounds of type 16 give a singlet at about
−135 ppm (compare with the above-mentioned spec-
tral data and [16]).
5
3
(3-F, J = 8 Hz), a doublet at −153 ppm (5-F, J =
19 Hz) and a doublet of doublets at −154 ppm (6-F,
3J = 18 Hz, 5J = 8 Hz).
◦
Increasing the temperature to 190 C has a signifi-
cant effect on the course of the reaction, leading in the
case of dimethylamine and pyrrolidine, after 72 h, to a
complex mixture of di- 5 – 7, tri- 8 and tetrasubstituted
9 products (Scheme 1). Piperidine produces mainly di-
and trisubstitututed derivatives, with small amounts of
the 1,2,4,5-product 9. Unfortunately, we could not iso-
late trisubstituted derivatives of type 8 from the prod-
ucts, due to their very close mobility on common sor-
bents to diamines 5. The absence of compounds of type
10 and 11 in the product mix can be explained on the
basis of the well-established rule that the substitution
site must have a maximum number of activating meta-
and ortho-fluorines [15]. Thus only intermediate 13,
and not 12, is produced on reaction of 6 with amines.
Compounds 16 become essentially the sole products
in the reaction with dimethylamine and pyrrolidine at
the end of 7 days. However, even under these condi-
tions piperidine gave a mixture of 15 and 16, and in or-
der to make the latter the main product, increasing the
◦
temperature to 190 C was required. The substitution
pattern for the two other amines at this temperature es-
sentially does not change, although the product yields
are lower. With dimethylamine about 20% of the penta-
substituted product 17 was detected, its 19F NMR spec-
tra contained a characteristic peri-coupling constant of
about 80 Hz in agreement with the proposed structure.
The exclusive β-substitution observed in the reac-
tion of OFN is again a result of maximizing the num-
ber of activating meta- and ortho-fluorines: following
substitution of two amino groups, only intermediate 18
has the maximum number of activating fluorines. Their
influence is so strong that they overcome the steric hin-
drance associated with the introduction of a relatively
bulky substituent ortho to an existing one.
Prolonged heating (up to 7 days) does not have a ma-
jor effect on the product distribution, increasing some-
what the abundance of compounds 8 and 9.
OFN, having more sites for fluorine substitution
along with a larger π-system, already after 3 days pro-
duces a mixture of di- 14, tri- 15, and tetrasubstituted
16 derivatives (Scheme 2). The characteristic feature
is substitution of β-fluorines exclusively. Triamines 15
show the following set of 19F NMR signals: a dou-
blet of doublets at δ = −133 ppm (4-F, Jperi = 69 Hz,
One possible way to increase the number of sub-
stituting amino groups, as was demonstrated previ-
ously for pentafluoroaniline [3] and heptafluoroamino-
5J = 15 Hz), a doublet of doublets at −134 ppm (5-F, naphthalene [5] derivatives, is the conversion of com-
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V. I. Sorokin et al. · Polykis(dialkylamino)arenes by Nucleophilic Fluorine Replacement
˚
Fig. 1. The solid-state structure of 3,6-difluoro-1,2,4,5-tetrakis(piperidin-1-yl)benzene. Selected bond lengths (A) and angles
(◦): C(1)-C(3A) 1.400(2), C(3A)-C(2A) 1.410(2), F(1)-C(1) 1.366(2), N(1)-C(2) 1.432(2), N(2)-C(3) 1.419(2), C(1)-C(2)-
C(3) 117.5(2), C(2)-C(3)-C(1A) 117.3(2), C(3)-C(1A)-C(2A) 125.0(2), N(1)-C(2)-C(1) 123.8(2), N(1)-C(2)-C(3) 118.6(2),
N(2)-C(3)-C(2) 119.1(2), N(2)-C(3)-C(1A) 123.4(2), F(1)-C(1)-C(2) 117.5(2), F(1)-C(1)-C(3A) 117.1(2), C(8)-N(1)-C(2)-
C(1) 37.5(3), C(4)-N(1)-C(2)-C(3) 80.8(2), C(13)-N(2)-C(3)-C(2) 76.5(2), C(9)-N(2)-C(3)-C(1A) 36.2(3).
pounds 5 and 16 into more electron deficient N-oxides. ethyl ether only compound 9 formed, the same re-
However, in acidic media (H2O2/acetic or formic acid action in dioxane leads to a mixture of tri- (8) and
[3, 5]) even at low temperatures, only oxidation with tetrasubstituted (9) products; for example, with lithium
tarring of all reaction mass takes place. On the other piperidide the ratio was 42 : 58. Lithium dimethy-
hand, in neutral conditions (H2O2 in methanol, sim- lamide was an exception giving in diethyl ether a mix-
ilar to [17]; t-butyl hydroperoxide in the presence of ture of 5, 8 and 9. This probably arises due to the lower
transition metals [18]; H2O2-urea adduct/phthalic an- solubility of dimethylamide in ether in comparison
hydride system [19]) the starting compounds remain with lithium piperidide and pyrrolidide. The addition
unchanged even after prolonged reaction times.
of excess amide or “disaggregating” agents, such as
N,N,N’,N’-tetramethylethylenediamine (TMEDA) and
HMPTA, to THF solutions does not increase the num-
ber of fluorines replaced.
Confirmation of the functional group arrangement
in tetrasubstituted benzenes was confirmed by X-ray
analysis for the product of the reaction between HFB
and lithium piperidide, namely 3,6-difluoro-1,2,4,5-
tetrakis(piperidin-1-yl)benzene (Fig. 1). Its distinctive
feature, along with considerable twisting (by 60◦) of
the piperidino groups relative to the benzene ring (c.f.
55◦ for 1,4,5,8-tetrafluoro-2,3,6,7-tetrakis(piperidin-1-
yl)naphthalene), is the significant deviation of fluo-
The relative reaction rates and product distributions
allows the nucleophilicity order for amines to be es-
tablished: pyrrolidine > dimethylamine > piperidine.
This sequence is in agreement with data for other nu-
cleophilic substitution reactions [20].
Reaction with lithium dialkylamides
The amides were prepared in situ◦by reaction of n-
butyl lithium with amines at −10 C. We used two
equivalents of amide for each fluorine atom with re-
actions carried out at 20 ◦C for a period of 24 h.
Tetrasubstituted derivatives 9 were the main prod- rines from the least-squares plane of the aromatic ring,
˚
˚
ucts in the case of HFB, with overall yields ranging 0.22 A in comparison with 0.054 A in a similar naph-
from 80 to 90%. Whereas in THF and refluxing di- thalene derivative of type 16 [13]. Despite the presence
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V. I. Sorokin et al. · Polykis(dialkylamino)arenes by Nucleophilic Fluorine Replacement
619
of sterically demanding substitutents, the benzene ring hexasubstituted product 19 and even heptasubstituted
is almost planar; atoms C(1) and C(1A) (Fig. 1) devi- products such as 21 and 23. Why do the substitution
ate from the least-squares plane by only around 0.5◦, patterns differ?
showing some tendency to adopt a boat form.
Despite the fact that we have not identified the prod-
With OFN, the addition of HMPTA to ethereal sol- ucts of mono- and disubstitution in the reaction of OFN
vents is necessary in order to prevent contamination with lithium amides, the course of nucleophilic sub-
with less substituted derivatives. The nature of the sol-
stitution begins similarly to that with neutral amines,
vent, along with nucleophile strength, are the major with initial replacement of fluorine at position 2 and
factors determining the number of fluorines substi- then positions 6 or 7. This assumption is based on pre-
tuted.
vious observations of the reaction of OFN and lithium
diisopropylamide [9]. Thereafter, the substitution pat-
tern differs, as with neutral amines positions 2, 3, 6
and 7 are substituted (see 16), whereas with amides
fluorines at positions 3 and 7 are typically not substi-
tuted in the final product, although all other fluorines
are (see 19). Thus the difference in substitution seems
to occur during replacement of the third fluorine.
The mechanism of nucleophilic aromatic substitu-
tion (SNAr) is generally held to proceed via a two-
stage process involving the covalent addition of a nu-
cleophile to a substituted (or unsubstituted) carbon
ring atom, followed by departure of the leaving group
(fluoride in this case) to form the substituted product
(Scheme 3). The usually negatively charged interme-
diate, containing both the nucleophile and the leaving
group, is known as a Meisenheimer complex [22], and
is the anionic equivalent of the Wheland intermediate
in electrophilic substitution [23]. The negative charge
in the Meisenheimer complex is delocalized into the
aromatic π-system which, like the Wheland intermedi-
ate, can be considered as a resonance hybrid of multi-
ple canonical forms.
Reaction with lithium piperidide in all solvents used
leads to the formation of the hexasubstituted product
19 exclusively; its structure was confirmed by X-ray
analysis [14].
Lithium dimethylamide give compound 20 only in
dioxane; in THF the substitution pattern changes, lead-
ing to the heptasubstituted derivative 21. With the more
nucleophilic lithium pyrrolidide reaction in dioxane
produced an inseparable mixture of 22 and 23 (45 and
55%, respectively), while in THF only 23 formed.
All efforts to achieve octasubstitution, by varying
the reaction conditions and the concentration of amide,
were unsuccessful.
Scheme 3.
Attempts to substitute the remaining fluorines
in tetrakis(dialkylamino)naphthalenes 16 were also
made. Neither lithium piperidide nor pyrrolidide gave
any new products, possibly due to repulsion between
the amino groups in the corresponding σ-complexes.
With lithium dimethylamide in THF, the amine 24 is
formed in about 42% yield. Its 19F NMR spectrum
showed a number of complicated multiplets, indicating
a “through space” interaction with the methyl protons
of the peri-dimethylamino group [21].
The American authors have presented a simple
model for determining the principal site for nucle-
ophilic substitution in aromatic perfluorocarbons [24]
based on the relative stabilities of the various Meisen-
heimer complexes as calculated via density functional
theory (using the hybrid B3LYP functional [25] with
the modest 6-31G∗ Gaussian basis set [26], denoted
B3LYP/6-31G∗). Basically all possible Meisenheimer
complexes for a given aromatic perfluorocarbon are
In general reaction of OFN with neutral amines calculated, using the fluoride ion as a model nucle-
results primarily in the tetrasubstituted product 16 ophile, with the lowest energy complex determin-
whereas reaction with lithium amides readily gives the ing the substitution site. This is essentially a purely
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V. I. Sorokin et al. · Polykis(dialkylamino)arenes by Nucleophilic Fluorine Replacement
Fig. 2. Transition state for reaction of 14 with lithium dimethylamide showing nucleophilic substitution at position 1. The
arrows indicate the atomic displacements in the imaginary mode. The lithium atom is “coordinated” to one of the ring fluorines
and the nitrogen atom of the N(CH3)2 group at position 2; this brings the nitrogen atom of the dimethylamide (N 20) over the
ring carbon at position 1, facilitating the attack. As can be seen a bond is forming between this nitrogen (arrow down) and the
˚
ring carbon atom (C 3, arrow up). The N-C distance in the transition state is 2.20 A.
thermodynamic argument, i. e., the thermodynamically [24] ought to be applicable to the latter case, as any ini-
most stable Meisenheimer complex is the one most tially formed Meisenheimer complex can decompose
likely to form, and the substitution pattern follows di- several times back into the reactants before forming
rectly from that.
products, which favors formation of the most thermo-
dynamically stable complex. On the other hand, if the
Meisenheimer complex decomposes readily to prod-
ucts, then the thermodynamics is of much less impor-
tance and the quantity that really needs to be computed
is the barrier height. In this situation, one would not
expect the model in ref. [24] to work at all.
Despite its simplicity, and the fact that it cannot pos-
sibly account for all the different nucleophiles, sol-
vents and reaction conditions found experimentally,
this model proved to be remarkably reliable, success-
fully predicting the principal substitution site in 16 dif-
ferent aromatic perfluorocarbons, including OFN [24].
The general consensus among experimentalists ap-
We have carried out B3LYP/6-31G∗ calculations
pears to be that for strong nucleophiles the rate- on all distinct Meisenheimer complexes derived
limiting step in nucleophilic substitution reactions is from 14 using dimethylamine as the nucleophile
Meisenheimer complex formation, whereas for weak (R = N(CH3)2). All calculations used the PQS pro-
nucleophiles (such as amines) the rate-limiting step is gram [28]. Such calculations are clearly in the spirit
decomposition of the Meisenheimer complex into the of the model in ref. [24]. The lowest energy Meisen-
products [2, 27]. The simple model presented in ref. heimer complex corresponds to substitution at posi-
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V. I. Sorokin et al. · Polykis(dialkylamino)arenes by Nucleophilic Fluorine Replacement
621
Fig. 3. Transition state for decomposition of the Meisenheimer complex derived from 14 by attachment of dimethylamine at
position 3. The arrows indicate the atomic displacements in the imaginary mode. The hydrogen atom directly attached to the
nitrogen in the dimethylamine ligand is leaving (arrow down) and forming a bond with the leaving fluorine atom formerly
˚
attached to the ring carbon at position 3. The ring carbon – leaving fluorine atom distance in the transition state is 1.97 A.
According to Weinhold’s NBO analysis [29], this fluorine is well on the way to being a fluoride ion, with a calculated atomic
charge of −0.64|e|.
tion 3, exactly as found experimentally. Additionally plexes in the reactions with dimethylamine. As ex-
we have located transition states for the reaction of pected, computed barrier heights are noticeably greater
LiN(CH3)2 with 14, with substitution at positions 1, than those for the reaction with amide, being around
3 and 4. We have not incorporated any solvent effects, 35 kcal/mol (gas phase), but the lowest barrier is for
and thus the transition states we have located formally loss of HF from position 3. Note that in addition to the
correspond to reaction in the gas phase. Nevertheless, corresponding Meisenheimer complex being the most
the lowest energy transition state corresponds to nu- stable energetically, the 3-substituted product is also
cleophilic attack at position 1, not position 3 which the most stable of the possible products. The transition
is actually the least favorable. The estimated barrier state for loss of HF from position 3 is shown in Fig. 3.
height for attack at position 1 is only 7.4 kcal/mol, in-
Basicity of hexa- and heptakis(dialkylamino)fluoro-
naphthalenes
dicating – as is found experimentally – that lithium di-
methylamide is very reactive. All transition states were
verified as such by vibrational analysis. A schematic
of the transition structure for 1-substitution with ar-
rows showing the atomic displacements in the imag-
inary mode is shown in Fig. 2. The transitions states
for 3- and 4-substitution are similar.
The basicity of the poly(dialkylamino)naphthalenes
19 – 24 is of particular interest, inasmuch as com-
pounds producing IHB of type 2 following protonation
are currently among the most intensively studied of all
organic bases [10]. These derivatives furthermore con-
Additionally we have calculated transition states for tain strongly electron donating β-amino groups, which
the loss of HF from the various Meisenheimer com- should significantly increase the resulting basicity.
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V. I. Sorokin et al. · Polykis(dialkylamino)arenes by Nucleophilic Fluorine Replacement
Table 1. pKa Values for some poly(dialk-
ylamino)naphthalenes in 80% aq. dioxane
(at 25 ◦C).
Compound
pKaa
Compound
pKaa
12.9 0.3
(7.6 0.1)
13.9 0.4
a
pKa1 values, along with pKa2 in parentheses;
b
pKa in water is 12.1 [30].
12.2 0.3
(8.2 0.2)
11.2 0.2
(6.9 0.1)
12.7 0.3
(8.2 0.2)
9.9 0.1b
Since the pyrrolidino substituted products 22 and 23 substitution in the corresponding perfluoroaromatic
readily oxidize upon exposure to air, we measured the compounds using secondary amines and secondary
basicity for piperidino 19 and dimethylamino 20, 21, lithium amides. With hexafluorobenzene (HFB) the
24 substituted derivatives. pKa values were determined same substitution pattern is observed with both amines
in 80% aq. dioxane along with values for the parent and amides, but with octafluoronapthalene (OFN) the
compounds 25 and 26 (Table 1).
subsitution pattern differs after the first two fluorines
have been replaced. Theoretical calculations indicate
that with lithium dimethylamide the third fluorine is
substituted at position 1, whereas with dimethylamine
it is position 3. The maximum number of fluorines that
can be replaced under our reaction conditions is four
for HFB and six (with lithium piperidide) or seven
(with dimethylamide and pyrrolidide) for OFN. The
hexa- and heptasubstituted naphthalenes are stronger
bases than the parent 1,8-bis(dimethylamino)naphthal-
ene 25, although the increase in basicity is smaller than
expected.
During our measurements derivatives 19 – 21 gave
mono- 27 and then diprotonated 28 salts, while hex-
aamine 24 gave only the monocation 29. As can be
seen from Table 1, all compounds synthesized, except
the piperidino substituted compound 19, are stronger
bases than 25 and 26, although the increase in basicity
is not as great as we anticipated based on the number
of animo groups. This is most likely due to the strongly
strained structures of compounds 19 – 24 and their pro-
tonated cations, which lead to IHB destabilization and
accordingly decrease the basicity.
Conclusions
Experimental Section
A series of dialkylaminosubstituted benzenes and
Hexafluorobenzene, octafluoronaphthalene, pyrrolidine
naphthalenes have been synthesized by nucleophilic and DMEU were purchased from Lancaster; HMPTA and
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623
1.6 M n-butyl lithium in hexane from Fluka. 1H and General procedure for the reaction of HFB and OFN with
19F NMR spectra were recorded on a Varian Unity-300 spec- lithium amides
1
trometer with (CH3)4Si as the internal standard for H and
To the amine (2 equivalents per each fluorine atom) in
CFCl3 for 19F. GC/MS were performed on Perkin Elmer PE-
anhydrous THF (or other solvent, 3 ml) 1.6 M n-BuLi in
5MS RX apparatus. A 25 m fused silica (methylphenylsili-
cone) capillary column was used with UHP grade helium as
the carrier gas. pKa values were measured by potentiomet-
hexane (2 equivalents per each fluorine atom) were added
dropwise at −10 ◦C under argon. The reaction mixture was
◦
stirred at −10 C for 20 min and then a solution of the per-
ric titration of corresponding conjugated acids with 0.1 M
fluoroaromatic (0.1 mmol) in THF (or other solvent, 2 ml)
aq KOH in 80% aqueous dioxane according to the method
was added. The solution was allowed to warm up to room
described in ref. [31]. 0.05 M aq KCl was used as stock elec-
temperature, stirred for 24 h and then quenched with MeOH
trolyte. Hydrogen ion activity was measured using an electric
(1 ml). The reaction mixture was then poured into 30% aq.
cell containing glass and Ag/AgCl (reference) electrodes.
KOH (15 ml) and the products were extracted with hexane
(5 × 3 ml). The extract was washed with water (3 × 15 ml),
General procedure for the reaction of HFB and OFN with
neutral amines
dried over Na2SO4, evaporated to dryness and crystallized
from a suitable solvent or separated by column chromatogra-
phy on alumina.
A solution of the perfluoroaromatic (0.1 mmol), amine
(4 equivalents per each fluorine atom) and DMEU (2 ml)
in a sealed tube was heated at the desired temperature for
the selected time (see below). The reaction mixture was then
poured into water (30 ml) and the products were extracted
with hexane (chloroform for the less soluble piperidino
substituted derivatives) (4 × 5 ml). The organic phase was
washed with water (4 × 20 ml), dried over Na2SO4, evapo-
rated to dryness and crystallized from an appropriate solvent.
3,6-Difluoro-1,2,4,5-tetrakis(dimethylamino)benzene
THF as solvent, yield 80%; colourless needles with m. p.
123 – 124 ◦C (from MeOH). – 1H NMR (300 MHz, CDCl3):
δ = 2.79 (24 H, m, N(CH3)2). – 19F NMR (272 MHz,
CDCl3): δ = −137.46 (s). – MS (EI, 70 eV): m/z (%) =
286 (100) [M]+, 256 (14) [M-CH2NH2]+, 225 (17) [M-
2CH2NH2]+, 58 (39) [C3H8N]+, 44 (71) [C2H6N]+. –
C14H24F2N4 (286.4): calcd. C 58.7, H 8.45, N 19.6; found
C 59.0, H 8.3, N 19.8.
2,3,5,6-Tetrafluoro-1,4-bis(dimethylamino)benzene
◦
3,6-Difluoro-1,2,4,5-tetrakis(pyrrolidin-1-yl)benzene
Optimal conditions: 95 C, 24 h; yield 79%; colourless
needles with m. p. 38 – 39 ◦C (purified by vacuum sublima-
tion) (lit.: 38.5 ◦C [4]). – 1H NMR (300 MHz, CDCl3): δ =
2.87 (12 H, s, N(CH3)2). – 19F NMR (272 MHz, CDCl3):
δ = −154.59 (s). – C10H12F4N2 (236.2): calcd. C 50.85,
H 5.1, N 11.9; found C 50.7, H 5.3, N 11.8.
THF as solvent, yield 90%; colourless needles with m. p.
197 – 198 ◦C (from MeOH). – 1H NMR (300 MHz, CDCl3):
δ = 1.86 (16 H, m, CH2CH2), 3.23 (16 H, m, N(CH2)2). –
19F NMR (272 MHz, CDCl3): δ = −137.17 (s). – MS
(EI, 70 eV): m/z (%) = 390 (100) [M]+, 195 (16) [M-
195]+, 70 (55) [C4H8N]+, 55 (20) [C4H7]+, 41 (38) [C4H7-
CH2]+. – C22H32F2N4 (390.5): calcd. C 67.7, H 8.3,
N 14.35; found C 67.6, H 8.1, N 14.2.
2,3,5,6-Tetrafluoro-1,4-bis(pyrrolidin-1-yl)benzene
◦
Optimal conditions: 95 C, 24 h; yield 78%; colourless
needles with m. p. 94 – 95 ◦C (from MeOH) (lit.: 88 ◦C [4]). –
1H NMR (300 MHz, CDCl3): δ = 1.90 (8 H, m, CH2CH2),
3.40 (8 H, m, N(CH2)2). – 19F NMR (272 MHz, CDCl3):
δ = −156.89 (s). – C14H16F4N2 (288.3): calcd. C 58.3,
H 5.6, N 9.7; found C 58.7, H 5.3, N 9.6.
3,6-Difluoro-1,2,4,5-tetras(piperidin-1-yl)benzene
THF as solvent, yield 79%; colourless needles with m. p.
224 – 225 ◦C (from MeOH). – 1H NMR (300 MHz, CDCl3):
δ = 1.55 (8 H, m, CH2), 1.61 (16 H, m, CH2CH2), 3.03
(16 H, m, N(CH2)2). – 19F NMR (272 MHz, CDCl3): δ =
−136.46 (s). – MS (EI, 70 eV): m/z (%) = 446 (100) [M]+,
378 (12) [M-C5H8]+, 295 (10) [M-C5H8-C5H9N]+, 83 (15)
[C5H9N]+, 43 (28) [C2H5N]+. – C26H40F2N4 (446.6):
calcd. C 69.9, H 9.0, N 12.5; found C 70.1, H 9.1, N 12.3.
2,3,5,6-Tetrafluoro-1,4-bis(piperidin-1-yl)benzene
Optimal conditions: 95 ◦C, 24 h; yield 80%; colour-
less plates with m. p. 134 – 135 ◦C (from MeOH) (lit.:
130 ◦C [4]). – 1H NMR (300 MHz, CDCl3): δ = 1.90 (12 H,
m, CH2CH2CH2), 3.40 (8 H, m, N(CH2)2). – 19F NMR
(272 MHz, CDCl3): δ = −156.90 (s). – C16H20F4N2
3,6-Difluoro-1,2,4,5,7,8-hexakis(piperidin-1-yl)naphthalene
THF as solvent, yield 46%; yellow powder with
(316.3): calcd. C 60.75, H 6.4, N 8.9; found C 60.6, H 6.4, m. p. 247 – 248 ◦C (from CH2Cl2). – UV/vis (n-hexane):
N 8.6.
λmax(lgε) = 224 (4.46), 259 (4.43), 368 nm (4.07). –
Unauthenticated
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624
V. I. Sorokin et al. · Polykis(dialkylamino)arenes by Nucleophilic Fluorine Replacement
1H NMR (300 MHz, CDCl3): δ = 1.59 (36 H, m, eral procedure. Yield 42%; yellow crystals with m. p.
◦
CH2CH2CH2), 3.03 (16 H, s, N(CH2)2), 3.16 (8 H, 176 – 177 C (from MeOH/hexane). – UV/vis (n-hexane):
m, N(CH2)2). – 19F NMR (272 MHz, CDCl3): δ =
λmax(lgε) = 220 (4.27), 303 (3.99), 360 nm (shoulder). –
−134.54 (s). – C40H60F2N6 (662.9): calcd. C 72.5, H 9.1, 1H NMR (300 MHz, CDCl3): δ = 2.77 (12 H, m, N(CH3)2),
N 12.7; found C 72.3, H 9.2, N 12.5.
2.81 (24 H, s, N(CH3)2), 2.83 (12 H, m, N(CH3)2). –
19F NMR (272 MHz, CDCl3): δ = −134.5 (m). – MS
(EI, 70 eV): m/z (%) = 447 (30) [M]+, 389 (17) [M-
C3H8N]+, 388 (12) [M-C3H8N-H]+, 374 (12) [M-C3H8N-
CH3]+, 58 (100) [C3H8N]+. – C24H42F1N7 (447.6): calcd.
C 64.4, H 9.5, N 21.9; found C 64.4, H 9.7, N 21.7.
7-Fluoro-1,2,3,4,5,6,8-heptakis(dimethylamino)naph-
thalene
THF as◦ solvent, yield 43%; yellow needles with m. p.
148 – 149 C (from MeOH/hexane). – UV/vis (n-hexane):
λmax (lgε) = 213 (4.54), 236 (4.50), 311 (3.41), 355 nm
(shoulder). – 1H NMR (300 MHz, CDCl3): δ = 2.75
(12 H, m, N(CH3)2), 2.77 (12 H, s, N(CH3)2), 2.78
(12 H, m, N(CH3)2), 2.81 (24 H, m, N(CH3)2), 2.82
(12 H, s, N(CH3)2). – 19F NMR (272 MHz, CDCl3): δ =
−134.0 (s). – MS (EI, 70 eV): m/z (%) = 447 (14) [M]+,
389 (11) [M-C3H8N]+, 58 (100) [C3H8N]+. – C24H42F1N7
(447.6): calcd. C 64.4, H 9.5, N 21.9; found C 64.4, H 9.4,
N 21.7.
Crystal structure determination of 3,6-difluoro-1,2,4,5-tetra-
kis(piperidin-1-yl)benzene
Single crystals suitable for X-ray diffraction were selected
directly from the analytical sample.
Crystal data: C26H40F2N4, M = 446.62, triclinic
space group P1, a = 6.5655(11), b = 8.8550(15), c =
¯
˚
10.8553(19) A, α = 77.893(4), β = 88.455(4), γ =
79.285(4)◦, Z = 1, Dcalc. = 1.223 g cm−3. Diffractome-
ter: Bruker SMART 1000 CCD, µ(Mo-Kα ) = 0.098 mm−1
,
7-Fluoro-1,2,3,4,5,6,8-heptakis(pyrrolidin-1-yl)naph-
thalene
graphite monochromator, crystal size 0.25×0.35×0.50 mm,
T = 120(2) K; 4357 reflection measured, 2858 unique
(Rint = 0.0246) which were used in all calculations, cut-off
criterion I > 2σs(I), µ = 0.083 mm−1, solution and refine-
ment with SHELXL-97 [32]. The final R and wR(F2) values
were 0.0608 and 0.1182 (all data), the residual electron den-
THF as solvent, yield of crude product 45%, which readily
oxidised on exposure to air and so was not characterised in
1
detail. – H NMR (300 MHz, CDCl3): δ = 1.86 (28 H, m,
CH2CH2), 3.24 (28 H, m, N(CH2)2).
sity was between 0.24 and −0.27 e A−3. Crystallographic
˚
data for the structure have been deposited with the Cam-
bridge Crystallographic Data Centre, CCDC-272720. Copies
of the data can be obtained free of charge on application to
The Director, CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK (Fax: int.code +(1223)336-033; e-mail for inquiry: file-
serv@ccdc.cam.ac.uk).
8-Fluoro-1,2,3,4,5,6,7-heptakis(dimethylamino)naph-
thalene
Obtained by reaction of 1,4,5,8-tetrafluoro-2,3,6,7-tetra-
kis(dimethylamino)naphthalene (0.1 mmol) with lithium di-
methylamide (0.8 mmol) in THF according to the gen-
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