August, 1965]
`
`Furan-, Thiophenedicarboxylic Acids and Their Esters
`
`1247
`
`A Study of the Acid Dissociation of Furan- and Thiophenedicarboxylic
`Acids and of the Alkaline Hydrolysis of Their Methyl Esters
`
`By Shigeru OAE, Naornichi FURUKAWA, Takao WATANABE
`Yoshio Orsun and Masayuki HAMADA
`
`(Received August 15, 1964)
`
`The physical and chemical behavior of furan—
`and thiophenemonocarboxylic acids and their
`derivatives has been investigated extensively
`and shown to be considerably different
`from
`that of benzoic acid.” Cocker et al. have
`suggested the formation of an intramolecular
`hydrogen bond in their study of the acid dis-
`sociations of four carboxylic groups and the
`infrared spectrum of furantetracarboxylic acid.”
`Meanwhile, a few dicarboxylic acids, such as
`succinic acid33' and maleic acid," have been
`known to form intra- or intermolecular hydro-
`gen bondings that create substantial differences
`between their
`first and second dissociation
`constants.
`
`Meanwhile, although there have been many
`reports on the alkaline hydrolysis of
`the
`rnonocarboxylic
`esters
`and
`the
`reaction
`mechanism of
`the saponification has been
`well elucidatedf? only a few investigations of
`the hydrolyses of dicarboxylic esters have been
`carried out.
`This
`is perhaps due
`to
`the
`
`* Preliminary results have been reported previously in
`Arm. Rept. of Radiation Center Osaka Pref-, 2, 106 (1961).
`1)
`a) C. C. Price and E. A. Dudley, J. Am. Chem.
`Soc., 78, 68 (1956);
`h) S. Oae and C. C. Price,
`ibid., 79,
`2547 (1957);
`c) B.
`lmoto, Y. Otsuji, T. Hirai and H.
`lnoue,
`J. Chem. Soc.
`Japan, Pure Chem. Sec.
`(Nippon
`Kagaku Zassi), 77, 804, 809 (1959).
`2) W. Cocker, W. J. Oavis, T. B. H. McMurry and P.
`A. Start. Tetrahedron, 7, 299 (1959).
`3) L. Eberson, Acta Chem. Scand., 2, 13 (1959).
`b) H.
`4)
`a) M. Shahat, Acre Crysz., 5, 763 (1962);
`M. E. Cardwell, J. D. Danitz and L. E. Orgel, J. Chem.
`Soc.. 1953, 3740.
`
`extreme difficulty of following the kinetics of
`the hydrolyses of these diesters, because they
`do not obey the simple second-order kinetic
`equation. However, a few noteworthy treat-
`ments have been made. Namely, one of the
`earliest treatments of the competitive consecu-
`tive second-order
`reaction for
`the alkaline
`saponification of diesters has been carried out
`by Ingold.” However, this graphic approxima-
`tion gives by no means an accurate estimation.
`Meanwhile, other investigators have made many
`efforts to get accurate kinetic data for
`those
`dicarboxylic esters.” Frost
`and Schwemer
`have presented what appears to be the first
`legitimate method for
`the calculation of the
`consecutive competitive second-order kinetic
`equation of the alkaline hydrolysis of dicar-
`boxylic esters.”
`to
`The present work was initiated in order
`investigate
`the
`nature of
`the
`interaction
`between the two carboxyl groups attached to
`the furan and thiophene rings and the alkaline
`hydrolyses of the diesters of these carboxylic
`
`J. I-line “ Physical Organic Chemistry,” McGraw-
`a)
`5)
`Hill Book Company, New York (1962), pp. 275-301; b)
`C. K. lngold, “Organic Chemistry," Cornell University
`Press, Ithaca, New York (1953); c) M. L. Bender, Chem.
`Revs., 60, 53 (1960).
`6) C. K. Ingold, J. Chem. Sac., 1931, 2170.
`F. H.
`b)
`7)
`a) M. Ritchie,
`ibid.,
`1931, 3112;
`Westheimer, W. A. Jones and R. A. Lad, J. Chem. Phys.,
`10, 478 (1942);
`c) D. French, J. Am. Chem. Soc., 72, 4806
`(1950); 73, 4541 (1951).
`8) A. A. Frost and W. C. Schwemer,
`(1952).
`
`ibid., 74, 1268
`
`Petitioners‘ Exhibit 1006, Page 1 of 7
`
`Petitioners' Exhibit 1006, Page 1 of 7
`
`

`
`l 248
`
`S. OAE, N. FURUKAWA, T. WATANABE, Y. Orsun and M. HAMADA
`
`[Vol. 38, No. 8
`
`acids in comparison with the dissociations of
`phthalic acids and maleic acid and the saponi-
`fication of their esters.
`
`Experimental
`
`Materials. —— 2, 3-Furandicarboxylic Acid.” —— 4,4-
`Diethoxybutyronitrile, obtained from acrolein, was
`condensed with diethyl oxalate, giving 2-ethoxalyl-
`4,4-diethoxybutyronitrile. Ethyl 3-carbamyl—2-furan-
`carboxylate, prepared by the cyclization of
`the
`above nitrile, was hydrolyzed to 2,3-furandicar-
`boxylic acid. Colorless crystals of the acid melted
`at 221-~—222°C, and the yield was 20% on the basis
`of the 2-ethoxaiyl-4,4—diethoxybutyronitrile used.
`The 2-Monomethyl Ester of 2,3-Furandicarboxylic
`Ac¢'d.——~The above acid was converted to its mono-
`silver salt by adding 1.2 mol. of silver nitrate to
`one mole of the monosodium salt in water. To a
`solution of one mole of the dried monosilver salt
`obtained above in benzene, one mole of methyl
`iodide was added, and then the mixture was refluxed
`for two hours and filtered to remove the silver
`iodide. The benzene solution was evaporated to
`dryness, and recrystallization from water gave the
`monoester in a 70% yield. M. p. 118°C.
`Found: C, 49.28; H, 3.97. Calcd. for C71-I507:
`C, 49.44; H, 3.56%.
`acid the 2-car-
`Since in 2,3--furandicarboxylic
`boxylic group is much more acidic than the 3-car-
`boxylic group,
`it
`is reasonable to assume that 2,3-
`furandicarboxylic acid is esterified first at
`the 2-
`position by the method used in this investigation.
`Thus the monoester obtained would have to be 2-
`monomethylester of 2,3-furandicarboxylic acid.
`3, 4-Furandicarboxylic Acid.‘°)—Diethyl a-formyl-
`succinate was converted to its acetal, which was
`again formylated to diethyl
`l-formyl-2-diethoxy-
`methylsuccinate.
`3, 4—Furandicarboxylic acid was
`prepared by the cyclization of
`the above com-
`pound. Recrystallization from water gave color-
`less crystals (m. p. 214°C), and the yield was 50%
`on the basis of the diethyl succinate used.
`The 3-Monomethyl Ester of 3, 4-Furandicarboxylic
`Acid.——This ester was obtained in a 76% yield by
`the method used for the esterification of 2,3-l'uran~
`dicarboxylic acid (in. p.
`l35——l37°C).
`Found: C, 49.06; H, 3.76. Calcd. for Cql-I505:
`C, 49.44; H, 3.56%.
`acid was
`2.5-Furandicarboxylic Acz'd.">—This
`obtained first by chloromethylating ethyl 2-furan-
`carboxylate and then by oxidizing the resulting
`compound (in. p. 365°C) in a 70% yield.
`2,4-Furandicarboxylic Acid.‘9>—This acid was pre-
`pared by the rearrangement of the methyl 6-bromo—
`coumalin 5-carboxylate obtained from coumalin 5-
`carboxylic acid (in. p. 268-269°C) in a 48% yield.
`3,4—Thiopheriedicarboxylic Acz'd.‘°>——This acid was
`prepared from diethyl 1-formyl-2-diethoxymethyl-
`
`9) R. G. Jones, ibid., '77. 4069 (1955).
`10) E. C. Kornfcld and R. G. Jones, J. Org. Chem., 19.
`I617 (1954).
`11) Y. Shane and Y. Hachihama, J. Chem. Soc. Japan.
`Ind. Chem. Sec. (Kagyo Kagaku Zassi), 57, 836 (1954).
`I2) H. Gilman and R. Burther, J. Am. Chem. 500., SS,
`2903 (1933).
`
`succinate, the method of synthesis which has been
`reported earlier.
`The cyclization of diethyl
`l-
`forrnyl—2-diethoxymethylsuccinate was carried out
`using phosphorous pentasulfide. The diethyl 3,4-
`thiophenedicarboxylate thus obtained was hydrolyzed
`with aqueous sodium hydroxide to the acid (m. p.
`225.5--226.5°C) in 20% yield.
`The 3-Monomer/zyl Ester of 3,4- T/ziophenedicarboxy
`lic Acid.—~The monoester of 3,4-thiophenedican
`boxylic acid was prepared by the same method as
`was used for the synthesis of the 3-monomethyl
`ester of 3,4—furandicarboxylic acid (m. p. 115.5-~
`1l6.5°C).
`2, 5- T/ziophenedicarboxylic Acid.“‘3——Thiophene was
`chloromethylated with paraformaldehyde as usual
`to give 2,5-dichloromethylthiophene, which was
`further treated with sodium acetate and subsequent
`hydrolysis to yield 2,5-dihydroxymethylthiophene.
`This alcohol was oxidized with potassium per-
`manganate to obtain the dicarboxylic acid (m. p.
`358.5°C) in a 75% yield.
`pK-Measurements.——pK measurements of the acids
`were made by potentiometric titrations using a
`Horiba model P pH meter (glass and calomel elec-
`trodes). The acids were dissolved in an aliquot
`amount of carbon dioxide-free distilled water, and
`then carbon dioxide-free nitrogen gas was added
`to the solution, while the temperature was main-
`tained constant during the measurements.
`The
`titration was carried out using a 0.l00N standard
`potassium hydroxide solution, and the pK‘s of the
`acids were calculated by the method described in
`the
`literature“)
`The graphical method
`using
`titration curves shown in Figs.
`1 and 2 was also
`applied to the acids for which the JpK was small
`(the difference between pK, and pK2).
`Infrared Spectrum.——The infrared spectra of the
`acids were taken in their potassium bromide disks.
`In the case of 3,4-furandicarboxylic acid, carboxylic
`hydrogen was exchanged with deuterium by repeated
`recrystallization from D20, and this deuterated
`dicarboxylic acid was examined similarly.
`
`ll
`
`c>~:o:«.o’5 N1,-sac! 123456 7
`
`3
`
`9
`
`l0
`
`0.l00N KOH, ml.
`
`1
`Fig.
`—~———~ 2,3-Furandicarboxylic acid
`————~--— 3,4-Furandicarboxylic acid
`
`J. M. Grilling and L. F. Salisburg,
`13)
`(1948).
`14) A. Albert and E. P. Serjeant, “Ionization Constants
`of Acids and Bases," John Wiley & Sons, New York
`(1962).
`
`ibid.. 70, 3416
`
`Petitioners‘ Exhibit 1006, Page 2 of 7
`
`Petitioners' Exhibit 1006, Page 2 of 7
`
`

`
`August, 1965]
`
`Furan-, Thiophenedicarboxylic Acids and Their Esters
`
`1249
`
`hydroxide and ester solutions of the same con-
`centration at
`the desired temperature, and then
`pippeting an aliquot
`into an excess of standard
`hydrochloric acid from time to time,
`it was then
`back titrated with a standard sodium hydroxide
`solution, using phenolphthalein as the indicator.
`The Calculation of Consecutive Competitive
`Rate Constants.—The calculation of the consecu-
`tive competitive rate constants for
`the saponifica-
`tion of the diesters was carried out using the
`following Frost equation”:
`k:
`k;
`A+B-—-+C+E, A+C—->D+E
`dA/dt=——k1AB——k2AC,
`dB/dt=—-k1AB,
`dC/dt=kiAB—k2AC
`
`the molar concentra-
`where A, B and C represent
`tions of the corresponding chemical species. Then
`the above equations were expressed as
`follws, by
`
`TABLE I. THE SAPONIFICATION RATE or DIMETHYL
`3,4—FURANDlCARBOXYLATE WITH SODIUM
`HYDROXIDE IN A 70% DlOXANE—WATER—0.20ON
`POTASSIUM CHLORIDE SOLUTION
`
`[OH‘l‘/[OH‘]o
`NaCt)iga1iri‘cl>nm 0”" N
`‘.l.‘Jé‘.°
`1.000
`0
`0.009738
`0
`0.905
`5.55
`0.00881
`98
`0.799
`6.06
`0.00778
`439
`0.713
`6.48
`0.00694
`797
`0.650
`6.79
`0.00633
`1079
`0.597
`7.04
`0.00581
`1458
`0.566
`7.19
`0.00551
`1833
`0.491
`7.55
`0.00478
`2411
`0.466
`7.67
`0.00454
`2762
`0.433
`7.78
`0.00432
`3194
`0.403
`7.97
`0.00393
`3789
`0.389
`8.04
`0.00379
`4139
`reactants,
`of
`Initial
`concentration
`Run 1
`0.00974 N; normality of sodium hydroxide for
`titration, 0.02016 N; normality of hydrochloric
`acid, 0.0200N; temperature at 20:1:0.01°C.
`
`TABLE II. CALCULATIONS or RATE CONSTANTS
`I-‘OR DIMETHYL 3,4—l-‘URANDICARBOXYLATE
`
`% Rx.
`20
`30
`40
`50
`60
`
`t, sec.
`436
`855
`1437
`2342
`3864
`
`Pgfrfgfrlggs
`60/20
`60/30
`60/40
`60/50
`50/20
`50/30
`
`1/It
`t, ratio
`5 .779
`8.862
`4.789
`4.519
`4.578
`2.689
`4.446
`1 .650
`7.010
`5.371
`5.101
`2.739
`Aver. 4.728
`
`20
`30
`40
`50
`60
`
`0.2684
`0.4835
`0.8014
`1.305
`2.175
`Aver.
`
`0.126
`0.116 k,=0.115 l.mol'*sec”
`0.114 k2-'~=0.115X(1/4.728)
`0.114
`=0.0243 1.mo1"sec‘1
`0.115
`0.115
`
`Petitioners‘ Exhibit 1006, Page 3 of 7
`
`11
`10
`
`9 8
`
`E 76
`
`5 4 3
`
`
`
`..-
`2
`121345678910
`
`0.l00N KOH, ml.
`
`Fig.2
`
`———— 2,4~Furandicarboxylic acid
`———— 2,5-Furandicarboxylic acid
`
`X-Ray Diffraction. --~ The X-ray diflraction of
`3,4-furandicarboxylic acid and its analysis”) were
`carried out by Williams and Rundle at Iowa State
`University.
`Kinetics.-——Di’met/zyl E5rers.—A11 the dimethyl
`esters except dimethyl terephthalate were synthesized
`in the following manner
`(dimethyl
`terephthalate
`was a commercia1ly—available product which was
`purified just before use‘). Dicarboxylic acid (0.064
`mol.) was
`refluxed with
`10ml. of
`anhydrous
`methanol in a benzene solution with one or
`two
`drops of concentrated sulfuric acid for
`several
`hours. After the removal of the excess methanol,
`the residual dimethyl ester was recrystallized from
`a suitable solvent several times to give the correct
`melting point.
`By this method the following compounds were
`obtained :
`
`D:.i.~:;:.:;.2.t.:;:W»
`D:i::;:.:;.:=.:;:W-
`
`S°::::;;:.°r 123-
`32%..
`5.222;...
`
`21.22;...
`"'..°.’;‘;i‘..’.l£.*i:‘;;““°"“°“°‘
`Monomethyl Ter'ephrhalate.—Dimethyl terephthalate
`(mg) was dissolved in 50 ml. of an alcoholic
`aqueous
`solution containing 5.6g. of potassium
`hydroxide and refluxed for
`several hours;
`then
`the unreacted dimethyl ester was filtered off. The
`aqueous alcoholic solution was acidified with con-
`centrated hydrochloric acid. The precipitated mono-
`ester was recrystallized several
`times from water.
`The yield was 5.0 g. (25%),
`(m. p. 216.5-—217°C).
`Kinetic Procedure. —-A detailed
`procedure
`for
`kinetic determination is described in the litera-
`ture.'8»‘>*‘> The solvent used was 70% aqueous
`dioxane, which was made by diluting 30ml. of
`carbon dioxide-free water with dioxane to 100ml.
`of
`the solution.
`The rate measurements were
`carried out by mixing equal volumes of sodium
`
`15) D. Williams and R. E. Rundle, J. Am. Chem. Soc..
`86, 1660 (1964).
`
`Petitioners' Exhibit 1006, Page 3 of 7
`
`

`
`1250
`
`S. OAE, N. FURUKAWA,
`
`'1‘. WATANABE, Y. OTSUJI and M. HAMADA
`
`[Vol. 38, No. 8
`
`introducing the dimensionless variables, a,
`and 1::
`
`/3, r
`
`7.'=Bok1t, K3=k2/kl
`fi==B/Bo.
`a=A/A0,
`A0, B0; initial «concentrations of A and B.
`A typical run is shown in Tables I and II.
`The rate constants of the monomethyl
`were calculated as usual.
`
`esters
`
`Results and Discussion
`
`The titration curves of the acids are shown
`in Figs.
`1 and 2. The pK’s of the acids are
`summarized in Table III. The rate constants
`of the esters are also tabulated in Table IV.
`
`The pK’s for the furan— and thiophene-dicar-
`boxylic acids change considerably with the
`change in the location of two carboxyl groups
`in the furan or thiophene ring. The acids in
`which two carboxyl groups are at adjacent
`carbon atom,
`e.g., 2, 3- and 3, 4-furan- or
`thiophene-dicarboxylic acids, have large ApK
`values, while the other acids
`(2, 4- and 2,5-
`
`acids) have relatively small ApK values. The
`relatively large z1pK values found for the for-
`mer acids are undoubtedly caused by the for-
`mation of strong intramolecular hydrogen bonds
`in the resulting acid ions, as is shown below:
`
`‘
`J
`
`~1
`ii
`
`\O
`.
`
`/
`
`\
`
`’
`
`
`0
`E:
`
`O
`
`e
`O--H-0
`/
`\
`O=C
`C=O
`\i
`l.l/
`I
`
`X; 0 or S
`
`the acids which would from a
`Therefore,
`strong intramolecular hydrogen bond increase
`the first dissociation of a dicarboxylic acid
`and decrease the second one. eventually giving
`rise to a large ApK value.
`in which the two
`In contrast, those acids
`carboxyl groups are separated by extra CH
`groups in the furan or
`thiophene ring and
`cannot form intramolecular hydrogen bonding,
`
`TABLE III.
`
`THE DISSOCIATION CONSTANTS OF ACIDS
`
`2, 3-Furan
`3,4-Furan
`2, 4-Furan
`2,5-Furan
`
`2-Furan”)
`3-Furanm
`3 , 4-Thiophenc
`2, 5-Thiophenc
`Phthalica)
`
`Isophthalic”
`Terephthalicw
`Benzoicw
`Maleic3>
`
`pK1
`2.45
`2.51
`2.63
`2.60
`(2 . 95*)
`3 . 12
`3 .95
`2 . 81
`(3.1s*)
`2 .98
`
`3 .46
`3.51
`4 .20
`1.92
`
`DK2
`7.25
`7.43
`3 .77
`3.55
`(4.13*)
`
`6 .93
`(4 . 28*)
`5 . 28
`
`4 - 46
`4.82
`
`6.23
`
`ApK
`4.30
`4.92
`1.14
`0.95
`
`4.02
`1.10
`2.30
`1.00
`1.31
`
`4.31
`
`pK.
`3.09
`3.75
`
`3.57*
`
`3.32
`
`ApK,
`0.64
`1.24
`
`(0.76)
`T‘
`0.34
`
`1.03
`
`30 Wt.% of EtOH—HzO
`*
`a) The pK’s of these compounds are taken from H. C. Brown, D. H. McDaniel and O. l-lafligen,
`“Dissociation Constants,” Chapter 14, “Determination of Organic Structure by Physical
`Method,"fAcademic7Press, New York (1955).
`first and second dissociation constants respectively.
`DK1. PK21
`ApK:
`thefdifference between pK; and pK2.
`the dissociation constants of monoesters.
`pK,,.:
`the difference between pK1 and pK,3.
`ApKe:
`
`TABLE IV. THE RATE CONSTANTS or THE ESTERS AT 20i0.01°C IN 70% DIOXANE SOLUTIONS
`
`Ester
`
`Dimethyl 2, 5-furandicarboxylate
`Dimethyl 3, 4-furandicarboxylate
`Dimethyl 2,5-thiophenedicarboxylate
`Dirnethyl 3,4-thiophenedicarboxylate
`Dimethyl terephthalate
`Monomethyl 3,4-furandicarboxylate
`Monomethyl 3,4-thiophenedicarboxylate
`Monomethyl terephthalate
`
`K1
`1. mo1"sec'1
`1.48
`0.115
`0.228
`0.0260
`0.0886
`0.0469
`0.0134
`0.0208
`
`K2
`l. mol“sec“
`0.553
`0.0243
`0.03
`0.005
`0.0113
`
`1/5
`=K,/K2
`2.67
`4.73
`7.36
`5.17
`7.84
`
`Petitioners‘ Exhibit 1006, Page 4 of 7
`
`Petitioners' Exhibit 1006, Page 4 of 7
`
`

`
`August, 1965]
`
`Furan~, Thiophenedicarboxylic Acids and Their Esters
`
`1251
`
`dicar—
`Symmetrical
`have small ApK values.
`boxylic acids usually have a small statistical
`ApK value (ca.. 0.1).
`A substantially larger value of ApK than
`the statistical value must result from a specific
`interaction between the functional groups in
`a dicarboxylic acid.
`In the case of furan and
`thiophene dicarboxylic acids, small deviations
`from the statistical ApK value are considered
`to be due to the polar
`interaction between
`the two carboxyl groups.
`2, 3- and 3, 4‘-Furan— or thiophenedicarboxylic
`acids were found to give large ApK values.
`A similar
`large ApK value has also been
`observed for maleic acid (Table III), where
`the difference has been explained in terms of
`the formation of an intramolecular hydrogen
`bond of the resulted acid anion. Recently
`evidence for the existence of hydrogen bonding
`
`in maleic acid in the crystalline state has been
`given by Schahat and by others from their
`investigations of the acid by X-ray and infrarred
`ana1yses.““3 Phthalic acid is also considered
`to form a fairly strong intramolecular hydrogen
`bond, but the zlpK value is found to be much
`smaller than those of 2, 3- and 3, 4~furan or
`thiophene—dicarboxylie acids. Hydrogen bonding
`is obviously involved as one of the important
`factors in determining these ApK values, and
`a heterocyclic aromatic ring such as furan or
`thiophene must also play a significant role in
`favoring the formation of a relatively stable
`acid ion from the furan- or thiophene-dicarbo-
`xylic acids than that from phthalic acid. One
`conceivable reason for this differences is the
`difference in geometry between the mono-
`hydrogen phthalate ion and the monohydrogen
`furan or
`thiophene dicarboxylate ion. The
`
`
`
`4000
`
`3000
`
`2000
`
`1800
`
`1600
`
`1400
`
`1200
`
`1000
`
`800
`
`Fig. 3
`—-— 3,4~Furandicarboxylic acid
`——-— 3,4-Thiophenedicarboxylic acid
`
`
`
`1600
`Fig. 4
`——-— 2,5—Furandicarboxylic acid
`~——— 2,5—Thiophenedicarboxylic acid
`
`1400
`
`1200
`
`1000
`
`800
`
`4000
`
`3000
`
`2000
`
`1800
`
`I600
`
`1400
`
`1200
`
`1()00
`
`8C0
`
`Fig. 5
`
`Monomethyl ester of 3,4-furandicarboxylic acid
`
`Petitioners‘ Exhibit 1006, Page 5 of 7
`
`Petitioners' Exhibit 1006, Page 5 of 7
`
`

`
`1252
`
`S. OAE, N. FURUKAWA, T. WATANABE, Y. Orsun and M. HAMADA
`
`[Vol. 38, No. 8
`
`latter hydrogen-bonded ions are of 5- and 7-
`membered binuclear condensed rings,
`like an
`azulene ring, which are known to be quite
`stable.
`In the case of
`the monohydrogen
`phthalate ion. the structure is composed of 6-
`and 7-membered rings, which may not provide
`a very stable arrangement for an intramolecu-
`lar hydrogen bond formation.
`It
`is
`also
`interesting to note that
`the Aplfa value for
`3, 4-furandicarboxylic acid is larger than that
`for the corresponding thiophene counterpart.
`It may be that the furan ring is geometrically
`more favored for the hydrogen bond formation
`because of
`the smaller
`size of
`the oxygen
`atom than that of the sulfur atom of
`the
`
`thiophene ring.
`the half
`A comparison of the strengths of
`esters of
`the dicarboxylic acids with these
`of the corresponding free acids, gives
`further
`support
`to the postulate that
`the internal
`hydrogen bonding in the carboxylate acid ions
`is an important
`factor.
`There is consider-
`able evidence that the polar effect of carboalk-
`oxyl group is similar
`to that ofa carboxyl
`group. Consequently, in the absence of specific
`interactions, such as hydrogen bonding between
`the two functional groups, it may be expected
`that zIpKe (the difference between pKt and PK42
`for the monoester of
`the dicarboxylic acid)
`would have the value of 0.3, corresponding
`to the statistical value for
`the dicarboxylic
`acids.
`Phthalic acid has a value close to 0.3.
`
`Other acids for which a strong intramolecular
`hydrogen bonding is proposed exhibit con-
`siderably larger values: 2,3-furandicarboxylic
`acid, 0.64;
`3, 4-furandicarboxylic acid, 1.24;
`3, 4—thiophened.icarboxylic acid, 0.76; maleic
`acid, 1.03. These values are consistent with
`the discussion above.
`the existence of an in-
`Other support for
`tramolecular hydrogen bonding in 2, 3- and
`3, 4-furan— or
`thiophene-dicarboxylic acids is
`given by the infrared data for the acids (Figs.
`3, 4, and 5) and by the X—ray analysis for
`3,4-furandicarboxylic acid (Figs. 6 and 7).
`
`o
`
`'\
`
`'
`
`
`
`Fig. 7.
`The structure projected onto the ring
`square plane.
`
`From the infrared spectra taken as KBr disks,
`the hydroxyl bands for all the acids investigated
`appear as broad absorption bands with many
`submaxima between 3000 cm" and 2000 cm“
`instead of
`the normal hydroxyl band near
`3500cm“. This fact
`is consistent with the
`existence
`of
`the
`intramolecular hydrogen
`bonding. Also,
`it has been proposed that
`the
`acids which are capable of forming an intra-
`molecular hydrogen bonding give the carbonyl
`absorption between 1670 cm“ and 1650 cm“ W)
`(the normal carboxylic acid C=O band ap-
`pears near
`1700 cm”) when examined in
`the solid or
`liquid state, while the normal
`aromatic acids absorb at 1700 cm“. Phthalic
`
`acid is normal in this regard, showing a simple
`C=O band at 1690 cm", 2, 4- and 2, 5-furan- or
`thiophenedicarboxylic acids were also found
`to give a single intense carbonyl band between
`1680 cm“ and 1700 cm“, indicating that these
`acids are normal. On the other hand, 2,3-
`and 3, 4-furan- or thiophenedicarboxylie acids
`have double carbonyl bands (Fig. 3), one of
`which is near 1700 cm“ and the other between
`l650cm“ and l620cm“‘. The latter bands
`are fairly intense as compared to the normal
`carbonyl absorption band. All
`these observa-
`tion are consistent with the assumption that
`these acids
`are
`intramolecularly hydrogen-
`bonded, even in undissociated forms. When
`hydroxyl hydrogen was replaced by deuterium,
`the absorption bands due to the —0H stretching
`shifted towards longer wavelengths. However,
`no remarkable effect appeared in the C=O
`stretching region.
`For example, acetic acid,
`which generally forms a dimer which absorbs
`at 3125 cm“ due to OH stretching, changes
`its band to 2299cm“‘ upon deuterium sub-
`stitution.”‘3
`A better
`example would be
`tropolone, which forms a strong intramolecular
`
`for example, L. J. Bellamy, “ The Infra-red
`16) See,
`Spectra of Complex Molecules,” John Wiley & Sons, New
`York (I958). Pp. 161-476.
`
`Petitioners‘ Exhibit 1006, Page 6 of 7
`
`<5
`s?»
`3] Eysoy
`7 Cl
`xii-7
`$592’
`(Y)
`<5’ Ca——-[Cat 124.0
`v“?
`Q-
`\0‘°'E’
`C’
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`1072
`_
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`81
`
`H1
`
`I
`
`1
`
`133.5
`
`H7’
`
`Fig. 6.
`
`Intra.molecular distances and angles.
`
`Petitioners' Exhibit 1006, Page 6 of 7
`
`

`
`August, 1965]
`
`Furan-, Thiophenedicarboxylic Acids and Their Esters
`
`1253
`
`hydrogen bond”) and the hydrogen—bonding
`structure of which is somewhat similar to that
`of 3, 4-furan- or thiophenedicarboxylic acid.
`The —OH band is also shifted to a longer wave-
`length when -—OH is changed to —OD, but no
`effect
`is observed in C=O stretching. Hadzi
`and Sheppard?” have reported that
`the sub-
`stituted anthraquinones
`show a
`remarkable
`shift of
`-01-] upon deuterium substitution,
`as is shown in Table V.
`
`0-~H\
`
`U0
`
`Tropolone
`
`TABLE V
`
`(on) or (on)
`cm‘1
`
`(c=o)
`cm"
`
`I
`1,4—diOl-I
`8 o I
`7I/\”/\“/\2 1,4-diOD
`°\/\,,/\/3 1,5-diOH
`Anthraquinone 1,5-diOD
`
`2860
`2260
`2950
`2280
`
`1626
`1626
`1637
`1637
`
`In the case of 3, 4-furandicarboxylic acid,
`in which carboxyl ~01-I was exchanged with
`—OD, a similar effect was observed; the band
`due to the -0----H stretching at 2500-2800 cm"
`disappeared and a new broad band was observed
`near 1980 cm", a band which is assumed to
`be that of the intramolecular hydrogen-bonded
`—OD.
`
`The X-ray analysis of 3, 4—furandicarboxylic
`acid in Figs. 6 and 7 gives fairly good proof
`for our suggestion of the existence ofa strong
`intramolecular hydrogen bonding in 2, 3- and
`3, 4-furan
`or
`thiophenedicarboxylic
`acids.
`The
`analysis of
`3, 4-furandicarboxylic
`acid
`shows
`that
`because of
`the
`intramolecular
`hydrogen bonding hydrogen atom lies just in
`the middle of the two adjacent carboxyl oxy-
`gens. The distance of the O-I-I—O hydrogen
`bond reveals a marked shortening of O—H—O
`linkage as compared to the acetic acid dimer
`or other hydrogen-bonded acids”)
`
`17) V. von Keussler and G. Rosomy, Z. Electrochem.,60,
`136 (1956).
`18) D. Hadzi and N. Sheppard, Trans. Faraday Soc., 50,
`911 (1956).
`19) R. Hofstadter. J. Chem. Phyr., 6, S40 (1938).
`
`In Table II one can see substantial fluctua-
`tions in the rate constants obtained.
`The
`main reason for
`the deviations is
`that
`the
`determination of the end point with phenol-
`phthalein is not sharp because of the facile
`hydrolysis of the second ester groups in the
`diesters during the
`hydrolysis.
`Therefore,
`each of
`the
`rates,
`actually observed
`and
`summarized
`in Table
`III, may contain a
`substantial margin of inherent error. How-
`ever, even at
`its greatest the error is not so
`large as to lead to a wrong conclusion.
`Despite the inherent errors, one can draw
`a few interesting conclusions from the data.
`First, the order of reactivity in the hydrolysis
`of the diesters is furan>thiophene>benzene.
`This is in accord with that of the alkaline
`hydrolysis of the ethyl esters of monocarboxylic
`acids in the same solvent” and also is
`to be
`expected from the magnitudes of the acidity
`constants of these mono or dicarboxylic acids.
`Here again, it was confirmed that the thiophene
`ring is more e1ectron—attracting than the ben-
`zene ring, but
`less so than the furan ring.
`The fact that the first hydrolysis rate constant,
`kl, for dimethyl 2,5-furandicarboxylate is of
`an especially high value,
`is
`to be expected
`from the calculation by the Hammett equation
`using the data for the hydrolysis rate constants
`of furoic acid.”
`is that the rates of
`Another interesting fact
`the hydrolyses of the diesters in which the
`two ester groups are attached to adjacent car-
`bon atoms are substantially lower
`than those
`of the esters in which the carboxyl groups are
`separated by CH groups. One reason for this
`may be that the nucleophilic attack with the
`hydroxyl ion on the first carbonyl carbon is
`retarded by the charge repulsion with the
`adjacent carboxyl oxygen.
`
`Department of Applied Chemistry
`Faculty of Engineering
`Osaka City University
`(S. 0., N. F. & T. W.)
`
`Department of Applied Chemistry
`College of Engineering
`The University of Osaka Prefecture
`Sakai, Osaka (Y. 0.)
`
`Department of Chemistry
`Radiation Center of Osaka Prefecture
`Sakai, Osaka (M. H.)
`
`Petitioners‘ Exhibit 1006, Page 7 of 7
`
`Petitioners' Exhibit 1006, Page 7 of 7