Victoria L Wait

CHEM 3695 Final Paper

The Preparation and Significance of 5,6,7,8-tetrafluoro-2,3-naphthalene-indanone.

Abstract
The vast array of fluorinated pharmaceuticals, agrochemicals, plastics, and aerosols clearly
demonstrates the importance of the element fluorine in contemporary chemistry and its
applications. The physiochemical altering effects of fluorine on functional materials is a
highly advantageous tool that the Etzkorn group is applying to the preparation of novel
molecular scaffolds. This current project is focused on devising a successful synthetic route to
the fluorinated anti-naphthyl dimeric compound by utilizing an isoindenone intermediate.
This work is analogous to a previous project, and will offer valuable insight on the impact of
fluorine functionality when it becomes displaced by one aromatic unit.
Keywords: isoindanone, isoindenone, naphthyl, synthesis, fluorine, dimer
Introduction
The addition of fluorine to functional
materials alters their physicochemical
properties, offering a vastly beneficial tool,
which the Etzkorn group is utilizing in the
preparation of novel molecular scaffolds.
The group has previously investigated
complex fluorinated scaffolds. Figure 1
depicts a fluorinated syn-bisquinoxaline (1)
with a molecular tweezer functionality.1 This
U-shaped compound utilizes fluorine to
promote effective interactions with electronrich compounds, thus functioning as a
molecular tweezer. Figure 1 also depicts a
fluorinated glycoluril-framework (2) that is
capable of self-assembly through both headto-head as well as head-to-tail interactions.
The fluorinated anti-dinaphthyl
dimeric compound (4) represents the target
scaffold, with laterally displaced arene units.
The isolation of this target scaffold, along
with subsequent reactions, is intended to aid
in answering fundamental research inquiries
of electronic delocalization, the effects of
fluorine on the electronics, and in pistacking between aromatic molecules. The
group is targeting the synthesis of (4)
through the production of its corresponding
isoindenone intermediate. This is analogous

to previous work with the anti-dibenzo

dimeric compound that was also synthesized
through the production of an isoindenone
intermediate2,
to
research
the
electrochemical
impacts
with
the
displacement of fluorine functionality by
one aromatic unit.
Figure
1.
Fluorinated
synbisquinoxaline
and
fluorinated
glycoluril-framework.
Isoindenones are cross-conjugated
10 pi-electron systems that have yet to be
isolated. The chemistry of isoindenones has
been intriguing chemists for several decades

due to their high reactivity and behavior as

fleeting intermediates. Thus, the isolation of
isoindenone derivatives has been futile so
far. Two general approaches for stabilizing

Victoria L Wait
CHEM 3695 Final Paper

these highly reactive species have been

attempted. One of these methods consists of
introducing bulky substituents to the
isoindenone compounds, while the other
involves electronic stabilization of the
highly reactive compound. Though not
entirely successful, these strategies have
resulted in a push-pull isoindenone that was
somewhat stable in dilute solution.
Generally,
literature
methods
use
isoindanone as a precursor for the generation
of the corresponding isoindenone.
Figure 2. The anti-naphthyl dimeric
compound will be targeted through
the formation of the isoindanone.

Results and Discussion

The Etzkorn group targets the
generation of halogenated isoindenones,
which are scarcely reported in the literature3,
through the synthesis of the corresponding
isoindanone precursor. The fluorinated
species is of particular interest, as the
fluorine substituents are expected to
radically alter the compounds properties.
Utilizing these intermediates as platforms
for the synthesis of the dimeric compounds,
such as 4, is the overall goal. Previous work
within the group has been successful in
affording the anti-dibenzo compounds, with
current research proving hopeful for the
synthesis of the anti-naphthyl compound. A
successful synthetic route affording the

5,6,7,8-tetrafluoro-2,3-naphthaleneindanone has been developed. This synthetic

route takes six steps to achieve the desired
isoindanone. Optimization of reaction
conditions became necessary as the
solubility became increasingly poor with
each subsequent reaction.
5,6,7,8-tetrafluoro-2,3-naphthaleneindanone (3) is readily synthesized in six
steps
from
5,6,7,8-tetrafluoro-2,3dimethylester-naphthalene (6) with an
overall yield of 35%, Scheme 1. 6 was
obtained in 83% yield by a cava reaction4
with bis(bromomethyl)-3,4,5,6-tetrafluorobenzene
and
dimethyl
acetylene
dicarboxylate. The diol (7) was obtained in
94% yield from a lithium aluminum hydride
reduction of the diester (6). Treatment of 7
with
sodium
iodide
and
tertbutyldimethylchlorosilane in acetonitrile
gives 8 in 79% yield.5 The dicyano (9) was
obtained in 97% yield upon treatment of 8
with sodium cyanide in benzene and
methanol. In the presence of sodium
ethoxide, 9 cyclizes to form the enamine
(10) in 92% yield.6 Decarboxylation of 10
with concentrated hydrochloric acid gives
the fluorinated isoindanone (3) in 76% yield.
Purification was necessary at two points in
this synthetic route. 6 was purified by
column chromatography over silica gel with
a 4:1 cyclohexane:ethyl acetate eluent. 3
was
also
purified
by
column
chromatography over
Compound
3
6
7
8
9
10

Mass
Balance
(g)
3.952
3.864
6.268
0.284
0.459
0.202

Percent
Yield (%)
83
94
79
97
92
76

Victoria L Wait
CHEM 3695 Final Paper

Scheme 1. The synthetic route to the fluorinated isoindanone.

Table 1. Mass balance and percent
yields for each of the synthesized

compounds.
silica gel with a 3:1 cyclohexane:ethyl
acetate eluent.
Now that a successful synthetic route
to the fluorinated naphthyl isoindanone has
been developed, future research within the
group will focus on targeting the antinaphthyl dimeric compound through the
formation of the isoindenone intermediate.7
The remaining synthetic route toward the
dimeric compound from the isoindanone is
three steps with the anticipation of only a
semesters worth of time before isolating
and characterizing the target compound.
Experimental Section

Preparation of 5,6,7,8-tetrafluoro-2,3dimethylester-naphthalene (6). To a

solution of 1,2-bis(bromomethyl)-3,4,5,6tetrafluorobenzene (5.013 g, 15 mmol) in

degassed DMF (85 mL) was added 1,4dimethylester-2-butynedioc acid (1.92 g,
13.5 mmol) and sodium iodide (12.17 g, 81
mmol), and the mixture was heated to 85 C.
After stirring for 36 h, the solution was
quenched with 150 mL water and 250 mL
saturated NaHSO3, and extracted with
CH2Cl2. The combined organic phase was
dried over anhydrous MgSO4. The solvent
was evaporated in vacuo, and the resulting
brown oil was purified by chromatography
(silica gel, cyclohexane:ethyl acetate = 4:1
as eluent) to afford the pure compound 4
(3.952 g, 12.5 mmol, 83% yield).

Victoria L Wait
CHEM 3695 Final Paper

Preparation of 5,6,7,8-tetrafluoro-2,3naphthalenedimethanol
(7).
To
a
suspension of LAH (1.227 g, 35.4 mmol) in
THF (40 mL) was added 4 (5.003 g, 15.8
mmol) at 0 C, and the mixture was warmed
to room temperature. After stirring 6 h, the
solution was cooled to 0 C, and quenched
with 10 mL water and 20 mL HCl (3 M).
The mixture was washed with saturated
NaHCO3 and extracted with CHCl3. The
combined organic phase was dried over
anhydrous MgSO4. The solvent was
evaporated in vacuo to afford the pure
compound 5 (3.864 g, 14.8 mmol, 94%
yield).
Preparation of 5,6,7,8-tetrafluoro-2,3naphthalenediiodo (8). A mixture of 7
(4.301 g, 16.5 mmol) and sodium iodide
(9.904 g, 66.1 mmol) was dissolved in
acetonitrile (100 mL). To this solution was
added TMSCl (12 mL) and the mixture was
heated to 70 C. After stirring 1 h, the
solution was cooled to room temperature,
quenched with 50 mL water, and extracted
with CHCl3. The combined organic phase
was dried with anhydrous MgSO4. After
removal of the solvent in vacuo, the residue
was washed with 50 mL MeOH and dried in
vacuo to afford the pure compound 6 (6.268
g, 13.1 mmol, 79% yield).
Preparation of 5,6,7,8-tetrafluoro-2,3naphthalenedimethylcyano (9). A solution
of 8 (0.500 g, 1.05 mmol) in benzene (2 mL)
and MeOH (4 mL) was brought to reflux. To
the refluxing solution was added sodium
cyanide (86.5 mg, 2.10 mmol) portion-wise
over 15 min. After refluxing for 1 h, the
solution was cooled to 0 C, acidified with 3
mL HCl (2M), and extracted with CH2Cl2.
The combined organic phase was dried with
anhydrous MgSO4. The solvent was
evaporated in vacuo to afford the pure
compound 7 (284 mg, 1.02 mmol, 97%
yield).

Preparation of 5,6,7,8-tetrafluoro-2,3naphthalene-enamine (10). To a solution of

9 (0.500 g, 1.05 mmol) in EtOH (40 mL)
was added NaOEt/EtOH (5 mg Na in 1 mL
EtOH). After refluxing for 6 h, the solution
was quenched with 1 mL CH3CO2H, and
stirred for an additional 10 min. The solvent
was evaporated in vacuo to afford the
desired compound 8 (459 mg, 1.65 mmol,
92% yield).
Preparation of 5,6,7,8-tetrafluoro-2,3naphthalene-indanone (3). To 15 mL of
concentrated HCl was added 10 (0.500 g,
1.05 mmol). After 15 min stirring at room
temperature, 10 mL water was carefully
added dropwise. After refluxing for 18 h, the
solution was diluted with 20 mL water and
extracted with CH2Cl2. The combined
organic phase was dried with MgSO4. The
solvent was evaporated in vacuo, and the
resulting colorless solid was purified by
chromatography
(silica
gel,
cyclohexane:ethyl acetate = 3:1 as eluent) to
afford the pure compound 2 (202 mg, 0.795
mmol, 76% yield).
References
1. Meyers, T. B. M. S. Thesis, UNCC
2012.
2. Jones, D. W.; Ryder, T. C. L. M. J.
Chem. Soc., Chem. Comm. 1997,
1169-70.
3. Hoffman, R.; Blatt, K. J. Chem. Soc.
Chem. Commun. 1969, 586.
4. Rawson, J. S.; Krishnamurthy, V.;
Hughes, T. S. Abstracts. 2008.
5. Takahashi, T.; Li, S.; Huang, W. J.
Org. Chem. 2006, 7967-77.
6. Rosowsky, A.; Dey, A. S.; Battaglia,
J.; Modest, E. J. J. Hetero. Chem.
1969, 613-22.

Victoria L Wait
CHEM 3695 Final Paper

7. Holland, J. M.; Jones, D. W. Chem.

Comm. 1969, 587-8.