Acid-Catalyzed Condensations of Ninhydrin with Aromatic Compounds. Preparation of 2,2-Diaryl-1,3-indanediones and 3-(Diarylmethylene)isobenzofuranones 1

Article abstract of DOI:10.1021/jo990197h

Ninhydrin (1) reacts with aromatic compounds in acid solution to give condensation products. In H₂SO₄, 1 reacts with arenes to give 2,2-diaryl-1,3-indanediones (2a-f). In superacidic triflic acid (CF₃SO₃H, TfOH)

Full text of DOI:10.1021/jo990197h

5152
J . Org. Chem. 1999, 64, 5152-5155
Acid -Ca ta lyzed Con d en sa tion s of Nin h yd r in w ith Ar om a tic
Com p ou n d s. P r ep a r a tion of 2,2-Dia r yl-1,3-in d a n ed ion es a n d
3-(Dia r ylm eth ylen e)isoben zofu r a n on es1
Douglas A. Klumpp,*,† Shyla Fredrick,† Siufu Lau,† Kevin K. J in,‡ Robert Bau,‡
G. K. Surya Prakash,‡ and George A. Olah*,‡
Department of Chemistry, California State Polytechnnic University, 3801 West Temple Avenue, Pomona,
California, 91768, and Department of Chemistry and Loker Hydrocarbon Research Institute, University of
Southern California, Los Angeles, California, 90089-1661
Received February 2, 1999
Ninhydrin (1) reacts with aromatic compounds in acid solution to give condensation products. In
H2SO4, 1 reacts with arenes to give 2,2-diaryl-1,3-indanediones (2a -f). In superacidic triflic acid
(CF3SO3H, TfOH), 1 reacts with arenes to give 3-(diarylmethylene)isobenzofuranones (3a -e).
Products 3a -e are proposed to have formed by a condensation and rearrangement involving
dicationic intermediates. Benzo[f]ninhydrin also reacts with C6H6 in H2SO4 to give a similar
condensation product.
In tr od u ction
We have been interested in the chemistry of 1,2-
dicarbonyl groups and their electrophilic chemistry in
triflic acid (CF3SO3H, TfOH). We recently reported the
superacid-catalyzed condensations of isatins to 3,3-dia-
ryloxindoles and parabanic acids to 5,5-diarylhydanto-
ins.7,8 Both of these studies showed that the 1,2-
dicarbonyl groups form highly reactive electrophiles in
superacidic triflic acid and that these electrophiles could
be exploited in synthesis. In a similar respect, Owada
and Shudo have studied the chemistry 1,2-diketones in
triflic acid and proposed that 1,2-dicarbonyl groups are
diprotonated in superacid.9 These diprotonated interme-
diates are shown to exhibit superelectrophilic chemistry
in electrophilic aromatic substitution reactions.10 Given
the tendency of 1,2-dicarbonyl groups to form reactive
electrophiles in superacid, it seemed likely that ninhydrin
(1) would also exhibit a protolytic activation in strong
acid and superacid systems.
Ninhydrin (1) is a compound which was first reported
in the literature in 1910.2a It is the stable, hydrated
product of 1,2,3-indanetrione (eq 1). Ninhydrin has been
a useful compound in organic chemical, biochemical,
analytical, and forensic sciences.2b Its varied applications
include the qualitative and quantitative assay for R-ami-
no acids in bioanalytical work and the visualization of
fingerprints in forensic science.
The chemistry of ninhydrin has been extensively
studied. Much of the work has been directed toward the
reaction of amines with ninhydrin.2 Primary amines and
R-amino acids react at the C-2 position of ninhydrin and
eventually lead to the formation of a highly colored,
condensation product known as Ruhemann’s purple. In
addition to nitrogen-based nucleophiles, the C-2 position
of ninhydrin has also been found to react with sulfur-,
oxygen-, and carbon-based nucleophiles.3 Despite the
highly electrophilic character of the C-2 position, little
work has been done to examine the electrophilic chem-
istry of ninhydrin toward aromatic substrates. Ninhydrin
was reported to react in high yields with phenols in acetic
acid, and more recently, a Friedel-Crafts type reaction
of 1 with arenes was described in which 2,2-diaryl-1,3-
indanediones were prepared.4-6
We report our studies of the electrophilic chemistry of
ninhydrin (1) in strongly acidic solutions. In addition to
reporting a general synthetic conversion involving 1 and
an improved procedure for the preparation of 2,2-diaryl-
1,3-indanediones, we also propose a mechanism for the
novel, superacid-promoted rearrangement of the conden-
sation products from 1.
Resu lts a n d Discu ssion
Reaction of ninhydrin (1) in H2SO4 with arenes gives
products of electrophilic aromatic substitution. For ex-
(4) (a) Schmitt, G.; Dinh An, N.; Poupelin, J . P.; Vebrel, J .; Laude,
B. Synthesis 1984, 758. See also, (b) Yamazaki, T.; Takizawa, T
Tetrahedron 1972, 28, 4675.
(5) Song, H. N.; Seong, M. R.; Son, J . S.; Kim, J . N. Synth. Commun.
1998, 28, 1865.
(6) In the earlier study (ref 5) reaction time was limited to 1 h, and
only 2.2 equivalents of H2SO4 was used in the conversion. Under the
more acidic conditions and longer reaction times used in the our study,
the condensation reaction goes to completion to give 2a and no
monoarylated product.
(7) Klumpp, D. A.; Yeung, K. Y.; Prakash, G. K. S.; Olah, G. A. J .
Org. Chem. 1998, 63, 4481.
(8) Klumpp, D. A.; Yeung, K. Y.; Prakash, G. K. S.; Olah, G. A.
Synlett 1998, 918.
† California State Polytechnic University.
‡ University of Southern CaliforniasLos Angeles.
(1) Considered to be Chemistry in Superacids, Part 46. For Part 45,
see Rasul, G.; Prakash, G. K. S.; Olah, G. A. J . Am. Chem. Soc.,
submitted.
(2) (a) Ruhemann, S. Trans. Chem. Soc. 1910, 97, 1438. (b) J oullie,
M. M.; Thompson, T. R.; Nemeroff, N. H. Tetrahedron 1991, 47, 8791.
(3) (a) Peet, N. P.; Huber, E. W.; Huffman, J . C. J . Heterocycl. Chem.
1995, 32, 33. (b) Black, D. St. C.; Bowyer, M. C.; Condie, G. C.; Craig,
D. C.; Kumar, N. Tetrahedron 1994, 50, 10983. (c) Bullington, J . L.;
Dodd, J . H. J . Org. Chem. 1993, 58, 4833. (d) Usmani, J . N.; Ismail, S.
M. Pak. J . Sci. Ind. Res. 1987, 30, 89.
(9) Yamazaki, T.; Saito, S.-i.; Ohwada, T.; Shudo, K. Tetrahedron
Lett. 1995, 36, 5749.
10.1021/jo990197h CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/10/1999

Condensations of Ninhydrin with Aromatic Compounds
J . Org. Chem., Vol. 64, No. 14, 1999 5153
Ta ble 1. P r od u cts fr om th e Rea ction of Nin h yd r in (1)
w ith Ar en es in H2SO4 or CF 3SO3H
From the results described above, two types of general
acid-catalyzed reactions of ninhydrin (1) with arenes have
become apparent: condensation of 1 in H2SO4 produces
2,2-diaryl-1,3-indanediones 2a -f and condensation of 1
in TfOH produces the isobenzofuranone derivatives 3a -
e. In considering the mechanisms for these two reaction
pathways for ninhydrin, the condensation products 2a -f
are clearly the result of an acid-catalyzed hydroxyalky-
lation reaction involving the hydrated carbonyl group at
the C-2 position of 1.11 The mechanism of product
formation is less obvious for the products 3a -e in the
superacidic reactions. When 2a was isolated from the H2-
SO4-induced conversion and then reacted with TfOH,
acid
arene
C6H6
product
% yielda
H2SO4
2a , X ) H
2b, X ) F
2c, X ) Cl
2d , X ) Br
2e, X ) I
96
94
97
97
86
91
98
77
81
91
91
94b
C6H5F
C6H5Cl
C6H5Br
C6H5I
C6H5CH3
C6H6
2f, X ) CH3
3a , X ) H
3b, X ) F
3c, X ) Cl
3d , X ) Br
3e, X ) I
CF3SO3H
C6H5F
C6H5Cl
C6H5Br
C6H5I
C6H5CH3
3f, X ) CH3
a
b
Isolated yields. Prepared from the reaction 2f and TfOH
(eq 5).
ample, 1 reacts with benzene in H2SO4 to provide 2,2-
diphenyl-1,3-indanedione (2a ) in high yield (Table 1). In
an earlier report,5 a significant quantity of the monoary-
lated product was formed; however, no monoarylated
product was detected in our study.6 The product 2a is
formed as the results of a hydroxyalkylation reaction
involving the hydrated carbonyl group at the C-2 posi-
tion.11 Like the chemistry involving amines, the C-2
position of ninhydrin is the most reactive position in these
electrophilic aromatic substitution reactions. With sub-
stituted arenes, the condensation products 2b-f are
produced regioselectively from 1 in H2SO4. Chorobenzene
is a moderately deactivated arene due to the electron-
withdrawing effect of the chlorine substituent, and
because of this deactivation, weak electrophiles do not
react with chlorobenzene in substitution reactions.12
Nevertheless, 1 reacts with chlorobenzene in high yield.
These results indicate that in strongly acidic solution, 1
forms a reactive electrophilic species.
product 3a is formed (eq 3). This result is in contrast to
an earlier report that 2a decomposes to benzophenone
and other indentified products in TfOH.5 Product 2f is
formed regioselectively from 1 and toluene in H2SO4.
Similarly, the reaction of 2f in TfOH generates 3f through
a rearrangement which occurs with complete retention
of the regiochemistry at the p-tolyl groups (eq 4). Given
these observations, the mechanism proposed for the
When 1 is reacted with C6H6 in the superacidic triflic
acid (TfOH), a different product is obtained in high yield.
The product from 1, C6H6, and TfOH was determined on
the basis of mass spectrum and NMR data to be the
isobenzofuranone derivative 3a (Table 1). The identity
of the product was further confirmed by an X-ray crystal
structure. If substituted arenes are reacted with 1 in
TfOH, similar products are formed. Thus, reaction of 1
with C6H5F, C6H5Cl, C6H5Br, or C6H5I produces 3b, 3c,
3d , and 3e, respectively (Table 1). In all cases, 3b-e are
produced regioselectively. Like the conversions in H2-
SO4,1H NMR analysis of the crude product mixtures
revealed that electrophilic attack occurred exclusively at
the para position of the halogen-substituted benzenes.
Reaction of 1 with toluene results in similar condensa-
tion; however, several regioisomers are formed (eq 2).
conversion of 1 to 3a is described in Scheme 1.
Protonation of 1 is followed by elimination of water to
produce the oxonium ion 4. In superacidic media, cation
4 may be in equilibrium with dication 5. Given that 1
reacts regioselectively with toluene in H2SO4 (eq 2) but
with poor regioselectivity with toluene in the superacid
(eq 3), this suggests that TfOH generates a more reactive
electrophile from 1 than does H2SO4. TfOH (Ho ) -14.1)
is 100 times more acidic than H2SO4 (anhydrous, Ho )
-12) and thus may be capable of forming the dication 5
as a superelectrophilic intermediate.13 Condensation
reaction steps lead to 6, which yields 2a as the product
of the H2SO4 induced reactions, but which gives the
rearrangement product 3a in TfOH. Dication 7 is formed
by protonation of 6, and this dication undergoes ring-
opening, bond rotation, and ring-closure to give 3a .
There may be several contributing factors which cause
the protosolvated dication 7 to undergo the proposed
rearrangement. Diprotonation of the carbonyl group gives
an accumulation of positive charge, and ring-opening
would serve to spread out the positive charge between
(10) Olah, G. A. Angew. Chem., Int. Ed. Engl. 1993, 32, 2, 767. (b)
Prakash, G. K. S.; Schleyer, P. v. R., Eds. Stable Carbocation
Chemistry; Wiley: New York, 1997. (c) Olah, G. A.; Wang, Q.; Neyer,
G. Synthesis 1994, 276. (e) Berkessel, A.; Thauer, R. K. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 2247. (f) Olah, G. A.; Klumpp, D. A.; Neyer,
G.; Wang, Q. Synthesis 1996, 321. (g) Klumpp, D. A.; Baek, D. N.;
Prakash, G. K. S.; Olah, G. A. J . Org. Chem. 1997, 62, 6667.
(11) Olah, G. A. Friedel-Crafts and Related Reactions; Wiley: New
York, 1964; Vol 2, pp 597-640.

5154 J . Org. Chem., Vol. 64, No. 14, 1999
Klumpp et al.
Sch em e 1
Sch em e 2
an acyl cation and a protonated enol group (8). Moreover,
the acyl cation is in conjugation with the diphenylmeth-
ylene group as shown by resonance structure 9. This
stabilizing effect of the gem-diphenyl group may be an
important aspect in the rearrangement,14 because when
2-phenyl-1,3-indanedione is reacted in TfOH, no rear-
rangement is observed and the starting material is
recovered quantitatively (eq 5).
other similar reaction involves the ninhydrin product 14.4
When 14 is reacted with 4-methylaniline in refluxing
acetic acid, rearrangement product 17 is produced (Scheme
2). Although no mechanism was proposed for the conver-
sion, it is similar to the formation of 3a from 1. For
example, 14 could form the iminium ion 15. Ring-opening
could generate the acyl cation which then leads to product
17 from a ring-closure and tautomerization reaction
steps.
In addition to the studies of 1, the electrophilic
chemistry of benzo[f]ninhydrin (18) was also examined.
When 18 is reacted with C6H6 in H2SO4, the expected
condensation product 19 is formed in high yield (eq 7).
However when 18 is reacted with C6H6 in TfOH, the
expected rearrangement product is not formed as the
major product, but instead a complex product mixture is
produced.
Another important factor in this conversion may be the
protolytic solvation of rearrangement product itself in the
acid. Protolytic product solvation can be an important
driving force in acid-catalyzed reactions.15
At least two similar conversion have been reported in
the literature. When diketone 11 is reacted with an
excess of AlCl3, rearrangement occurs to give a high yield
of product 13 (eq 6).16 Presumably, this occurs through a
ring-opening step to give an intermediate like 12. An-
(12) March, J . Advanced Organic Chemistry, 4th ed.; Wiley: New
York, 1992; Chapter 9.
(13) (a) Saito, S.; Saito, S.-i.; Ohwada, T.; Shudo, K. Chem. Pharm.
Bull. 1991, 39, 2718. (b) Olah, G. A., Prakash, G. K. S., Sommer, J . In
Superacids; Wiley: New York, 1985.
(15) (a) Olah, G. A.; Laali, K.; Farooq, O. J . Org. Chem. 1985, 50,
1483. (b) Olah, G. A.; Kuhn, S. J . In Friedel-Crafts and Related
Reactions; Olah, G. A., Ed.; Wiley: New York, 1964; Vol. 3, Chapter
38.
(14) Freedman, H. H. In Carbonium Ions; Olah, G. A., Schleyer, P.
v. R., Eds.; Wiley: New York, 1973; Vol 4; pp 1501-1578.
(16) Hasek, R. H.; Clark, R. D.; Mayberry, G. L. In Oganic Syntheses;
Baumgarten, H. E., Ed.; Wiley: New York, 1973; Coll. Vol. 5, p 456.

Condensations of Ninhydrin with Aromatic Compounds
J . Org. Chem., Vol. 64, No. 14, 1999 5155
10 mL of concentrated H2SO4. The mixture is stirred at 25 °C
for 8 h and then poured over 10-20 g of ice. The product is
extracted into CHCl3, and the organic phase is washed twice
with water, twice with brine, dried over MgSO4, and concen-
trated in vacuo. The resulting white solid (1.60 g, 5.4 mmol,
96%) can be further purified by recrystallization from CHCl3
to give 2,2-d ip h en yl-1,3-in d a n ed ion e (2a ): colorless crystals,
Con clu sion
1
mp 123-125 °C. H NMR (CDCl3) δ 7.27-7.34 (m, 10H), 7.91
(m, 2H), 8.1 (m, 2H). 13C NMR (CDCl3) δ 67.6, 124.1, 127.8,
128.6, 128.8, 136.2, 138.1, 141.6, 199.7. IR (NaCl, thin film)
3000 cm-1, 1710, 1480, 1205, 740. HRMS m/e calcd for
C21H14O2 (M+) 298.0994, found 298.0983.
We have found that ninhydrin (1) forms highly reac-
tive, electrophilic species from acidic solution. Ninhydrin
reacts at the hydrated carbonyl (C-2 position) and
condenses with aromatic compounds in high yields. From
H2SO4, the condensation of 1 provides 2,2-diarylin-
danediones (2a -f), and from TfOH, the condensation and
subsequent rearrangement gives 3-(diarylmethylene)-
isobenzofuranones (3a -e). The results suggest diproto-
nated, superelectrophilic species are intermediates in the
superacid-catalyzed conversions. In accord with results
from 1,2-dicarbonyl compounds, these results indicate
that 1,2,3-tricarbonyl groups also generate reactive elec-
trophiles in acidic media and that these electrophilic
reactions may be exploited in synthesis.
Gen er a l P r oced u r e for th e Syn th esis of 3-(Dia r ylm -
eth ylen e)isoben zofu r a n on es (3a -e). Ninhydrin (0.4659 g,
2.62 mmol) is combined with 2 mL of benzene (or other arene),
and 5 mL of triflic acid is added. The mixture is stirred at 25
°C for 8 h and then poured over 10-20 g of ice. The product is
extracted into CHCl3, and the organic phase is washed twice
with water, twice with brine, dried over MgSO4, and concen-
trated in vacuo. The resulting white solid (0.7634 g, 2.56 mmol,
98%) can be further purified by recrystallization from C6H6 to
give 3-(d ip h en ylm eth ylen e)isoben zofu r a n on e (3a ): color-
1
less crystals, mp 159-162 °C. H NMR (CDCl3) δ 6.30 (d, J )
7.8 Hz, 1H), 7.30-7.46 (m, 8H), 7.51-7.58 (m, 4H), 7.91 (d, J
) 7.5 Hz, 1H). 13C NMR (CDCl3) δ 123.6, 124.9, 125.2, 128.1,
128.2, 128.7, 129.3, 129.4, 130.4, 130.5, 133.9, 137.4, 137.6,
139.6, 167.1. IR (NaCl, thin film) 3050 cm-1, 1780, 1095, 1000,
750. HRMS m/e calcd for C21H14O2 (M+) 298.0994, found
298.0991.
Exp er im en ta l Section
1H NMR spectra were recorded at 300 MHz, and 13C NMR
spectra were recorded at 75 MHz. High-resolution mass
spectra were recorded at the Southern California Mass Spec-
trometry Facility, University of California, Riverside. GCMS
spectra were recorded from a gas chromatograph fitted with
a DB-5 capillary column and electron impact MS detector.
Column chromatography was done with Merck silica gel (grade
9385) according to standard procedures.14 Triflic acid was
obtained from 3M and distilled prior to use. Concentrated
sulfuric acid was obtained from Aldrich and used as received.
Benzene was dried over Na and distilled. Ninhydrin was
obtained from Aldrich and used as received. Reactions were
done under a dry, N2 atmosphere.
Ack n ow led gm en t. The support of the NIH through
an MBRS Grant (D.A.K.; SO6GM53933-0251) and the
NSF (G.A.O) and the Loker Hydrocarbon Research
Institute is gratefully aknowledged.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 2a and 3a ; experimental procedures
and spectroscopic data for compounds 2b-f, 19, 3b-f; X-ray
structure and data for compound 3a including tables of atomic
coordinates, bond lengths, and bond angles. This material is
available free of charge via the Internet at http://pubs.acs.org.
Gen er a l P r oced u r e for th e Syn th esis of 2,2-Dia r yl-1,3-
in d a n ed ion es (2a -f) a n d P r od u ct 5. Ninhydrin (1.00 g, 5.6
mmol) is combined with 2 mL of benzene (or other arene) and
J O990197H