Patai S., Rappoport Z. 1997 The chemistry of functional groups. The chemistry of double-bonded functional groups / 1617 162

Supplement A3: The Chemistry of Double-Bonded Functional Groups. Edited by Saul Patai Copyright 1997 John Wiley & Sons, Ltd.

ISBN: 0-471-95956-1

CHAPTER 25

Biological activity of organic compounds elicited by the introduction of double bonds

ASHER KALIR

Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel

Fax: [phone]

and

HENRY H. KALIR

Department of Histology and Cell Biology, Sackler Faculty of Medicine,

Tel Aviv University, Tel Aviv 69978, Israel and Department of Psychiatry, Ichilov Hospital, Tel Aviv, Israel

e-mail: [e-mail]

I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	1617
II. COMPARISON OF TOXICITY OF SATURATED AND
UNSATURATED COMPOUNDS . . . . . . . . . . . . . . . . . . . . . . . . . .	1618
III. UNSATURATED COMPOUNDS OF PHARMACOLOGICAL
INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	1621
IV. DETECTION AND LOCALIZATION OF DOUBLE BONDS . . . . . . .	1622
V. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .	1623

I. INTRODUCTION

Many aspects of the characteristics of the double-bonded functional groups have been reviewed in an impressive series of treatises, published over a period of more than 30 years. These reviews cover mostly the physicochemical aspects of double bonds: electrophilic additions to carbon carbon double bonds1, directing and activating effects of doubly bonded groups2 etc.

1617

1618	Asher Kalir and Henry H. Kalir

The review ‘Double bonds from a biochemical perspective’3 summarizes the importance of the biochemical reactions of selected groups of physiologically active unsaturated compounds, e.g. those that react with the amino groups of amino acids, polyunsaturated fatty acids and vitamin A.

II. COMPARISON OF TOXICITY OF SATURATED AND

UNSATURATED COMPOUNDS

The purpose of the present paper is to compare the toxicity and pharmacology of saturated compounds with their unsaturated analogs (wherever possible) and to list some important, physiologically active substances, bearing one or more double bonds.

TABLE 1. Hydrocarbons

Saturated			Toxicity	Unsaturated	Toxicity
Ethane5	narcotic in high concn.			Ethylene6	950,000 ppma
Propane7	narcotic in high concn.			Propylene4	asphyxiant
Butane8	narcotic in high concn.			1-Butene9	asphyxiant
				1,3-Butadiene10	250,000 ppmb
				Isoprene11	0.144 mg/lc
Cyclopentane12	38,000 ppma			Cyclopentene13	2.14 g/kgd
Cyclohexane14	0.06		0.07 mg/la	Cyclohexene15	300 ppme
Ethylbenzene16	5.46	g/kgd		Styrene17	0.09 g/kgf
Propylbenzene18	6.04	g/kgd		Allylbenzene19	3.6 g/kgd
Diethylbenzene20	1.2 g/kgd			Divinylbenzene19	4.04 g/kgd

a LC (lethal concentration) for mice in air.

b LC for rabbits in air. c LD50 for mice in air. d LD50 for rats (oral).

e Permissible exposure limit. f LD50 for mice (iv).

TABLE 2. Halides

Saturated		Toxicity	Unsaturated	Toxicity
Ethyl chloride21	0.18	g/la	Vinyl chloride22	47,660 ppma
(irritating, topical anaesthetic)
1,2-Dichloroethane13	0.97	g/kgb	1,2-Dichloroethene(trans)23	1.28	g/kgb
1,1,2-Trichloroethane13	0.84	g/kgb	1,1,2-Trichloroethane13	7.33	g/kgb
1-Propyl chloride24	LD100 > 3 g/kgc		Allyl chloride25	0.7 g/kgb
Isopropyl chloride24	potent anaesthetic
1,2-Dichloropropane13	2.2 g/kgb		2,3-Dichloro-1-propene16	0.39	g/kgb
1-Butyl chloride26	2.67	g/kgb	1-Chloro-2-butene27	irritating
Ethyl bromide28	16,200 ppm (1 h)a		Vinyl bromide24	0.5 g/kgb
1,2-Dibromoethane29	0.22	g/kgc	1,2-Dibromoethene30	0.117 g/kgb

a LC (lethal concentration) for mice in air. b LD50 for rats (oral).

c LD50 for mice (ip).

25. Biological activity of organic compounds elicited by double bonds

1619

As E. E. Sandmeyer stated, ‘in general, diunsaturation increases the toxicity’4. This is also true, although with some exceptions, for mono-unsaturation.

The toxicity evaluations of the various compounds were carried out on various animals. The most common test was the LD50 (the dose needed to produce the death of 50% of all tested animals) orally in rats. Cases where other animals or other conditions were applied, will be so noted.

Tables 1 9 present a listing of various groups of saturated compounds and of their analogs, bearing a double bond. Table 9 includes several hydroxy and keto derivatives (RCHOH vs RCDO).

As a rule the unsaturated analogs are more toxic. There are some exceptions: diethylbenzene20 and divinylbenzene19 (Table 1), 1,1,2-trichloroethane13 and 1,1,2-trichloroethy- lene13 (Table 2), 2-propanol25 and acetone16 (Table 9) etc.

TABLE 3. Alcohols

	Saturated	Toxicity	Unsaturated		Toxicity
	Ethanol31	10.6 g/kga
	1-Propanol26	1.87 g/kga	Allyl alcohol25		0.064 g/kga
	2-Propanol25	5.8 g/kga
	1-Butanol32	4.36 g/kga
	2-Butanol26	6.48 g/kga	Crotyl alcohol16		0.79 g/kga
	a LD50 for rats (oral).
TABLE 4. Aldehydes and ketones
Saturated		Toxicitya		Unsaturated	Toxicitya
Propionaldehyde32		1.4 g/kg	Acrolein32		0.046 g/kg
Butyraldehyde32		5.89 g/kg	Crotonaldehyde33		0.3 g/kg
Methyl ethyl ketone16		5.52 g/kg	Methyl vinyl ketone34		0.035 g/kg
a LD50 for rats (oral).
TABLE 5. Acids
Saturated		Toxicity		Unsaturated	Toxicity
Propionic acid16		4.29 g/kga	Acrylic acid16		2.59 g/kga
Butyric acid26		8.79 g/kga	Crotonic acid33		1.0 g/kga
Valeric acid35		1.29 g/kgb	2-Methyl-2-butenoic acid
Isovaleric acid35		1.12 g/kgb	cis36,	trans37
			(found in plants)
Stearic acid35		0.022 g/kgb	Oleic acid35		0.23 g/kgb

a LD50 for rats (oral). b LD50 for mice (iv).

1620				Asher Kalir and Henry H. Kalir
	TABLE 6.		Esters
	Saturated			Toxicitya		Unsaturated	Toxicitya
	Ethyl formate38			4.3	g/kg	Vinyl formate38	2.82 g/kg
	Propyl formate38			3.98	g/kg	Allyl formate38	0.124 g/kg
	Ethyl acetate38			5.6	g/kg	Vinyl acetate38	2.92 g/kg
	n-Propyl acetate38			9.37	g/kg	Allyl acetate38	0.142 g/kg
	Isopropyl acetate38			3.0	g/kg	Isopropenyl acetate38	3.0 g/kg
	n-Propyl butyrate38			15.0	g/kg	Allyl butyrate38	0.25 g/kg
	Ethyl benzoate26			6.48	g/kg	Vinyl benzoate38	3.25 g/kg
	Diethyl succinate32			8.53	g/kg	Diethyl fumarate16	1.78 g/kg
	a LD50 for rats (oral).
		TABLE 7. Amines
		Saturated		Toxicitya		Unsaturated	Toxicitya
		1-Propylamine16		0.57 g/kg		1-Allylamine39	0.106 g/kg
		Isopropylamine32		0.52 g/kg
		Dipropylamine16		0.93 g/kg		Diallylamine16	0.65 g/kg
		Diisopropylamine26		0.77 g/kg
		Tripropylamine39		0.096 g/kg		Triallylamine39	1.31 g/kg
		a LD50 for rats (oral).
	TABLE 8.		Ethers
	Saturated			Toxicity		Unsaturated	Toxicity
	Diethyl ether40			2.53 g/kgb		Ethyl vinyl ether13	6.22 g/kgb
						Divinyl ether41	51,233 ppma
	Allyl ethyl ether26			14.53 g/kgb		Allyl vinyl ether40	0.55 g/kgb
	Di-n-propyl ether42					Diallyl ether40	0.26 g/kgb

a LC (lethal concentration) for mice in air. b LD50 for rats (oral).

TABLE 9. Alcohols vs keto compounds

Saturated	Toxicitya		Unsaturated	Toxicitya
Ethanol31	10.6 g/kg		Acetaldehyde32	1.93		g/kg
1-Propanol26	1.87	g/kg	Propionaldehyde32	1.4	g/kg
2-Propanol25	5.8 g/kg		Acetone16	8.43		g/kg
1-Butanol32	4.36	g/kg	Butyraldehyde32	5.89		g/kg
2-Butanol26	6.48	g/kg	2-Butanone16	5.52		g/kg
Cyclohexanol16	1.98 g/kg		Cyclohexanone13	1.53 g/kg
Benzyl alcohol32	3.1 g/kg		Benzaldehyde18	1.3	g/kg
Phenethyl alcohol18	1.79	g/kg	Acetophenone25	0.9	g/kg

a LD50 for rats (oral).

25. Biological activity of organic compounds elicited by double bonds

1621

III. UNSATURATED COMPOUNDS OF PHARMACOLOGICAL INTEREST

A significant number of unsaturated compounds are biologically active and known as drugs, agricultural materials etc.

Ethylene6 (CH2DCH2, Table 1) has been found to exert major effects on plant growth and development43. The ethylene precursor in plants is 1-aminocyclopropane- 1-carboxylic acid44 (1). Much attention is given to the carcinogenic45,46 1,3-butadiene10 (CH2DCH CHDCH2, Table 1), an important starting material for synthetic rubbers. Its carcinogenicity is due to the action of its metabolites, the butadiene oxides46 48. Its 2-methyl analog, isoprene10 (CH2DCMe CHDCH2, Table 1), is also carcinogenic49. Interestingly, isoprene is produced in nature by Gram-negative and Gram-positive bacteria50.

	H		Me
		O
O	N		N
HOOC NH2
	HN	CH2 CH CH2
		CH2 CH CH2
			CH2 CH CH2
	O	Ph	OCCH2 CH3
			O
(1)		(2)	(3)

Other examples include allicin51, CH2DCHCH2S(O)CH2CHDCH2, which is an antibacterial; allyl substituted substances like allobarbital (2)52 are sedatives; allylprodine

(3)53 is a narcotic analgesic; ergosterol (4)54 is an antirachitic vitamin; toremiphene (5)55 is an antineoplastic; undecylenic acid (CH2DCH(CH2)8COOH)56 is an antifungal; hexalure

(6)57 and muscalure (7)58 are insect attractants.

CH3

CH3

CH3

CH3

CH3

CH3

HO

(4)

Prostaglandins59, like prostaglandin E2 (8), are implicated in many physiological and pharmacological functions of living organisms. Another very interesting group of naturally occurring polyunsaturated compounds are retinoids (9) that include vitamin A (9, XDCH2OH, YDH). All these are involved in many essential physiological processes, e.g. vision, reproduction etc. Recently they were found to inhibit carcinogenesis. Their activity is summarized in a number of books and reviews60,61.

1622	Asher Kalir and Henry H. Kalir
				OCH2 CH2 N(CH3 )2
	Ph
		C	C
ClCH2 CH2			Ph
			(5)
					O
CH3 (CH2 )7	(CH2 )12 CH3			CH3 (CH2 )7	(CH2 )6 CCH3
CH CH				CH	CH
(6)					(7)
O
	CH2		CH2	CH2
		CH	CH	CH2	COOH
		CH	CH2	CH2	CH3
	CH		CH	CH2	CH2
HO
			OH
			(8)
CH3		CH3	CH3	CH3
					X

Y

CH3

(9)

The presence of double-bonded fatty acids in proteins and their isomerization was found to help some bacteria to adapt to ambient temperature changes62. The alteration of CDC bonds in liposomes plays a role in protection against radiation-induced damage63.

IV. DETECTION AND LOCALIZATION OF DOUBLE BONDS

There are numerous methods for detection and localization of double bond(s) in polyunsaturated compounds64. Recent papers mention derivatization and further detection, usually by GC/MS. The reagents used are 2,2-dimethyl-2-aminoethanol (Me2C(NH2)CH2OH) for conversion to oxazolines in nearly quantitative yield65, oxidation with potassium permanganate66, ozonization67 and reduction with hydrazine and subsequent reaction with dimethyl disulfide68.

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1623

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1624	Asher Kalir and Henry H. Kalir

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