Influence of some thia- or azasubstituted butyric acid derivatives on the chemical shift of the benzene ring carbon atoms

Article abstract of DOI:10.3390/50300616

Eight thia- or azasubstituted butyric acid derivatives were prepared and the influence of these substituents on the chemical shifts of the benzene ring carbon atoms was studied.

Full text of DOI:10.3390/50300616

Molecules 2000, 5, 616-619
molecules
ISSN 1420-3049
http://www.mdpi.org
Influence of Some Thia- or Azasubstituted Butyric Acid
Derivatives on the Chemical Shift of the Benzene Ring
Carbon Atoms
Johannes Fröhlich1, Fritz Sauter1 and Viktor Milata2*
1Institut for Organic Chemistry, Technical University Wien, Getreidemarkt 9, A-1110 Vienna, Austria
E-mail: jfroehli@pop.tuwien.ac.at; fsauter@pop.tuwien.ac.at
2Department of Organic Chemistry, Faculty of Chemical Technology, Slovak Technical University,
Radlinského 9, SK-812 37 Bratislava, Slovak Republic
E-mail: vmilata@cvt.stuba.sk, URL: http://www.chtf.stuba.sk/KATEDRY/koch/milata/viktor.htm
* Author to whom correspondence should be addressed.
Received: 26 January 2000 / Accepted: 17 March 2000 / Published: 22 March 2000
Abstract: Eight thia- or azasubstituted butyric acid derivatives were prepared and the influ-
ence of these substituents on the chemical shifts of the benzene ring carbon atoms was
studied.
Keywords: 4-phenyl-3-thiabutyric acid derivatives, 4-phenyl-3-azabutyric acid derivatives,
substituent chemical shifts.
Introduction
For the synthesis of derivatives of (iso)thiochromanone and isoquinolone it was necessary to pre-
pare eight appropriately substituted 4-phenyl-3-(or 4-)thia(or aza)butyric acids and derivatives 1. We
now report a study of the influence of these substituents on the chemical shifts of the benzene ring car-
bon atoms of the compounds prepared (Table 1).
© 2000 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.

617
Molecules 2000, 5
Table 1.
R2
R1
R
Y
X
1a-h
No.
1a
X
CH2
S
Y
S
R1 R2
R
No.
X
Y
R1
R2
R
H
H
H
H
H
H
H
H
COOH
COOH
COOMe
COOMe
CH2
CH2
NH
NH
- ( CH2 )4 -
CN
1e
1f
CH2
S
- ( CH2 )4 - COOH
CN
CH2 NMe - ( CH2 )4 - COOH
1b
1c
CH2
S
CH2 NMe - ( CH2 )4 -
1g
1h
CH2
1d
Results and Discussion
Chemical shifts of all of the compounds studied were assigned on the basis of comparisons between
the experimental values acquired from recorded spectra and those calculated using the following pro-
grams: ACD / CNMR ver. 1.1 [6], CS Chem Draw Pro, ver. 4.5 [7] and ChemWindow3, ver. 3.0.0
with C13-module [8], respectively. We obtained a good agreement between the measured chemical
shifts values and those calculated using all three programs.
Chemical shifts (d) and the substituent chemical shift (D d) of all of the compounds with hetero-
atoms in the b- position are in the same range for all compounds studied. The compounds with the he-
teroatom in the a -position (1b,d) have the ipso-carbon less shifted than the analogues having the he-
teroatom in the b-position (1a,1c,1e-1h). Substituent chemical shifts of meta-carbon atoms of the ben-
zene ring of compounds 1a, 1b and 1d have positive values unlike all the other compounds: 1c, 1e-1h.
The influence of the studied substituents on the chemical shifts of the benzene ring carbon atoms of
can be compared, for example with CH2SMe (1a, 1c), SMe (1b, 1d) or CH2NHCHMe2,
CH2NMeCH2Ph substituents [9] which show good agreement with model compounds (see Table 2).
Perhaps Dd for Cipso are slight reduced for all compounds by about 2 ppm and 1b, 1d have positive val-
ues for Cortho in comparison with the compounds bearing the SMe substituents, but this also depends on
the solvents used [9].

618
Molecules 2000, 5
Table 2. Chemical shifts (d, in ppm) and substituent chemical shifts (D d) of the benzene ring carbon
atoms of 4-phenyl-3-(or 4-)thia(or aza)butyric acid derivatives.
C
C
C
C
Other signals
- X - Y - CR R R*
ipso
orto
meta
para
1 2
- CH -S-CH -COOH, 1a
136.8 129.2 128.6
127.4 176.8, 36.3, 31.9
d
2
2
+8.3 +0.7 +0.1
135.0 130.1 129.0
-1.1
D d
d
-S-CH CH -COOH, 1b
126.6 177.1, 34.4, 30.9
2
2
+6.5 +1.6 +0.5
137.0 128.9 128.3
-1.9
D d
d
-CH -S-CH -COOMe, 1c
127.0 170.5, 52.0, 36.1, 31.8
2
2
+8.5 +0.4
135.0 129.8 128.8
-0.2
-1.5
D d
d
-S-CH CH -COOMe, 1d
126.3 171.8, 51.5, 33.9, 28.7
2
2
+6.5 +1.3 +0.3
139.2 128.5 128.3
-2.2
D d
d
-CH -NH-C(CH ) CN, 1e
2 4
127.3 122.9, 61.2, 50.2, 39.0, 23.5
2
+10.7
0
-0.2
140.0 128.4 127.7
+11.5 -0.1 -0.8
138.3 128.5 128.2
+9.8 -0.3
140.0 128.3 128.2
+11.5 -0.2 -0.3
-1.2
D d
d
-CH -NH-C(CH ) COOH, 1f
2 4
127.0 179.5, 70.0, 48.4, 35.8, 24.2
2
-1.5
D d
d
-CH -NMe-C(CH ) CN, 1g
2 4
126.8 120.2, 68.8, 58.4, 38.5, 37.9, 23.2
2
0
-1.7
D d
d
-CH -NMe-C(CH ) COOH, 1ha
2 4
126.7 176.6, 74.7, 56.7, 36.0, 32.1, 24.8
2
-1.8
D d
*d (Benzene) = 128.5 ppm, d (Chloroform) = 77.0 ppm, ain DMSO-d6, d (DMSO) = 39.0 ppm
Experimental
General
13
The synthesis of thiabutyric acid derivatives was described long ago [1-3] but their C NMR spec-
tra have not been published until now. In the case of 3-azabutyronitrile derivatives, the modified
Strecker method [4] was applied for the synthesis of the corresponding 2,2-tetramethylene analogs ac-
cording to the lit. [5]. NMR spectra were determined with a Bruker AC 200 FT-NMR spectrometer
and are expressed in ppm downfield from tetramethylsilane (internal standard).
4-Phenyl-3-aza-2,2-tetramethylene butyric acid derivatives 1e and 1g
To avoid hydrogen cyanide evolution a solution of potassium cyanide (30 mmol) in water (10 mL)
was slowly added dropwise to a magnetically stirred mixture of benzylamine or N-methylbenzylamine
(20 mmol), hydrochloric acid (20 mmol), 25% ethanol (40 mL) and cyclopentanone (20 mmol). The
mixture was stirred 4 days and the resulting precipitate was filtered off (1e) or the reaction mixture was
extracted with ether, dried with sodium sulfate and evaporated (1g). The nitriles were hydrolyzed to
the corresponding acids with concentrated sulfuric acid at 20-100°C for 12 hours, followed by neu-

619
Molecules 2000, 5
tralization and filtration or extraction, drying and evaporation. 1e: 62%, m.p. 42-43°C; 1g: 76%, b.p.
130-140°C / 0.45 Torr.
References and Notes
1. Petropoulos, J.C.; McCall, M.A.; Tarbel, D.S. J. Amer. Chem. Soc. 1953, 75, 1133.
2. Kiang, A.K.; Mann, F.G. J. Chem. Soc. 1951, 1911.
3. Fong, H.O.; Hardstaff, W.R.; Kay, D.G.; Langler, R.F.; Morse, R.H.; Sandoval, D.-N. Can. J.
Chem. 1979, 57, 1206.
4. Strecker, A. Justus Liebigs Ann. Chem. 1850, 75, 27.
5. Euerby, M.R.; Waigh, R.D. J. Chem. Res. (M) 1982, 2417.
6. ACD / CNMR: Advanced Chemistry Development Inc., 141 Adelaide Street West Suite 1501,
Toronto, Ontario, M5H 3L5, Canada.
7. CS Chem Draw Pro: CambridgeSoft Corporation, 875 Massachusetts Avenue, Cambridge, MA
02139, USA.
8. ChemWindow 3: SoftShell International, 715 Horizon Dr Suite 390, Grand Junction, CO 81506,
USA.
9. Ewing, D.F. Org. Magn. Reson. 1979, 12, 449.
Samples Availability: Not available.
© 2000 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.