Pseudoacids. III: Formation and structures of new cyclic oxocarboxylic acids

Article abstract of DOI:10.1023/A:1024226029750

Crystal and molecular structures for aryl- and benzyl-substituted 3-hydroxy-3,4-dihydroisobenzopyran-1 -one are described. For the 4,4-dimethyl derivative, two monoclinic modifications are produced on sublimation: (1) P2₁/c, a = 23.668(6) A; b

Full text of DOI:10.1023/A:1024226029750

C
Journal of Chemical Crystallography, Vol. 33, Nos. 5/6, June 2003 ( 2003)
Pseudoacids. III: formation and structures
of new cyclic oxocarboxylic acids
W. John Cooper,(1) Tyler N. Smith,(1) Andrea K. Barker,(1)
Jason A. Webb,(1) and Edward J. Valente(1)
Received July 1, 2002
Crystal and molecular structures for aryl- and benzyl-substituted 3-hydroxy-3,4-
dihydroisobenzopyran-1-one are described. For the 4,4-dimethyl derivative, two monoclinic
˚
˚
modifications are produced on sublimation: (1) P21/c, a = 23.668(6) A; b = 11.749(4) A;
3
˚
˚
˚
c = 7.215(2) A; = 96.70(2) ; V = 1992.6(10) A ; (2) P21/c, a = 11.509(4) A, b =
˚
˚
˚
12.429(4) A, c = 6.933(2) A, = 91.12(3) , V = 991.6(6) A. In both, hydroxy groups
are pseudoaxial, and molecules form dimeric complementary but noncooperative hydro-
˚
˚
gen bonds. In the 6-methoxy derivative (3), P21/c; a = 14.185(7) A; b = 4.105(4) A;
3
˚
˚
c = 15.598(13) A; = 98.59(6) ; V = 898.1(10) A , the hydroxy group is pseudoequa-
torial, and the intermolecular hydrogen bonding forms infinite chains. In the 4,4-dimethyl-
7-nitro derivative (4), C2/c, a = 19.365(4), b = 8.425(2), c = 13.464(4), = 92.62(2),
3
˚
V = 2194.2(7) A , the hydroxy group is pseudoaxial, and the intermolecular hydrogen
bonding forms chains. Compared to the unmethylated compounds, the interbond angles
within the ring at the dimethylated carbon are contracted.
KEY WORDS: Hydrogen bonding; oxocarboxylic acids; pseudoacids; dimethyl effect.
Introduction
distinct from though analogous to the two-
dimensional dimers formed commonly between
Pseudoacids are formed by the cycliza-
carboxylic acids. In other pseudoacid compounds,
infinite hydrogen-bonded chains form between
oxocarboxylic acids.1 Pseudoacid systems are
even more complex than normal carboxylic acids
since cyclization produces a stereogenic cen-
ter and the open-cyclic equilibrium can have
anomeric consequences. For example, pyranoid
lactols can have pseudaxial or pseudoequatorial
hydroxy groups which may influence the hydro-
gen bonding possibilities. In this study, the synthe-
ses of a group of arylpyran pseudoacids intended
to address various structural questions in pseu-
doacid chemistry are described.
tion of certain 4- and 5-oxocarboxylic acids.
The resulting bifunctional compounds have hy-
drogen bond donors and acceptors more dis-
tantly separated than those of normal carboxylic
acids. In some cases, hydrogen-bonded dimers
form between the pseudoacid lactol carboxyl
and hydroxy groups of adjacent molecules which
show three-dimensional intermolecular recog-
nition (complementarity) features. These are
(1) Department of Chemistry and Biochemistry, Mississippi College,
Clinton, Mississippi.
To whom correspondence should be addressed. E-mail: valente@
mc.edu
Ring-chain tautomerisms are potentiated in
openmolecularsystemspossessingtwofunctional
375
C
1074-1542/03/0600-0375/0 2003 Plenum Publishing Corporation

376
Cooper, Smith, Barker, Webb, and Valente
groups, one of which contains a multiple bond and
the other is capable of effecting an addition reac-
tion at that multiple bond. As the extensive study
by Jones showed, hydrogen ion from a carboxyl
group is a common electrophile to the multiply
bonded group.2 Thus, oxocarboxylic acids may
be thought to cyclize in two steps: proton trans-
fer from the carboxylic acid to the carbonyl oxy-
gen followed by nucleophilic addition at the car-
bonyl carbon by carboxylate. Factors which can
serve to enhance the formation of pseudoacids
include formation of the more stable 5- and
6-membered rings from 4- and 5-oxocarboxylic
acids with trans-disubstituted aliphatic, cis-
disubstituted alkenes, o-disubstituted aryl sys-
tems intervening between the functional groups.
The parent system reported here consists of 3-
hydroxy-3,4-dihydroisobenzopyran-1-one. This
arylpyran pseudoacid is formed by the reaction
of a carboxylic acid and aldehyde groups with
an ortho-benzene disubstitution connection be-
tween them. In one part of this study, aryl sub-
stituents provide Hammett influences bearing on
thedistantpseudoacidgroup. Inanotherpart, gem-
dimethyl groups are placed adjacent to the lactol
hydroxy to stabilize the pseudoacid form and pre-
vent subsequent elimination reactions. This influ-
ence is commonly called the gem-dimethyl effect
or Thorpe–Ingold effect.3 Cyclization is promoted
by increasing the population of a particularly reac-
tive rotamer and compressing the angle between
the groups opposite the dialkyls.4
troscopy was performed on an Hewlett-Packard
5890-5972 GC-MSD using a 30 m
OV-1701 capillary column.
0.25 mm
3,3-Dimethyl-1-indanone
In an open beaker, 18 g of polyphosphoric
acid was stirred briskly while heating to 363 K.
Then, 5.00g (28.1 mmol) molten 3-phenyl-3-
methylbutanoic acid5 was added all at once with
continued stirring and heating. After 3 min, an-
other 15 g of polyphosphoric acid was added and
the whole stirred for 2 min more. The thick brown
mixture was heated on a steam bath for 4 min,
then allowed to cool to room temperature. Ice was
added to bring the volume to about 50 mL, and
the mixture was twice extracted with ether. The
ethereal extracts were combined, washed with sat-
urated aqueous sodium bicarbonate, and the sol-
ventremovedinvacuoproducingapaleyellowoil,
4.04 g (90%). GC: 95% pure; MS (EI): 160, par-
ent; 145, base; identical with NIST98 compound
65295. This material may be used in the subse-
quent step without distillation.
2-Acetoxy-3,3-dimethyl-1-indanone
A solution is prepared comprised of 13.15 g
(84.3 mmol) 3,3-dimethyl-1-indanone, 30 mL
glacial acetic acid and 10 mL of acetic anhy-
dride. While stirring under a dinitrogen atmo-
sphere, 57.50 g (129.7 mmol) lead(IV) acetate
was added and the reaction mixture was heated to
343 K. As the exothermic reaction set in, heating
was discontinued; total reaction time was about
2 h. After cooling, 100 mL water was added to
the mixture, which was then extracted twice with
ether. The combined ethereal extracts were back-
extracted with saturated aqueous sodium bicar-
bonate, and dried over anhydrous sodium sulfate;
the solvents were then removed in vacuo. The re-
sulting yellow–orange oil (16.13 g, 88%) slowly
crystallized; it was recrystallized from cyclohex-
aneorsublimedat308Kinvacuoandrecoveredas
a nearly colorless solid. mp 348.3 K (DSC peak);
Experimental
Reagents and solvents were obtained from
Aldrich Chemical in their highest available pu-
rities and used as received. Melting points were
measured on a Shimadzu DSC-50 Differential
Scanning Calorimeter (DSC) under nitrogen at
a heating rate of 10 C/min and referenced to
pure indium and tin (99.9995%) standards. Nu-
clear magnetic resonance spectra were recorded
on a JEOL AS400 spectrometer and referenced
to tetramethylsilane. Chromatography-mass spec-

New cyclic oxocarboxylic acids
377
1H NMR (CDCl3): 7.69, dd, 1H, H7; 7.63, dd,
1H, H4; 7.47, t, 1H, H5; 7.37, t, 1H, H6; 5.40,
ored material has left the column. Fractions
containing the product were pooled, and after re-
moval of the solvent in vacuo, the pale yellow
oil slowly crystallized giving 1.91 g (76%). Thin
colorless diamond shaped crystals, mp 331.7 K
(DSC peak) (phase 1) and colorless blocky prisms,
mp 341.8 K (DSC peak) (phase 2) slowly sub-
limed onto the walls of the vessel over several
s, 1H, H2; 2.21, s, 3H, MeCO; 1.51, s, 3H, MeC;
1
==
---
1.13, s, 3H, MeC; IR (KBr): 1730 cm , C O;
1
1
1470 cm , HCH; 1225, 1075 cm , C O’s;
1
768, 702 cm , Ar-ortho.
2-Hydroxy-3,3-dimethyl-1-indanone
1
weeks at room temperature in vacuo. H NMR
(25 C, CDCl3): 7.96, dd, 1H, H8 (peri); 7.52,
dt, 1H, H7; 7.32, dt, 1H, H5; 7.27, dt, H6;
6.05, s, 1H, OH; 5.45, s, 1H, H3; 1.32, s,
3H, MeC cis to OH; 1.27, s, 3H, MeC cis to H;
Following the procedure of Ishiwara,6
a
solution of 1.16 g (5.32 mmol) 2-acetoxy-3,3-
dimethyl-1-indanone in 25 mL methanol was
quickly added to a stirred solution of 0.808 g
(5.85 mmol) potassium carbonate in 25 mL water
under a dinitrogen atmosphere. After 1 h, the re-
action was halted by addition of 25 mL water and
3.25 mL (10%) H2SO4 to neutralize the carbon-
ate. The mixture was saturated with sodium sul-
fate decahydrate and extracted twice with ether.
The ether extracts were combined, dried over an-
hydrous sodium sulfate, and the solvent was re-
moved in vacuo. The product was a light yellow
1
1
==
IR (KBr): 3317 cm , OH; 1700 cm , C O;
1
1
1473, 1456 cm , HCH; 1383, 1368 cm ,
CH3; 1264, 1126 cm , C O’s; 754,703 cm ,
Ar-ortho.
1
1
---
3-Hydroxy-6-methoxy-3,4-
dihydroisobenzopyran-1-one (3)
A solution of 4 mL tetrahydrofuran, 4 mL
water, and 0.746 g (4.19 mmol) 2-hydroxy-5-
methoxy-1-indanone was cooled to 273 K and
stirredtoeffectsolution. Tothis, 9mLofan0.50M
solution of H5IO6 (4.50 mmol, 1.1 equiv.) was
added. After 15 min, the solution was diluted with
10 mL water and extracted three times with ether.
Theetherealsolutionwaswashedwithbrine, dried
with anhydrous sodium sulfate, and the solvent
was removed in vacuo. The resulting white solid
(0.52 g, 64%) was recrystallized from methanol or
ethyl acetate. mp 420.8 K (DSC peak); IR (KBr):
1
oil, 0.713 g (76%). H NMR (CDCl3): 7.63, d,
1H, H7; 7.58, dt, 1H, H5; 7.44, d, 1H, H4;
7.30, dt, 1H, H6; 4.68, s (v. br), 1H, OH; 4.22,
s, 1H, H2; 1.49, s, 3H, MeC; 1.09, s, 3H,
1
1
MeC; IR (KBr): 3445 cm , OH; 1723 cm ,
1
1
==
---
C O; 1471 cm , HCH; 1146 cm , C O;
1
766, 702 cm , Ar-ortho.
3-Hydroxy-4,4-dimethyl-3,4-
dihydroisobenzopyran-1-one(1,2)
1
1
==
3274 cm , OH; 1688 cm , C O; 1257,
A mixture of 20 mL dichloromethane,
2.08 g (11.8 mmol) 2-hydroxy-3,3-dimethyl-1-
indanone, and 5.95 g sodium bicarbonate was
prepared and cooled to 273 K with an ice-water
bath. Then, 5.24 g (11.8 mmol) of lead(IV) ac-
etate was added and the mixture was stirred for
10 min. The reaction mixture was then applied to
1
1
---
1159 cm , C O’s; 766, 713 cm , Ar-ortho;
1H NMR (22 C, CDCl3): 8.04, d, 1H, H8 (peri);
7.25, s, 1H, H5; 6.82, dd, 1H, H7; 5.91, t, 1H,
H3; 3.86, s, 3H, OCH3; 3.28, dd, 1H, HaCHb;
3.07, dd, 1H, HaCHb; 2.2, s (br), 1H, OH.
the top of a column (2.5 cm
10 cm) consist-
3-Hydroxy-4,4-dimethyl-7-nitro-3,4-
ing of equal amounts of diatomaceous earth and
250 mesh silica which had been prepared using
dichloromethane. Eluting with dichloromethane,
the product emerges after the faster-running col-
dihydroisobenzopyran-1-one (4)
To
a
cooled mixture (273 K) of
2.5 mL concentrated nitric acid and 2.5 mL

378
Cooper, Smith, Barker, Webb, and Valente
minimizing differences in F2. Atomic scattering
factors were from the International Tables for
Crystallography.9 Hydrogens atoms, with the ex-
ceptions of those on O, were assigned calculated
positions and allowed to ride on their attached
atoms with isotropic vibrational factors equal to
120% of the equivalent isotropic vibrational fac-
concentrated sulfuric acid, 1.00 g (6.25 mmol)
3,3-dimethyl-1-indanone dissolved in 2.5 mL
concentrated sulfuric acid was quickly added.
The reaction was occasionally removed from the
ice-water bath and allowed to warm to but not
exceed 288 K. After 20 min, the deep orange mix-
ture was poured into a large excess of cold water
and extracted twice with ether. The combined
ether extracts were back-extracted with saturated
sodium bicarbonate. The ether solution was dried
over anhydrous sodium sulfate, and on removal
of the solvent in vacuo, slightly yellow crystals
of the title compound (4) separated and were
isolated by filtration (0.27 g, 18%). The balance
of the ether soluble product was 3,3-dimethyl-6-
nitro-1-indanone (0.28 g, 22%); acidification of
the bicarbonate aqueous wash gave 0.95 g, 60%
of the nitrated homophthalic acid 2-(20-carboxy-
40-nitrophenyl)-2-methylpropanoic acid. As a
result of several trials, the fractions of the three
products was found to be sensitive to the reaction
time and temperature. For 4, mp: 459.1 K (DSC
---
tor of the attached atom. Positions of the O
H
hydrogens were fit to the location of the elec-
tron density maximum near the O-atom with a
torsion angle variable. Attendant isotropic vibra-
tional factors were calculated as for other hydro-
gens. In all cases, satisfactory H-bonded locations
were thus identified. Comparative relevant struc-
tural and spectroscopic information is given in
Table 2 including 13C-mr frequencies of the lactol
carbons. Positions of the non-H atoms are given
in Tables 3–6. Thermal ellipsoid plots of 2, 3, and
4 are given in Figs. 1–3, respectively; the molecu-
lar structures of the crystallographically inequiv-
alent molecules in 1 are essentially the same as 2.
In subsequent calculations of hydrogen bonding
in Table 2, the H-atom positions were reassigned
1
peak); H NMR (295 K, CDCl3): 8.91, d, 1H,
H8 (peri); 8.44, dd, 1H, H6; 7.62, d, 1H, H5;
7.25, s (br), 1H, OH; 5.57, s, 1H, H3; 1.51, s,
3H, MeC cis to OH; 1.40, s, 3H, MeC cis to H.
---
along the O H bond vectors to distances of
˚
0.96 A, a value closer to the unbiased bond length.
1
1
==
IR (KBr): 3318 cm , OH; 1698 cm , C O;
Additional crystallographic information
1
1
1528, 1346 cm , NO’s; 1264, 1106 cm ,
---
C O’s.
Structures of several intermediates and prod-
ucts in the syntheses were confirmed by single
crystal structure determinations not described in
detail here. They include 3,3-dimethyl-6-nitro-1-
Crystallography
˚
Relevant crystallographic information for
indanone, monoclinic, P21/m, a = 7.664(6) A,
˚
˚
compounds 1–4 are given in Table 1. Data were
collected on a Siemens R3m/v automated diffrac-
tometer with graphite monochromatized Mo K
b = 6.612(6)
A,
c = 10.453(10)
A,
3
˚
= 92.83(6) , V = 529(2) A ; 5-methoxy-
˚
1-indanone, monoclinic, P21/c, a = 7.436(3) A;
˚
˚
˚
radiation ( = 0.71073 A) using omega scans of
b = 10.609(4) A; c = 10.921(6) 0 A;
=
3
˚
width 2.0 . Three standards were monitored pe-
riodically (every 197 reflections). Reflection data
were corrected for Lorentz, polarization, and de-
terioration effects but not for absorption which
is slight in crystals of these materials. Structures
were discovered with SHELXS937 and the mod-
els were refined with SHELXL97.8 Positions and
anisotropic vibrational parameters were refined
for all non-H atoms by full-matrix least-squares
103.80(4) ; V = 836.7(7) A ; 2-(2 -carboxy-
40-nitrophenyl)-2-methylpropanoic acid, mono-
˚
˚
3
clinic, C2/c, a = 27.78(3) A, b = 11.81(1) A,
˚
˚
c = 7.277(4) A, = 90.02(6) , V = 2387(4) A .
Discussion
A convenient method for simultaneous pro-
duction of the interacting functional groups

New cyclic oxocarboxylic acids
379
Table 1. Crystallographic Data for Pseudoacids 1–4.
Compound
1
2
3
4
Formula weight
CCDC deposit no.
Specimen dimensions (mm)
Crystal system
192.21
192259
0.2 0.15 0.04
Monoclinic
P2(1)/c
192.21
192260
0.6 0.4 0.3
Monoclinic
P2(1)/c
194.18
192261
0.6 0.25 0.04
Monoclinic
P2(1)/c
237.21
192262
0.4 0.2 0.2
Monoclinic
C2/c
Space group
Temperature, K
Cell constants
293(2)
293(2)
293(2)
293(2)
˚
a, A
23.668(6)
11.749(4)
7.2148(19)
90.
11.509(4)
12.429(4)
6.933(2)
90.
14.185(7)
4.105(4)
15.598(13)
90.
19.365(5)
8.4247(19)
13.464(4)
90.
˚
b, A
˚
c, A
, deg
, deg
, deg
Cell volume, A
Formula units/cell
96.70(2)
90.
1992.6(10)
8
1.281
0.093
91.117(3)
90.
991.6(6)
4
1.288
0.093
98.59(6)
90.
898.1(12)
4
1.436
0.112
92.62(2)
90.
2194.2(9)
8
1.436
0.115
3
˚
3
(Mg m
)
calc
1
, cm
Decomposition, %
range, deg
Index ranges (h, k, l)
0.035
+0.043
1.8–30.0
16–16
17–13
0–9
+0.142
2.6–27.5
0–18
0–5
20–20
2200
+0.028
2.1–27.5
0–25
0–10
17–17
2579
1.9–21.5
24–24
12–0
0–7
4316
Reflections measured
Rmerge
4198
0.039
0.071
0.040
0.051
Unique reflections
Observed refl. (I > 2
2291
884
2885
962
2071
929
2513
1072
)
I
No. parameters, restraints
Transmission coef., min./max.
Extinction coefficient
2621,2
0.996, 0.982
0.0018(2)
129,0
0.974, 0.948
0.115(4)
132,0
0.996, 0.936
0.019(2)
156,0
0.977, 0.955
0.0216(7)
2
2
(Fo)
Weights
a
Final R (all data)
R (observed data)
Rw (all data)
1/
+ (aP)2, where P = max(Fo2, 0) + 2Fc2/3
0.005
0.124
0.045
0.056
0.700
0.02
0.148
0.048
0.098
0.965
0.03
0.107
0.051
0.098
0.938
0.02
0.115
0.047
0.080
0.940
S (goodness-of-fit, observed data)
3
˚
Final difference features (e A
)
+0.17, 0.14
+0.16, 0.16
+0.20, 0.23
+0.18, 0.17
of oxocarboxylic acids is oxidative cleavage.
Hence, appropriate precursors to the arylpyran
oxocarboxylic acids are 2-hydroxy-1-indanones.
Following Scheme I, the -hydroxyketone pre-
cursor of the pseudoacid 3-hydroxy-4,4-dimethyl-
3,4-dihydroisobenzopyran-1-one is made by the
method of Koelsch and LeClaire.5 After the ad-
dition of mesityl oxide to benzene, the resulting
ketone is oxidized to 3-methyl-3-phenylbutanoic
acid. Then, this acid was cyclized to 3,3-dimethyl-
1-indanone efficiently in hot polyphosphoric acid.
Oxidation of the 2-position can be accomplished
with dibromine,10 but the displacement of the
bromide by acetate is hindered by the adjacent
dimethyls. Alternatively, the indanone is con-
verted directly to the 2-acetoxy derivative with
lead(IV) acetate.11 After saponification to the
-hydroxyketone,6 the pseudoacid is made by
oxidative cleavage of 2-hydroxy-3,3-dimethyl-1-
indanone with lead(IV) acetate but not with peri-
odic acid. Two phases (1, 2) of this substance with
clearly differing crystalline morphologies were
isolated by sublimation.
3,3-Dimethyl-1-indanone also serves as
a starting point for preparation of the ni-
tropseudoacid 3-hydroxy-4,4-dimethyl-7-nitro-3,

380
Cooper, Smith, Barker, Webb, and Valente
the oxidation is not certain, it seems likely that
after aryl nitration, a considerable amount of
oxidation of the indanone can take place since
a substantial yield of the nitrated homophthalic
acid is obtained. If this oxidation proceeds at least
in part through an intermediate -hydroxyketone,
then cyclization of the aldehydoacid accounts
for the formation of the pseudoacid. Since
this system has a gem-dimethyl group present
which may act to bring the interacting aldehyde
and acid groups together, the survival of the
nitro pseudoacid might be a consequence of an
operative gem-dimethyl effect. Additionally, the
nitro group is meta to the aryl carboxylic acid
4
Scheme 1.
which increases its acidity (Ka = 3.2 10 for
5
m-nitrobenzoic acid vs. 6.3 10 for benzoic
4-dihydroisobenzopyran-1-one, 4 (Scheme I).
Nitric acid is known to be both a nitrating agent
and oxidizing agent. While the mechanism of
acid). It may be argued that pseudoacid formation
is enhanced in both the proton transfer step
and the addition of the improved carboxylate
Table 2. Selected Structural and Spectroscopic Data for 1–4a
1
2
3
4
Ref.b
˚
---
---
Endocyclic C3 O2 length (A)
1.466
1.384
0.082
109.3
111.3
1.2
1.458, 1.470
1.395, 1.389
0.063, 0.081
107.6, 109.1
109.1, 109.0
1.3, 0.4
67.9, 69.2
,
5.52
102.4
1.80, 1.92
172, 159
110, 119
R22(12), R22(12)
1.455
1.386
0.069
109.3
107.8
2.1
1.479
1.379
0.100
106.0
109.9
+1.5
81.9
1.468
1.385
0.083
108.3
108.4
0.3
˚
Exocyclic C3 O3 length (A)
1[(C3 O2) (C3 O3)] (A)
˚
---
---
---
--- ---
O2 C3 O3 (deg)
C4a C4 C3 (deg)
--- --- ---
--- --- ---
(H O3 C3 O2) (deg)
Anomeric configuration
1H NMR (H on C3)c
13C NMR (C3)c
--- ---
--- ---
1(O3 C3 C4) (O2 C3 C4) (deg)
59.5
64.4
87.8
5.94
96.0
1.81
168
118
R22(12)
5.91
95.4
1.89
162
109
C11(6)
5.57
102.6
1.83
159
127
C11(6)
0
d
˚
---
O3
O3
H
H
O2 (A)
1.86
169
114
R22(12)
O20 ( )d
---
C1 O1
H0 ( )d
Intermol. H-bonding type
Intermol. H-bonding type
R
S
R
S
R
S
R
R
R
R
a
˚
˚
Esd.’s about 0.002 A, angles 0.2 (0.006 A, 0.5 for 1).
bUnsubstituted 3-hydroxy-3,4-dihydroisobenzopyran-1-one (Ref. (1)).
cIn CDCl3 at 22 C, referenced to tetramethylsilane.
d
˚
˚
---
Normalized O H to 0.96 A; Esd’s about 0.01 A, angles about 1 .

New cyclic oxocarboxylic acids
381
Table 3. Atomic Coordinates (104) and Equivalent Isotropic Dis-
Table 4. Atomic Coordinates (104) and Equivalent Isotropic Dis-
2
2
placement Parameters (103 A ) for 3-Hydroxy-4,4-Dimethyl-3,4-
placement Parameters (103 A ) for 3-Hydroxy-4,4-Dimethyl-3,4-
˚
˚
Dihydroisobenzopyran-1-One (1)
Dihydroisobenzopyran-1-One (2)
a
a
Atom
x
y
z
Ueq
Atom
x
y
z
Ueq
O1A
O2A
O3A
C1A
C3A
C4A
C4AA
C6A
C5A
C7A
C8A
C8AA
C9A
C10A
O1B
O2B
O3B
C1B
C3B
C4B
C4AB
C5B
C6B
C7B
C8B
C8AB
C9B
C10B
361(2)
315(1)
686(1)
604(2)
588(2)
8129(3)
9632(3)
11331(3)
8880(4)
10692(5)
10435(4)
9707(4)
9063(4)
9731(4)
8348(4)
8301(4)
8978(4)
11594(4)
9805(4)
3229(3)
4999(2)
5665(3)
3876(4)
5778(4)
5540(4)
4287(4)
3898(4)
2710(5)
1938(4)
2329(4)
3499(4)
6351(3)
5782(3)
488(6)
2296(6)
1399(5)
1396(9)
2961(10)
4088(8)
2946(7)
2088(8)
3159(6)
784(8)
100(2)
76(1)
87(1)
69(2)
77(2)
59(2)
49(1)
75(2)
55(2)
74(2)
67(2)
51(2)
85(2)
97(2)
57(1)
46(1)
53(1)
48(1)
44(1)
40(1)
36(1)
57(2)
63(2)
66(2)
54(1)
39(1)
60(2)
57(1)
O1
O2
O3
C1
C3
C4
C4A
C5
C6
C7
C8
9313(1)
9377(1)
8495(1)
8769(2)
8771(2)
7658(2)
6930(2)
5727(2)
5096(2)
5661(2)
6856(2)
7496(2)
7963(2)
7036(2)
1834(1)
351(1)
1208(1)
1124(2)
631(2)
381(2)
369(1)
405(2)
1118(2)
1808(2)
1801(2)
1094(2)
186(2)
364(2)
2084(2)
950(2)
1164(3)
2608(3)
3675(3)
2431(2)
2477(2)
1339(3)
133(3)
93(1)
69(1)
78(1)
64(1)
63(1)
53(1)
46(1)
55(1)
68(1)
76(1)
68(1)
51(1)
81(1)
74(1)
1161(2)
1505(2)
2407(2)
2099(2)
2128(3)
1541(3)
1235(2)
1436(2)
1045(2)
5035(1)
4744(1)
4048(1)
4643(2)
4260(2)
3802(2)
3641(2)
3103(2)
2996(2)
3419(2)
3952(2)
4064(2)
3305(2)
4035(2)
532(7)
63(3)
1646(7)
4641(7)
5873(7)
1850(4)
1905(4)
385(4)
1985(7)
1483(7)
2719(6)
2557(6)
2822(6)
2805(7)
2555(6)
2262(6)
2282(6)
2150(6)
4759(5)
C8A
C9
C10
1218(3)
5593(3)
4081(3)
1447(2)
aUeq is defined as one third of the trace of the orthogonalized U
tensor; esd’s in parentheses.
ij
condensation to form m-methoxycinnamic acid
(Scheme II).12 After reduction and cyclization,10
the 5-methoxy-1-indanone was converted to 2-
hydroxy-5-methoxy-1-indanone in two steps as in
the unsubstituted case (vide infra). The hydrox-
yketone is then oxidatively cleaved with periodic
acid to produce the pseudoacid (3).
ij
aUeq is defined as one third of the trace of the orthogonalized U
tensor; esd’s in parentheses.
---
Structures: C O bond length disparities
Eachofthestructures1–4arearylpyranpseu-
doacids. Table 2 contains relevant structural in-
formation on these and the relevant parent system
nucleophile. The pseudoacid product may then
possess some resistance to further oxidation.
The yield of the pseudoacid is poor by this
route, however, and several attempts to modify
the reaction conditions to improve it proved futile.
Under more stringent nitration conditions, the
product is largely the nitrated homophthalic acid
2-(20-carboxy-40-nitrophenyl)-2-methylpropanoic
acid.
In an additional case designed to display
Hammet influences, a methoxy group has been in-
troduced onto the aryl ring in a system without the
dimethyl influence. 3-Hydroxy-6-methoxy-3,4-
dihydroisobenzopyran-1-one (3) was prepared be-
ginning with a Knovenagle variant of the aldol
Scheme 2.

382
Cooper, Smith, Barker, Webb, and Valente
Table 5. Atomic Coordinates (104) and Equivalent Isotropic
2
Displacement Parameters (103 A ) for 3-Hydroxy-6-Methoxy-3,4-
˚
Dihydroisobenzopyran-1-One (3)
a
Atom
x
y
z
Ueq
O1
O2
O3
O6
C1
C3
C4
C4A
C5
C6
6977(1)
5781(1)
4490(1)
9186(1)
6708(2)
5381(2)
6010(2)
7011(2)
7616(2)
8541(2)
8875(2)
8277(2)
7338(2)
8884(2)
38(5)
1025(4)
1698(5)
7115(5)
1289(7)
2973(7)
2635(7)
3541(6)
4927(7)
5717(7)
5044(8)
3660(7)
2901(6)
7870(8)
3198(1)
2179(1)
1130(1)
470(1)
2493(2)
1412(2)
728(2)
1090(2)
570(2)
916(2)
59(1)
43(1)
49(1)
59(1)
43(1)
39(1)
41(1)
36(1)
41(1)
45(1)
53(1)
50(1)
39(1)
62(1)
Fig. 1. Plot (50% probablility enclosures) of the struc-
ture of 3-hydroxy-4,4-dimethyl-3,4-dihydroisobenzopyran-
1-one (2) showing the complementary hydrogen bonded
dimers.
---
been noted. In monosaccharides, C O distances
C7
C8
C8A
C9
1789(2)
2299(2)
1955(2)
419(2)
at the anomeric carbon are nearly the same since
each oxide leaving group has similar basicities.13a
---
In contrast, the endocyclic and exocyclic C O
aUeq is defined as one third of the trace of the orthogonalized Ui j
tensor; esd’s in parentheses.
lengths of pseudoacids show considerable dis-
parity in each case. The old aldehyde carbon in
each (C3) is bound to carboxylate and hydroxy
groups. Their implied leaving group tendencies
(as judged by the pKa’s of their conjugate acids
of 5 and 16, respectively) are consistent with a
model of differing contributions to the ground-
state model B. Since carboxylate is the better leav-
3-hydroxy-3,4-dihydroisobenzopyran-1-one pre-
viously reported.1 The arylpyran systems may
be thought to be distant relatives to the pyra-
nose sugars for which anomeric effects have long
---
ing group, the endocyclic C O is longer than the
---
exocyclic C O bond (Table 2). By way of il-
Table 6. Atomic Coordinates (104) and Equivalent Isotropic
2
Displacement Parameters (103 A ) for 3-Hydroxy-4,4-Dimethyl-7-
˚
lustration then, these differences favor resonance
contributions to the ground state from model A
in contrast to C. The difference is greater in the
-anomeric structure (3), since the pseudoequato-
rial hydroxy is more nearly in the -system plane
which may be thought to bridge the carboxylate
and hydroxy groups attached to the lactol carbon
(C3), thereby making the charge transfer more ef-
Nitro-3,4-Dihydroisobenzopyran-1-One (4)
a
Atom
x
y
z
Ueq
O1
C1
O2
C3
O3
C4
C4A
C5
3058(1)
3249(1)
2773(1)
3004(1)
3174(1)
3608(1)
4180(1)
4879(1)
5380(1)
5161(1)
5693(1)
6295(1)
5487(1)
4477(1)
3987(1)
3833(1)
3370(1)
451(2)
915(3)
3731(1)
3614(2)
3425(1)
3105(2)
2119(1)
3756(2)
3745(2)
3820(2)
3830(2)
3775(2)
3758(2)
3821(2)
3711(2)
3704(2)
3687(2)
3349(2)
4821(2)
56(1)
42(1)
51(1)
48(1)
61(1)
44(1)
35(1)
46(1)
47(1)
38(1)
56(1)
91(1)
85(1)
37(1)
33(1)
80(1)
69(1)
2024(2)
3595(3)
3493(2)
4193(3)
2971(3)
3328(3)
2146(3)
599(3)
---
ficient. A smaller but similar C O bond length
disparity is found between the anomeric forms of
pyranoses and pyranosides.13b Bond length dis-
parity is accompanied as expected by a weak cor-
relation with angle deformations about the central
carbon bearing two oxygens.14
C6
C7
N7
O4
O5
C8
C8A
C9
685(3)
293(3)
2042(3)
190(3)
1374(3)
5802(3)
4390(3)
C10
ij
aUeq is defined as one third of the trace of the orthogonalized U
tensor; esd’s in parentheses.

New cyclic oxocarboxylic acids
383
ferences are small and consistent with the solid
state information, but with just two compounds,
additional data are needed before a trend can be
identified.
Gem-dimethyl effect
Dimethyl groups in compound 1–2 were de-
signed to demonstrate two stabilizing features on
the pseudoacid structure. First, since the dimethyl
groups are adjacent to the pseudoacyl hydroxy,
-eliminationissuppressed, preventingfurtherre-
action to an isochromenone. Second, the dimethyl
groups in a putative open chain aldehydo acid pre-
cursor would act to decrease the distance between
these two functional groups and promote cycliza-
tion. A significant upfield shift in both lactol H
and C resonances (Table 2) is seen in the gem-
dimethylated compounds (1, 2, 4) relative to the
unsubstituted compounds. This is consistent with
diminished “aldehyde character” at the lactol.
The gem-dimethyl effect is most often
ascribed to conformational restriction and a
bond-angle compression opposite the dimethyl
substituents. The latter feature is retained, ap-
parently, in the cyclic pseudoacid structures
of the dimethylated compounds 1, 2, and 4
compared to the non-methylated analogs 3
and the reference compound 3-hydroxy-3,4-
dihydroisobenzopyran-1-one (Table 2). The divi-
sion occurs at about the tetrahedral angle. Ring
internal angles at the dimethylated carbon pseu-
doacids are lower than 109.5 , while those in the
unsubstituted cases are greater.
Fig. 2. Plot (50% probablility enclosures) of the structure of
3-hydroxy-6-methoxy-3,4-dihydroisobenzopyran-1-one (3).
The effects of the aryl substitution on the
pseudoacidstructurearefoundtobeminimal. In 3,
the occurance of the -anomeric form with its lo-
cal effect on the lactol structure (vide infra) more
than compensates for weak changes that might
have been anticipated from the modification of
the carboxylate basicity by the p-methoxy group.
---
In 4, the pseudoacid endocyclic C O distance is
---
longer and the exocyclic C O distance is shorter
thantheaveragesofthecorrespondingvaluesfrom
1 and 2. Structures 1, 2, and 4 are -anomers, and
---
the C O length disparities are suggestive of a
slight weakening of the carboxylate contribution
in 4 relative to the unsubstituted case. The chem-
ical shifts of the lactol H and C are found slightly
downfield of the positions in the parent. The dif-
Hydrogen bonding
In forming hydrogen bonds, pseudoacids are
found to form dimers or chains.1 Complementary
dimer hydrogen bonding is found in 1 and 2, with
carboxyl oxygens acceptors and lactol hydroxy
oxygens donors (Fig. 1). These effectively form
rings with two donors and acceptors among its
12 atoms, designated R22(12).15 This type of hy-
drogen bonding is not cooperative as in the dimer
Fig. 3. Plot (50% probablility enclosures) of the structure of
3-hydroxy-4,4-dimethyl-7-nitro-3,4-dihydroisobenzopyran-
1-one (4).

384
Cooper, Smith, Barker, Webb, and Valente
hydrogen bonding of carboxylic acids. Rather,
the contributing structures in the pseudoacids are
the dissimilar open and cyclic oxocarboxylic acid
forms. The resulting associations are weaker than
in carboxylic acids, as judged by the hydrogen
bond distances (Table 2). Generally, (normalized
from the Cambridge Crystallographic Data
Centre (CCDC), 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44(0)1223-336033; email:
deposit@ccdc.cam.ac.uk].
Acknowledgments
˚
X-ray) H
O distances are longer (1.80–1.92 A)
in the dimer pseudoacids than found in carboxylic
acid dimers (1.64–1.70 A). This underscores
We thank W. Reid Dreher and Daniel Osborne for
their exploratory synthetic work. We thank the National
Science Foundation (0087619), W. R. Keck Founda-
tion, and Camille and Henry Dreyfus Foundation (SG-
01-052) for grants in support of instrumentation. We
thank the Office of Naval Research for diffraction facil-
ities and Dr. Jeffrey Zubkowski, Department of Chem-
istry, Jackson State University for access to them.
16a
˚
the importance of cooperativity added to comple-
mentarity in improving hydrogen bond strength.
Nonetheless, in 1 and 2, the pseudoacid dimer hy-
drogen bonds incorporate four favorable features.
First, they are found with the pseudoacid in the
-anomeric form, with evidence supporting the
enhanced hydrogen bond donation properties of
the group.16b Second, the hydroxy groups are near
their lowest energy conformations about the exo-
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---
cyclic C O bond with torsion angles in the neigh-
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the complementary monomers are enantiomeric,
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C11(6).15 In these cases, the exocyclic hydroxyl
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at the carboxyl oxygen acceptor are at the lim-
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Supplementary material
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supplementary crystallographic data for this pa-
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at www.ccdc.cam.ac.uk/conts/retrieving.html [or
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