Influence of sulfur groups on carboxylic acid strengths

Article abstract of DOI:10.1016/j.tet.2018.04.007

The relative acid strength for a series of monocarboxylic acids of the general formula R–X–(CH₂)_n–COOH and related dicarboxylic acids of the general formula HOOC–(CH₂)_n–X–(CH₂)_n–COOH, where R = Ph or Me, X = CH₂, –S– –SO– or –SO₂–; and n = 1 or 2 as appropriate; have been studied as a function of X. It is found that sulfur containing acids have lower pKa values than the corresponding carbon analogues, that the pK_a is highest for the thioacids and lowest for the sulfonyl acids, that the pK_as increase as n increases, and that for the dicarboxylic acid systems only the thio members show a significant reduction in pK_a (2) – pK_a (1) differences upon changing n from 1 to 2.

Full text of DOI:10.1016/j.tet.2018.04.007

Accepted Manuscript
Influence of sulfur groups on carboxylic acid strengths
Erwin Boschmann, Roger D. Miller
PII:
S0040-4020(18)30375-2
10.1016/j.tet.2018.04.007
TET 29422
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 30 January 2018
Revised Date: 2 April 2018
Accepted Date: 3 April 2018
Please cite this article as: Boschmann E, Miller RD, Influence of sulfur groups on carboxylic acid
strengths, Tetrahedron (2018), doi: 10.1016/j.tet.2018.04.007.
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Graphical Summary

ACCEPTED MANUSCRIPT
1
Influence of Sulfur Groups on Carboxylic Acid Strengths
Erwin Boschmann*
†
Roger D. Miller
*
To whom correspondence should be addressed at Indiana University Purdue University at
Indianapolis, 402 N. Blackford Street, Indianapolis, IN 46202-3374 USA. E-mail address:
Erv@iu.edu.
†
Eli Lilly and Company, Indianapolis, IN 46285 USA (gpa1124@msn.com).
Abstract
The relative acid strength for a series of monocarboxylic acids of the general formula R-
X-(CH ) -COOH and related dicarboxylic acids of the general formula HOOC-(CH ) -X-
2
n
2 n
(
CH ) -COOH, where R = Ph or Me, C H -, C H -CH -, CH -, or HOOC-(CH ) -; X =
2 n 6 5 6 5 2 3 2 n
CH , -S-, -SO-, or -SO -; and n = 1 or 2 as appropriate; have been studied as a function
2
2
of X. It is found that sulfur containing acids have lower pKa values than the
corresponding carbon analogues, that the pK is highest for the thioacids and lowest for
a
the sulfonyl acids, that the pK s increase as n increases, and that for the dicarboxylic acid
a
systems only the thio members show a significant reduction in pK (2) – pK (1)
a
a
differences upon changing n from 1 to 2. These trends are rationalized on the basis of
electronic features of the sulfur groups.
Keywords:
Thio carboxylic acid strength
Influence of sulfur groups
Strength comparison
Introduction
This study determines the pK s of some sulfur containing carboxylic acids. Such
a
determination is important in and of itself, but of even greater value is the pK study of a series
a
of sulfur containing carboxylic acids.
The strength of an acid depends largely on the ability of its conjugate base to delocalize
the negative charge. Thus, The presence of resonance systems and electron-withdrawing groups,
are among factors that drastically increases charge delocalization and consequently the strength
2
3
of the acid . During our studies of metal complexation of β-ketosulfoxides , it became of interest
to know the effect of the sulfur groups -S-, -SO-, and –SO -, on the acidity of their carboxylic
2
acids. We conducted an orderly study of the influence of sulfur groups on the strength of some
1
5 mono- and di-carboxylic acids. While it has been several decades since these studies were
conducted, a recent thorough literature search revealed no new relevant studies.
1

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The table summarizes our data for fifteen acids along with their carbon analogues
obtained in aqueous media at 25ºC. For completion the acids were also studied in 66% DMF,
a
dimethyl formamide, indicating higher pK values but following the same trend as that in
aqueous media. The graphs display our findings visually.
pK
a
Values of Sulfur Containing Carboxylic Acids
----Water------
-
-- Differences --
Acid
pK (1) pK (2)
pK (2) – pK (1)
a
a
a
a
Series 1
-Phenylpropionic acid
Phenylthioacetic acid
Phenylsulfinylacetic acid
Phenylsulfonylacetic acid
3
C
6
H
5
-CH
2
-CH
2
2
-COOH
4.37a
C H -S-CH -COOH
3.55
6
6
5
5
b
C
H
-SO-CH
2
-COOH
2.70c
C H -SO -CH -COOH
6
2.33
5
2
2
Series 2
4
-Phenylbutyric acid
C H -CH -CH -CH -COOH
4.76d
3.76
2.71
2.30
6
5
2
2
2
s-Benzylthioacetic acid
Benzylsulfinylacetic acid
Benzylsulfonylacetic acid
C H -CH -S-CH -COOH
6
6
5
5
2
2
2
C
H
-CH
2
-SO-CH -COOH
C H -CH -SO -CH -COOH
6
5
2
2
2
Series 3
Butyric acid
CH -CH -CH -COOH
4.81e
3.73
2.85
2.5
3
2
2
2
. Methylthioacetic acid
CH -S-CH -COOH
3 2
Methylsulfinylacetic acid
Methylsulfonylacetic acid
CH -SO-CH -COOH
3 2
CH -SO -CH -COOH
3
2
2
Series 4
Pentanedioic acid
Thiodiacetic acid
Sulfinyldiacetic acid
Sulfonyldiacetic acid
CH -(CH -COOH)
4.34
5.41g
4.23
3.43
2.80
1.07
1.58
0.83
0.75
2
2
2
f
S-(CH
2
-COOH)
2
2.65
2.60
h
SO-(CH -COOH)2
2
i
SO -(CH -COOH)
2.05
2
2
2
Series 5
Heptanedioic acid
(CH ) -(CH -COOH)
4.71
4.05
3.42
3.40
5.35
4.95
4.41
4.45
0.64
0.90
0.99
1.05
2
3
2
2
Thiodipropionic acid
Sulfinyldipropionic acid
Sulfonyldipropionic acid
S-(CH
2
-CH
2
-COOH)
2
SO-(CH -CH -COOH)
2
2
2
SO
2
-(CH
2
-CH
2
-COOH)
2
a Reference 5 reports 3.566; reference 7 reports 3.59; H. D. Crockford and T. B. Douglas, J.
Amer. Chem. Soc., 56, 1472 (1934) report 3.56; Otto Behaghel, J. prakt. Chem., 114, 287
(1926) reports 3.53; Erik Larson, Ber., 63 B, [6], 1347 (1930) reports 3.52.
2

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b Reference 5 reports 2.732; Crockford and Douglas (see footnote a) report 2.66; Behaghel
(footnote a) reports 2.668.
c Reference 5 reports 2.513; Crockford and Douglas (footnote a) report 2.44.
d Larsson (footnote a) reports 3.73.
e Larsson (footnote a) reports 3.73.
f Erik Larsson, Z. anorg. allgem. Chem., 125, 281 (1922) reports 3.31; W. Ostwald, Z. Physik.
Chem. 3, 183 (1889) reports 3.3; Karl Jönsson, Svensk Kem. Tids., 34, 192 (1922)
reports 3.3.
g Larsson (footnote f) reports 4.4 at 18º; Wegscheider, Monatshefte f. Chem., 37, 251 (1916)
reports 4.5 at 25º.
h Jönsson (footnote f) reports 2.19.
i Jönsson (footnote f) reports 1.9.
Discussion
The table and graphs show pK s for five series of acids,: the monocarboxylic acids of the
a
2 n
general formula R-X-(CH ) -COOH and related dicarboxylic acids of the general formula
HOOC-(CH ) -X-(CH ) -COOH, where R = Ph or Me, C H -, C H -CH -, CH -, or HOOC-
2
n
2 n
6
5
6
5
2
3
(
CH
2
)
n
-; X = CH
2
2
, -S-, -SO-, or -SO -; and n = 1 or 2 as appropriate.
Figure 1. Bar graphs of pK values for Series 1-3 acids.
a
(The numbers on the x-axis refer to the Series number, followed by the type of acid)
3

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R-X-(CH ) -(COOH) , where R = C H -, C H -CH -, CH -, or HOOC-(CH ) -; X = -S-
2
n
n
6
5
6
5
2
3
2 n
,
-SO-, or -SO -; and n = 1 or 2. Each series is headed by the carbon analogue for comparison.
2
Several observations may be made.
a a
Figure 2. Bar graphs of pK (1) and pK (2) values for Series 4 and 5 acids.
(The numbers on the x-axis refer to the Series number, followed by the type of acid)
a
pK (1) values for thio carboxylic acids in aqueous media fall in the two to four range
indicating high acidity relative to the carbon analogues. Thus, comparing the carbon analogue
4
a
values in the table with the thio acids, one finds values which are 0.5 to 1.5 pK units above
those of the corresponding thio analogues. This is an strong indication of the higher inductive
5
effect, among others, of thio vs. carbon groups and the resulting ease to stabilize the anion .
Increased oxygenation of the S group (as well as solvent effects and ionic strength)
lowers the pK s. Compare Series 1-5. The higher the electron withdrawing ability (with higher
a
oxygenation) of the thio groups, the more stabilized the anion becomes leading to higher acidity.
The type of R group has little effect on acidity. Compare Series 1 through 3: phenyl,
benzyl, and methyl groups all display virtually the same acidity for the -S- groups. The same
holds for the -SO-, and -SO - groups. R groups are either too far removed from the anion or have
2
no electron withdrawing units to stabilize the anions.
4

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a
Increasing the chain length between the thio and acid groups increases the pK s (compare
Series 4 and 5), and reduces the pK (2) – pK (1) difference for the S acids. Of the two
a
a
dicarboxylic acid systems studied, Series 4 and 5, only the acidity of the sulfide members appear
to be affected by the reduced field effect brought about by longer chains [pK (2) – pK (1) for
a
a
S(CH COOH) is 1.58, while it is only 0.90 for S(CH CH COOH) ]. This is the same trend
2
2
2
2
6
2
observed for aliphatic saturated dicarboxylic acid systems . For the sulfoxide and sulfone
members the stronger electron withdrawing ability of these oxygenated sulfurs is eliminated by
the increased chain length effects.
a
As with all dicarboxylic acids the pK (2) values are naturally higher than the
corresponding pK (1) values, since it is more difficult to remove a hydrogen ion from a moiety
a
already negative. This effect becomes less important the farther the second carboxylic hydrogen
is from the initial anion.
Figure 1 shows the pK values obtained for acids plotted vs. X, the type of sulfur group
a
for Series 1-3. The carbon analog is given for reference. The values decrease from left to right
indicating acid strength increases as a function of the oxidation state of sulfur. Sulfur stabilizes
the anion through polarization and the presence of the more electronegative oxygens in -SO- and
2 a
-SO - will increase polarizability even more. It is noteworthy, however, that the drop in pK
values between the sulfoxides and sulfones is generally less than that observed between sulfides
and sulfoxides. Obviously, the introduction of the second oxygen does not double the electron-
7
withdrawing power of the first. It has been shown that the preferred conformation of sulfoxide-
containing carboxylic acids is such that intra-molecular hydrogen bonding between the carboxyl
hydrogen and the sulfoxide oxygen is not possible, but is possible for sulfones thus confirming
the smaller drop from sulfoxide to sulfone :
O
H
ǁ
ǀ
R―
S
ǁ
―
C --- H
\
O
⁞
C ═ O
ꢀ
H― O
Figure 3. Intra-molecular hydrogen bonding between the carboxyl hydrogen and the sulfone
oxygen.
Thus, it is reasonable to expect the effect of increased acidity due to two highly
electronegative sulfonyl oxygens to be partially offset by intra-molecular hydrogen bonding. It
8
has been pointed out not to ascribe acid strength variations solely to inductive effects, but to
5

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allow for entropic differences attributable to order-disorder solvent effects. Thus, the solvent,
temperature, ionic strength, and molecular structure must also be considered.
EXPERIMENTAL SECTION
Synthesis of Compounds
9
The commercially available sulfides were generously donated by Evans Chemicals, Inc. .
1
0
The sulfoxides and sulfones were prepared according to published procedures via stepwise
hydrogen peroxide oxidation of the corresponding sulfides in glacial acetic acid. The products
were purified through recrystallization from a 1:3 ethylacetate/benzene solution, or, in the case
of long chain acids, from water. All melting points agreed with published values. Others are:
Benzysulfinylacetic acid 127-8ºC
Benzylsulfonylacetic acid 137-8ºC
Methylsulfonylacetic acid 113-4ºC
Sulfonyladiacetic acid 110ºC
Sulfinyldipropionic acid 219ºC
Sulfonyldipropionic acid 224-6ºC
-1
The sulfoxides showed the typical strong broad infrared absorption at 1000 cm , and the
-1
-1
sulfones showed the two expected absorptions around 1300 cm and 1140 cm .
Titrations
a
The pK s of the acids were determined at 25ºC using an electrometric titration assembly
1
1
designed by and in use at Eli Lilly and Co., Indianapolis, Indiana. It consists of pH-sensitive
glass and saturated calomel electrodes wired to a pH meter and the x-axis of a flatbed x-y
recorder. The delivery of standard titrant is accomplished with a precision of 0.0002 mL by
means of a variable speed motor driven micro buret delivering the titrant at a constant rate. The
gear chain driving the buret is connected to the y-axis of the x-y recorder through a precision
potentiometer. The assembly records pH variations vs. the amount of titrant delivered with errors
generally not over ±0.04 pK units.
a
a
Each pK is determined graphically from the titration equivalence point and the use of the
Henderson-Hasselbalch equation. By locating the half-way point of titrant added, finding the
point on the titration curve, and plotting back to the pH axis, determines the exact pH. Because at
this point the amount of acid and base added are equal, the pH = pKa.
6

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Conclusion
Largely d Due to their ability to delocalize negative charge (among others), sulfur,
sulfoxide, and sulfone containing carboxylic acids are stronger than their carbon analogues.
Sulfur containing carboxylic acids are weaker than for the sulfoxide, with two electronegative
oxygens in the sulfone yield the strongest acids. The type of R group has no influence on the
strength of the acid. The closer the thio groups are to the acid group, the stronger its acidity.
More recent studies of possibly relevant compounds studied such things as electron-transfer
1
2
13
14
reactions , computer modeling , or crystal structures .
Acknowledgements
The financial assistance by Eli Lilly and Company and that of the Indiana University
Foundation are gratefully acknowledged. Methylthioacetic acid was prepared by Dr. Charles
Kelley, Indiana University, Bloomington, Indiana. A debt of gratitude is expressed to Drs. Partha
Basu and Sébastien Laulhé of the chemistry department at Indiana University-Purdue University
Indianapolis, Indiana, for valuable discussions. Dr. Laulhé prepared the bar graphs.
1
2
. Presented, in part, before the ACS Meeting-In-Miniature, Indianapolis, Indiana,
December 11, 1971.
. For example, the pK values for acetic acid decrease with chlorine substitution:
a
CH
3 a 2 a 2 a
COOH pK = 4.75; CH ClCOOH pK = 2.85; CHCl COOH pK = 1.48; and
4
a
CCl COOH pK = 0.70 .
3
a
3
4
. Erwin Boschmann, J. Inorg. Nucl. Chem., 35, 1025 (1973).
. (a) Robert C. Weast, ed. Handbook of Chemistry and Physics, 50 ed., The Chemical
Rubber Co., Cleveland, Ohio, 1969, pp. D 118-9.
th
(
b) Richard Gane and Christopher K. Ingold, J. Chem. Soc., 1931, 2153 for the pK (2)
a
value of pentane heptanedioic-1,5-dicarboxylic acid.
5
6
. D. J. Pasto, D. McMillan, and T. Murphy, J. Org. Chem., 30, 2688 (1965).
. (a) W. Simon, Doris Meuche, and E. Heilbronner, Helv. Chim. Acta, 39, 290 (1956),
(b) A.P. Kreshkov, N.Sh.Aldarova, B.Ya.Eryshev, and B.B. Tanganov, Zhurnal Obshchei
Khimii, 40(4), 894-8 (1970).
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8
. D. J. Pasto and R. Kent, J. Org. Chem., 30, 2684 (1965).
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9
1
. Evans Chemetics, Inc., 90 Tokeneke Road, Darien, Connecticut 06820.
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(1961).
1
1
1. Eli Lilly and Company World Headquarters, Lilly Corporate Center, Indianapolis,
Indiana 46285 USA.
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1
1
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8