Anthranilic acid

Anthranilic acid
Skeletal formula of anthranilic acid	C=black, H=white, O=red, N=blue
Names
	Preferred IUPAC name 2-Aminobenzoic acid[1]
	Systematic IUPAC name 2-Aminobenzenecarboxylic acid
	Other names Anthranilic acid; o-Aminobenzoic acid; 2-Aminobenzoic acid; Vitamin L1; Anthranilate (conjugate base); 2-AA, 2AA, AA;
Identifiers
CAS Number	118-92-3 ;
3D model (JSmol)	Interactive image;
3DMet	B00027;
Beilstein Reference	471803
ChEBI	CHEBI:30754 ;
ChEMBL	ChEMBL14173 ;
ChemSpider	222 ;
DrugBank	DB04166 ;
ECHA InfoCard	100.003.898
EC Number	204-287-5;
Gmelin Reference	3397
KEGG	C00108 ;
PubChem CID	227;
RTECS number	CB2450000;
UNII	0YS975XI6W;
CompTox Dashboard (EPA)	DTXSID8020094 ;
	InChI InChI=1S/C7H7NO2/c8-6-4-2-1-3-5(6)7(9)10/h1-4H,8H2,(H,9,10) Key: RWZYAGGXGHYGMB-UHFFFAOYSA-N ; InChI=1/C7H7NO2/c8-6-4-2-1-3-5(6)7(9)10/h1-4H,8H2,(H,9,10) Key: RWZYAGGXGHYGMB-UHFFFAOYAS;
	SMILES O=C(O)c1ccccc1N;
Properties
Chemical formula	C7H7NO2
Molar mass	137.138 g·mol−1
Appearance	white or yellow solid
Odor	odorless
Density	1.412 g/cm3
Melting point	146 to 148 °C (295 to 298 °F; 419 to 421 K)[2]
Boiling point	200 °C (392 °F; 473 K) (sublimes)
Solubility in water	0.572 g/100 mL (25 °C)
Solubility	very soluble in chloroform, pyridine ; soluble in ethanol, ether, ethyl ether ; slightly soluble in trifluoroacetic acid, benzene
log P	1.21
Vapor pressure	0.1 Pa (52.6 °C)
Acidity (pKa)	2.17 (carboxyl; H2O); 4.85 (amino; H2O)[3];
Magnetic susceptibility (χ)	-77.18·10−6 cm3/mol
Refractive index (nD)	1.578 (144 °C)
Thermochemistry
Std enthalpy of; formation (ΔfH⦵298)	-380.4 KJ/mol
Hazards
Safety data sheet	External MSDS
GHS pictograms
GHS Signal word	Danger
GHS hazard statements	H318, H319
GHS precautionary statements	P264, P280, P305+351+338, P310, P337+313
NFPA 704 (fire diamond)	1 2 0
Flash point	> 150 °C (302 °F; 423 K)
Autoignition; temperature	> 530 °C (986 °F; 803 K)
	Lethal dose or concentration (LD, LC):
LD50 (median dose)	1400 mg/kg (oral, rat)
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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	Infobox references

Anthranilic acid is an aromatic acid with the formula C₆H₄(NH₂)(CO₂H) and has a sweetish taste.[4][5][6] The molecule consists of a benzene ring, ortho-substituted with a carboxylic acid and an amine. As a result of containing both acidic and basic functional groups, the compound is amphoteric. Anthranilic acid is a white solid when pure, although commercial samples may appear yellow. The anion [C₆H₄(NH₂)(CO₂)]⁻, obtained by the deprotonation of anthranilic acid, is called anthranilate. Anthranilic acid was once thought to be a vitamin and was referred to as vitamin L₁ in that context, but it is now known to be non-essential in human nutrition.[7]

Structure

Although not usually referred to as such, it is an amino acid. Solid anthranilic acid consists of both the amino-carboxylic acid and the zwitterionic ammonium carboxylate forms.[8]

Production

Many routes to anthranilic acid have been described. Industrially it is produced from phthalic anhydride, beginning with amination:

C₆H₄(CO)₂O + NH₃ + NaOH → C₆H₄(C(O)NH₂)CO₂Na + H₂O

The resulting sodium salt of phthalamic acid is decarbonylated via a Hofmann rearrangement of the amide group, induced by hypochlorite:[9]

C₆H₄(C(O)NH₂)CO₂Na + HOCl → C₆H₄NH₂CO₂H + NaCl + CO₂

A related method involves treating phthalimide with sodium hypobromite in aqueous sodium hydroxide, followed by neutralization.[10] In the era when indigo dye was obtained from plants, it was degraded to give anthranilic acid.

Anthranilic acid was first obtained by base-induced degradation of indigo.[11]

Biosynthesis

Anthranilic acid is biosynthesized from chorismic acid. In organisms capable of tryptophan synthesis, anthranilate is a precursor to the amino acid tryptophan via the attachment of phosphoribosyl pyrophosphate to the amine group.

Anthranilate is the biosynthetic precursor to the amino acid tryptophan.

Uses

Industrially, anthranilic acid is an intermediate in the production of azo dyes and saccharin. It and its esters are used in preparing perfumes to mimic jasmine and orange, pharmaceuticals (loop diuretics, such as furosemide) and UV-absorber as well as corrosion inhibitors for metals and mold inhibitors in soy sauce.

Anthranilate-based insect repellents have been proposed as replacements for DEET.

Fenamic acid is a derivative of anthranilic acid,[12]^:235 which in turn is a nitrogen isostere of salicylic acid, which is the active metabolite of aspirin.[12]^:235 Several non-steroidal anti-inflammatory drugs, including mefenamic acid, tolfenamic acid, flufenamic acid, and meclofenamic acid are derived from fenamic acid or anthranilic acid and are called "anthranilic acid derivatives" or "fenamates".[13]^:17

Reactions

Anthranilic acid can be diazotized to give the diazonium cation [C₆H₄(CO₂H)(N₂)]⁺. This cation can be used to generate benzyne,[14] dimerized to give diphenic acid,[15] or undergo diazonium coupling reactions such as in the synthesis of methyl red.[16]

It reacts with phosgene to give isatoic anhydride, a versatile reagent.[17]

Chlorination of anthranilic acid gives the 2,4-dichloro derivative, which can undergo reductive coupling to form a biaryl compound.[18]

Safety and regulation

It is also a DEA List I Chemical because of its use in making the now-widely outlawed euphoric sedative drug methaqualone (Quaalude, Mandrax).[19]

References

"Front Matter". Nomenclature of Organic Chemistry : IUPAC Recommendations and Preferred Names 2013 (Blue Book). Cambridge: The Royal Society of Chemistry. 2014. p. 748. doi:10.1039/9781849733069-FP001. ISBN 978-0-85404-182-4.
IPCS
Haynes, William M., ed. (2016). CRC Handbook of Chemistry and Physics (97th ed.). CRC Press. pp. 5–89. ISBN 978-1498754286.
Acton, Q. Ashton (2013). Aminobenzoic Acids—Advances in Research and Application (2013 ed.). Atlanta: ScholarlyEditions. p. 23. ISBN 9781481684842 – via Google Books.
Hardy, Mark R. (1997). "Glycan Labeling with the Flurophores 2-Aminobenzamide and Antranilic Acid". In Townsend, R. Reid; Hotchkiss, Jr., Arland T. (eds.). Techniques in Glycobiology. Marcel Dekker, Inc. p. 360. ISBN 9780824798222 – via Google Books.
The Merck Index, 10th Ed. (1983), p.62., Rahway: Merck & Co.
Davidson, Michael W. (2004). "Anthranilic Acid (Vitamin L)]". Florida State University. Retrieved November 20, 2019.
Brown, C. J. (1968). "The crystal structure of anthranilic acid". Proceedings of the Royal Society of London. Series A. Mathematical and Physical Sciences. 302 (1469): 185–199. Bibcode:1968RSPSA.302..185B. doi:10.1098/rspa.1968.0003.
Maki, Takao; Takeda, Kazuo (2000). "Benzoic Acid and Derivatives". Ullmann's Encyclopedia of Industrial Chemistry. doi:10.1002/14356007.a03_555. ISBN 3527306730..
Vogel's Textbook of Practical Organic Chemistry, 4th Ed., (B. S. Furniss et al., Eds.) (1978), p.666, London: Longman.
Sheibley, Fred E. (1943). "Carl Julius Fritzsche and the discovery of anthranilic acid, 1841". Journal of Chemical Education. 20 (3): 115. Bibcode:1943JChEd..20..115S. doi:10.1021/ed020p115.
Sriram D, Yogeeswari P. Medicinal Chemistry, 2nd Edition. Pearson Education India, 2010. ISBN 9788131731444
Auburn University course material. Jack DeRuiter, Principles of Drug Action 2, Fall 2002 1: Non-Steroidal Antiinflammatory Drugs (NSAIDS)
Logullo, F. M.; Seitz, A. H.; Friedman, L. (1968). "Benzenediazonium-2-carboxy- and Biphenylene". Organic Syntheses. 48: 12.
Atkinson, E. R.; Lawler, H. J. (1927). "Diphenic Acid". Organic Syntheses. 7: 30. doi:10.15227/orgsyn.007.0030.
Clarke, H. T.; Kirner, W. R. (1922). "Methyl Red". Organic Syntheses. 2: 47.
Wagner, E. C.; Fegley, Marion F. (1947). "Isatoic anhydride". Org. Synth. 27: 45. doi:10.15227/orgsyn.027.0045.
Atkinson, Edward R.; Murphy, Donald M.; Lufkin, James E. (1951). "dl-4,4',6,6'-Tetrachlorodiphenic Acid". Organic Syntheses. 31: 96.
Angelos SA, Meyers JA (1985). "The isolation and identification of precursors and reaction products in the clandestine manufacture of methaqualone and mecloqualone". Journal of Forensic Sciences. 30 (4): 1022–1047. PMID 3840834.

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[iupac2013-1] "Front Matter". Nomenclature of Organic Chemistry : IUPAC Recommendations and Preferred Names 2013 (Blue Book). Cambridge: The Royal Society of Chemistry. 2014. p. 748. doi:10.1039/9781849733069-FP001. ISBN 978-0-85404-182-4.

[2] IPCS

[CRC97-3] Haynes, William M., ed. (2016). CRC Handbook of Chemistry and Physics (97th ed.). CRC Press. pp. 5–89. ISBN 978-1498754286.

[4] Acton, Q. Ashton (2013). Aminobenzoic Acids—Advances in Research and Application (2013 ed.). Atlanta: ScholarlyEditions. p. 23. ISBN 9781481684842 – via Google Books.

[5] Hardy, Mark R. (1997). "Glycan Labeling with the Flurophores 2-Aminobenzamide and Antranilic Acid". In Townsend, R. Reid; Hotchkiss, Jr., Arland T. (eds.). Techniques in Glycobiology. Marcel Dekker, Inc. p. 360. ISBN 9780824798222 – via Google Books.

[6] The Merck Index, 10th Ed. (1983), p.62., Rahway: Merck & Co.

[7] Davidson, Michael W. (2004). "Anthranilic Acid (Vitamin L)]". Florida State University. Retrieved November 20, 2019.

[8] Brown, C. J. (1968). "The crystal structure of anthranilic acid". Proceedings of the Royal Society of London. Series A. Mathematical and Physical Sciences. 302 (1469): 185–199. Bibcode:1968RSPSA.302..185B. doi:10.1098/rspa.1968.0003.

[9] Maki, Takao; Takeda, Kazuo (2000). "Benzoic Acid and Derivatives". Ullmann's Encyclopedia of Industrial Chemistry. doi:10.1002/14356007.a03_555. ISBN 3527306730..

[10] Vogel's Textbook of Practical Organic Chemistry, 4th Ed., (B. S. Furniss et al., Eds.) (1978), p.666, London: Longman.

[11] Sheibley, Fred E. (1943). "Carl Julius Fritzsche and the discovery of anthranilic acid, 1841". Journal of Chemical Education. 20 (3): 115. Bibcode:1943JChEd..20..115S. doi:10.1021/ed020p115.

[Sriram-12] Sriram D, Yogeeswari P. Medicinal Chemistry, 2nd Edition. Pearson Education India, 2010. ISBN 9788131731444

[13] Auburn University course material. Jack DeRuiter, Principles of Drug Action 2, Fall 2002 1: Non-Steroidal Antiinflammatory Drugs (NSAIDS)

[14] Logullo, F. M.; Seitz, A. H.; Friedman, L. (1968). "Benzenediazonium-2-carboxy- and Biphenylene". Organic Syntheses. 48: 12.

[15] Atkinson, E. R.; Lawler, H. J. (1927). "Diphenic Acid". Organic Syntheses. 7: 30. doi:10.15227/orgsyn.007.0030.

[16] Clarke, H. T.; Kirner, W. R. (1922). "Methyl Red". Organic Syntheses. 2: 47.

[17] Wagner, E. C.; Fegley, Marion F. (1947). "Isatoic anhydride". Org. Synth. 27: 45. doi:10.15227/orgsyn.027.0045.

[18] Atkinson, Edward R.; Murphy, Donald M.; Lufkin, James E. (1951). "dl-4,4',6,6'-Tetrachlorodiphenic Acid". Organic Syntheses. 31: 96.

[19] Angelos SA, Meyers JA (1985). "The isolation and identification of precursors and reaction products in the clandestine manufacture of methaqualone and mecloqualone". Journal of Forensic Sciences. 30 (4): 1022–1047. PMID 3840834.