The separation and synthesis of lipidic 1,2- and 1,3-diols from natural phenolic lipids for the complexation and recovery of boron

Chemistry and Physics of Lipids 126 (2003) 177–199

The separation and synthesis of lipidic 1,2- and

1,3-diols from natural phenolic lipids for the

complexation and recovery of boron^ଝ

John H.P. Tyman^∗, Satinderjit K. Mehet

Department of Chemistry, Brunel University, Uxbridge, Middlesex UB8 3PH, UK

Received 17 April 2003; received in revised form 25 July 2003; accepted 13 August 2003

Abstract

A study has been made of the semi-synthesis of 1,3-diols (anacardic alcohols) from natural phenolic lipid resources from

Anacardium occidentale and Anacardium giganteum which have given C₁₅and C₁₁derivatives, respectively. An isomeric 1,3-diol

(isoanacardic alcohol) has been obtained from cardanol separated from technical cashew nut-shell liquid. Homologous1,3-diols

have been synthesised from a range of synthetic 2-alkyl-, 3-alkyl- and 4-alkylphenols and from 6-alkylsalicylic acids. The natural

1,2-diol, urushiol, from Rhus vernicifera has been puriﬁed. All these lipidic compounds have been studied for their complexation

and the potential recovery of boron as boric acid.

Keywords: Alkyl- and arylalkyl-1,3-diols; Alkylsalicyl alcohols; Saligenins; Aryl-1,2-diols; Boric acid complexation; Solvent extraction of

boron compounds

1. Introduction

2001), and notably by lipidic diols, 2-ethylhexane-

1,3-diol (Brown and Sanderson, 1978b), nonane-

1,3-diol, decane- and dodecane-1,3-diols (Shvarts

et al., 1995; Svares et al., 1983), and in the

aromatic o-hydroxymethylphenolic (alkylsalicyl al-

cohol) series, with 2-chloro-6-hydroxymethyl-4-

isooctylphenol (Brown and Sanderson, 1978b ). Some

of these studies have led to commercial interest in

the prospect of recovery through solvent extraction

as, for example, by the American Potash and Chem-

ical Corporation (Havighorst, 1963; Klopfenstein and

Arnold, 1966), with ‘octylchlorosaligenin’, 2-chloro-

6-hydroxymethyl-4-t-octylphenol (OCS) for the re-

covery of boric acid from Californian salt lake brines

having borate concentrations below those applicable

to conventional recovery by crystallisation In other

The interaction between polyhydroxy compounds

and boric acid has been of interest since the clas-

sical conductometric work on the absolute conﬁg-

uration of glycols and of the ␣- and ␤-glucoses

(Boesekin, 1913 ). More recent experimental work

has concentrated on the complexation and extrac-

tion of boric acid by monohydric alcohols, such as

isoamyl alcohol (Vinogradov, 1962), 2-ethylhexanol

(Brown and Sanderson, 1978a, Vinogradov et al.,

ଝ

Long Chain Phenols, Part 38.

Corresponding author. Tel.: +44-20-8878-6314;

∗

fax: +44-20-8878-6314.

E-mail address: jhptyman@hotmail.com (J.H.P. Tyman).

doi:10.1016/j.chemphyslip.2003.08.004

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J.H.P. Tyman, S.K. Mehet / Chemistry and Physics of Lipids 126 (2003) 177–199

Fig. 1. Formulae of phenolic lipids and structures of unsaturated side chains b, c, d of 1, 3 and b, c, d, e of 4 .

cases, where boron contamination is undesirable, for

example, in agricultural citrus crop cultivation, or

in magnesium production (Folkestad et al., 1972),

solvent extraction involving 2-ethylhexanol and iso-

octanol in petroleum ether has found a role in the se-

lective recovery/removal of boric acid. In the present

preparative work, amongst the replenishable raw ma-

terials used for the semi-synthesis of lipidic 1,3-diols,

anacardic acid (1) (n = 0, 2, 4, 6) is the chief C₁₅

component of natural cashew nut-shell liquid (Tyman,

1979, 1996), in Anacardium occidentale indigenous

to India and Brazil and (2) the C₁₁analogue in Anac-

ardium giganteum. In the industrial heat-processing of

cashew, the technical cashew nut-shell liquid formed

by decarboxylation contains mainly the by-product,

cardanol (3) (n = 0, 2, 4, 6). Urushiol (4) (n = 0, 2,

4, 6) is the major aromatic C₁₅3-alkenyl-1,2-diol in

Rhus vernicifera (from Japan and China) and in Rhus

toxicodendron (Tyman, 1979, 1996).

The natural isomeric 4-alkenyl analogue, thitsiol,

occurs in the Burmese lac tree, Melanorrhea usitata.

Fig. 1 depicts the structures of the ﬁrst four materials.

Anacardic acid (1) and cardanol (3) have unsaturated

side chains (b, c and d) while urushiol (4) has unsat-

urated structures (b, c, d and e) (Fig. 1).

Fossil fuel-derived 4-t-butyl, 4-t-nonyl, and 4-

t-octylphenol have served as starting materials

for the synthesis of analogous saligenins, with 2-

hydroxymethylphenolic structures.

The compounds synthesised, namely 2-hydroxy-

methyl-3-alkyl-, 4-alkyl-, 5-alkyl- and 6-alkylphenols

(isomeric saligenins) are depicted in Scheme 1 (5 and

Scheme 1. Synthesis of anacardic alcohols (2-hydroxymethyl-3-alkylphenols). Reagents: (i) LiAlH₄, THF; HCl.

J.H.P. Tyman, S.K. Mehet / Chemistry and Physics of Lipids 126 (2003) 177–199

179

Scheme 2. Synthesis of 2-hydroxymethyl-3-alkylphenols. Reagents: (i) LDA, THF, HMPA, RBr; H₃O⁺, (ii) BBr₃, CH₂Cl₂, −78 ^◦C, H₂O,

(iii) LiAlH₄, THF; HCl.

Scheme 3. Synthesis of 2-hydroxymethyl-4-alkylphenols. Reagents: (a) (i) EtMgBr, Et₂O, HMPA, (CH₂O)_n; HCl, (ii) NaBH₄, MeOH;

HCl.(b) (iii), (iv) as in (a), respectively.

Scheme 4. Synthesis of isoanacardic compounds (2-hydroxymethyl-5-alkylphenols). Reagents: (i) (R = R¹= H), CO₂, KOH, ꢀ; HCl, (ii)

(R¹= H), LiAlH₄, THF; HCl, (iii) EtMgBr, Et₂O, HMPA, (CH₂O)_n; HCl, (iv) NaBH₄, MeOH, 0 ^◦C; HCl, (v) NaOH, MeOH, HCHO.

180

J.H.P. Tyman, S.K. Mehet / Chemistry and Physics of Lipids 126 (2003) 177–199

Scheme 5. Synthesis of 3-n-alkylphenols, 2-hydroxy-4-n-alkyl-benzaldehydes and 2-hydroxymethyl-5-n-alkylphenols. Reagents: (i)

RCH₂P⁺(Ph)₃Br⁻, BuLi, THF, (ii) Pd–C, H₂, EtOH, (iii) EtMgBr, Et₂O, HMPA, (CH₂O)_n; HCl, (iv) NaBH₄, MeOH; HCl.

Scheme 6. Synthesis of 2-hydroxy-3-alk ylbenzaldehydes and 2-hydroxymethyl-6-alkylphenols. Reagents: (a) (i) C₈H₁₇P⁺(Ph)₃Br⁻, BuLi,

THF, (ii) Pd–C, H₂, EtOH, (iii) EtMgBr, Et₂O, HMPA, (CH₂O)_n,; HCl, (iv) NaBH₄, MeOH; HCl, (v) Al, ꢀ, C₈H₁₆; aqueous H₂SO₄,

(vi) EtMgBr, Et₂O, HMP A, (CH₂O)_n; HCl, (vii) NaBH₄, MeOH; HCl.

6), Scheme 2 (24), Scheme 3 (19 and 21), Scheme 4

(9, R¹= H), Scheme 5 (12) and Scheme 6 (15)

(Section 3). To aid structure/property correlation,

homologous members of the structurally isomeric

saligenins, not available from natural sources, were

synthesised to determine the role of chain length and

the position of the alkyl chain substituent in the aryl

ring on the efﬁciency of the resultant boric acid ex-

tractant. The effect of branching in the side chain was

studied by a comparison of fossil fuel-derived syn-

thetic compounds having t-butyl, t-octyl and t-nonyl

side chains with those in the isomeric n-alkyl series.

2. Experimental procedures

2.1. Materials

Cashew nuts, of Indian and Mozambique origin,

were obtained from Gill, Duffas and Landauer, Lon-

don, SE1 and half shells from Mr. M. Grimminger,

Buhler Miag, Barnet, London. Technical cashew nut-

shell liquid was obtained from 3M Research Ltd.,

St Paul, MN, USA. Japanese lac was obtained with

the help of the Japanese Trade Centre, London, from

Dr. M. Sato, Industrial Research Laboratory, Sendai,

J.H.P. Tyman, S.K. Mehet / Chemistry and Physics of Lipids 126 (2003) 177–199

181

Japan. A. giganteum was made available with the

help of Prof. Tereza Pastore, University of Brasilia,

Brazil.

were made by the SERC Mass Spectrometry Centre

at the University College of Wales, Swansea.

Chemicals were obtained from Aldrich Chemical

Co. other than t-nonylphenol (3,5,5-trimethylhexyl-

phenol) and t-octylphenol, which were both from ICI.

2.4. Separations of phenolic lipids

2.4.1. Anacardic acid (1) from natural cashew

nut-shell liquid (CNSL), Anacardium occidentale

The described method (Tyman et al., 1989) was

used with cashew nuts (400.0 g), from which by car-

bon tetrachloride extraction, natural CNSL (91.08 g,

32.6%) was recovered and thence by lead salt pre-

cipitation, ﬁltration and regeneration with cold dilute

nitric acid and ethereal extraction, anacardic acid

was obtained as a viscous brown liquid (26.68 g,

29.3%). Recoveries varied between 29 and 35%.

R_f0.56 (solvent B); ν_max(ﬁlm, cm⁻¹), 3100, 1220

2.2. Chromatography

Analytical thin layer chromatography (TLC) was

effected with Whatman silica gel 60AMK6F plates

(1 in. × 3 in.) having a 250 ␮m layer and preparative

TLC with Merck silica gel 60GF (20 cm×20 cm) with

a 1 mm layer. Solvents A to N had the following com-

positions: A, chloroform:ethyl acetate (95:5); B, chlo-

roform:ethyl acetate:formic acid (95:5:2); C, chloro-

form:ethyl acetate (90:10); D, dichloromethane:light

petroleum (40–60 ^◦C) (50:50); E, diethyl ether:light

petroleum (40–60 ^◦C) (50:50); F, chloroform:light

petroleum (60–80 ^◦C) (50:50); G, acetone; H, chlo-

roform:ethyl acetate (98:2); I, diethyl ether:light

petroleum (40–60 ^◦C) (40:60); J, chloroform:light

petroleum (60–80 ^◦C) (70:30); K, diethyl ether:light

petroleum (40–60 ^◦C):0.880 ammonia (70:30:4); L,

diethyl ether:light petroleum (40–60 ^◦C):formic acid

(70:30:2); M, light petroleum (60–80 ^◦C):chloroform

(70:30); N, light petroleum (60–80 ^◦C):chloroform

(80:20).

For synthetic work, diethyl ether and benzene

were dried over anhydrous calcium chloride and then

overnight over sodium wire. Dry dichloromethane was

obtained by reﬂuxing over calcium hydride prior to

distillation. THF was dried by reﬂuxing over sodium

with benzophenone ketyl radical as indicator.

Column chromatography was carried out with BDH

silica gel, particle size 0.13–0.25 mm.

For ﬂash chromatography, Merck kieselgel 60

(230–400 mesh) was used, and for dry ﬂash chro-

matography, Merck kieselgel 60H and 60GF.

=

(OH), 3010, 1610 (C C), 1660 (C O), 1380 (C–O);

δ_H(CFT20, CCl₄), 0.73–1.0 (CH₃, unresolved t),

=

1.17–1.63 [m, (CH₂)_n], 1.83–2.20 (CH₂CH CH,

=

m), 2.6–3.06 [CH₂Ar, CH₂(CH CH)₂], 4.73–5.30

=

(CH₂CH, CH CH, m), 6.57–7.43 (HAr, m, 3H),

11.23 (HO, HO₂C, bs, 2H, D₂O exch.); m/z, M⁺(%),

348.6 (7.7), 346.6 (53.3), 344.6 (17.6), 342.6 (28.7).

2.4.2. Anagigantic acid (2)

(2-hydroxy-6-undecylbenzoic acid) from Anacardium

giganteum

The shells from the nut were cracked and the phe-

nolic lipids extracted in the same way as described

for the cashew. The shell liquid (6.71 g) in methylated

spirit (50 cm³) was added to lead hydroxide prepared

from lead nitrate (3.81 g, 0.012 mol) and sodium

hydroxide (0.92 g, 0.023 mol) and the precipitated

red/brown solid ﬁltered and washed with methylated

spirit (3 × 100 cm³). A suspension in methylated

spirit (100 cm³) was acidiﬁed with cold nitric acid to

liberate anagigantic acid which was extracted with

diethyl ether. The combined extracts were washed

with saturated brine (7 × 50 cm³), dried with mag-

nesium sulphate and the solvent evaporated to give a

brown solid (2.45 g, 36.5%) which was crystallised

(light petroleum) to afford cream crystals (2.22 g,

90.6%), mp, 75.5–76.6 ^◦C; R_f0.92 (solvent B); ν_max

(KBr disc, cm⁻¹), 3350, 1220 (OH), 3050, 1310 (OH,

2.3. Spectroscopy

Infrared spectra were recorded on a Perkin Elmer

1420 spectrophotometer. H NMR spectra were de-

1

=

termined with Varian T60 (60 mHz) and CFT20

instruments with tetramethylsilane as internal stan-

dard. Mass spectra were obtained on a modiﬁed AEI

MS902 instrument and accurate mass determinations

carboxylic acid), 1650 (C O), 1610 (C C), 1380

(C–O); δ_H(CCl₄), 0.80–1.57 [(CH₂)₉, Me, m, 21H],

2.70–3.07 (CH₂Ar, t, 2H, J 8 Hz), 6.50–7.30 (HAr, 2d

superimposed on dd, J 8 and 16 Hz), 10.30 (HOAr and

182

J.H.P. Tyman, S.K. Mehet / Chemistry and Physics of Lipids 126 (2003) 177–199

cm⁻¹), 3450, 1190, 3000, 1610, 1380; δ_H(CFT20,

CDCl₃), 0.82–1.00 (Me, unresolved t), 1.16–2.00 [m,

HO₂C, bs, 2H, D₂O exch.); m /z , M⁺(%), 292.4 (9.1).

C₁₈H₂₈O₃requires 292.4, 274.4 (3.9), M⁺–H₂O.

=

(CH₂)_n, CH₂CH CH], 2.30–2.83 [m, CH₂Ar and

=

CH₂(CH CH)₂], 4.83–6.16 (m, CH CH and HAr),

6.33(HOAr, s, 2H, D₂O exch.); m/z, M⁺, 320, 318.6

(monoene, 21.7%), 316.5 (diene, 4.8%), 314.6 (triene,

10.1%).

2.4.3. Cardanol (3) from technical CNSL (Tyman,

1983, 1992; Patel et al., 1981; Tyman et al., 1992)

A variety of methods are available and the follow-

ing is dependent on the more selective hydroxymethy-

lation and subsequent polymerisation of cardol,

compared with cardanol. To technical CNSL (250.0 g,

8.33 mol) in methanol (1000 cm³) at 45 ^◦C, concen-

trated HCl (20 cm³) was added to give pH 1, and

then 40% (w/v) methanolic formaldehyde solution

(217.6 g, 7.25 mol) dropwise over 1 h. The mixture

was stirred and heated at 45–50 ^◦C for 48 h after

which it was cooled, neutralised with 1 M sodium

hydroxide and concentrated in vacuo. The residue

(305.0 g) in diethyl ether (500 cm³) was washed with

saturated brine (6 × 500 cm³), dried with magnesium

sulphate, ﬁltered and the solvent evaporated in vacuo

to give a brown oil (303.65 g), vacuum distillation

of which afforded cardanol as a clear yellow oil, bp

190 ^◦C/0.1 mmHg (126.69 g, 41.7% of CNSL used),

free from cardol; R_f0.71 (solvent B); argentation TLC

(solvent B), 0.97 (15:0), 0.64 (15:1), 0.43 (15:2), 0.20

(15:3); ν_max(ﬁlm, cm⁻¹), 3350, 1170 (OH), 1590

2.4.5. Isoanacardic acid (7, R = n^ꢀ= H) from

carboxylated technical CNSL

Isoanacardic acid was extracted from carboxy-

lated technical CNSL, prepared as described (Durrani

et al., 1980). The reaction product from carboxyla-

tion (200.35 g) in methylated spirit (100 cm³) was

added to lead hydroxide suspended in methylated

spirit (100 scm³), [prepared from lead nitrate (97.04 g,

0.582 mol) in water (300 cm³) and sodium hydroxide

(23.44 g, 0.582 mol) in water (150 cm³)]. The mix-

ture was stirred for 30 min, the red brown solid was

ﬁltered, washed with methylated spirit and acidiﬁed

with cold dilute nitric acid to liberate the product

which was extracted with diethyl ether (2 × 100 cm³).

The combined extracts were washed with saturated

brine (2 × 200 cm³), dried with magnesium sulphate,

ﬁltered and evaporated in vacuo to give a viscous

brown oil (20.86 g, 10.4%); R_f0.44 (solvent B),

argentation TLC (solvent B), 0.98, saturated, 0.62,

monoene, 0.43, diene, 0.26, triene; ν_max(ﬁlm, cm⁻¹),

=

(C C), 1370 (C–O), 700 (1,3-disubstituted ring);

δ_H(CCl₄), 0.73–1.0 (unresolved t, Me), 1.17–1.60

=

[(CH₂)_n, m], 1.83–2.23 (CH₂CH CH, m), 2.30–2.90

=

3150, 13,200, 1220 (OH), 3010, 1625 (C C), 1660

(C O), 1390 (C–O) (phenol); δ_H(CCl₄), 0.73–1.0

(Me, unresolved t), 1.13–1.50 [(CH₂)_n, m], 1.87–2.23

=

[CH₂Ar, CH₂(CH CH)₂], 4.73–5.70 (CH₂CH,

=

CH CH, m), 6.43–7.17 (HAr and HOAr, m, 5H, 1H,

D₂O exch.); m/z, M⁺(%), 304.6 (1.9, 15:0), 302.6

=

(CH₂CH CH, m), 2.40–2.87 [CH₂Ar and CH₂

(7.3, 15:1), 300.6 (3.7, 15:2), 298 (4.4, 15:3).

=

(CH CH)₂, m], 4.77–5.37 (CH₂CH and CH CH,

m) 6.53–6.80 (HAr, s superimposed on d, J 8 Hz, 2H),

7.63–7.87 (HAr, d, J 8 Hz, 1H), 10.20–10.63 (HOAr

and HO₂C, bs, 2H, D₂O exch.); m/z, M⁺(%), 348.6

(6.7), 346.6 (22.1), 344.6 (12.0), 342.6 (143.2).

2.4.4. Urushiol (4) (Matthews and Tyman, 1982)

Analytical TLC (solvent C) of Japanese lac (10%

in chloroform) indicated cardanol (R_f0.82), urushiol

constituents (R_f0.63, 0.42, 0.29 and 0.27) and poly-

meric material (R_f0.11). Column chromatography of

Japanese lac (15.00 g) gave the following fractions,

eluent, weight: 1–12, chloroform, 0.84 g; 13–48, chlo-

roform:ethyl acetate (90:10), 9.75 g; residue on col-

umn, diethyl ether, 4.21 g.

Urushiol was obtained from fractions 13–48 by

dry ﬂash chromatography with light petroleum

(60–80 ^◦C)/chloroform with gradient elution and ﬁ-

nally chloroform/ethyl acetate giving 9.15 g (61.0%

on urushiol used); R_f0.57 (solvent C); ν_max(ﬁlm,

2.5. Semi-synthetic preparation of 1,3-diols from

phenolic lipid sources

2.5.1. Anacardic alcohol (5, n = 0)

(2-hydroxymethyl-3-pentadecylphenol)

(i) (15:0)-Anacardic acid, prepared by catalytic hy-

drogenation of (5) as described (Lam and Tyman,

1982) (2.83 g, 0.008 mol) in dry THF (50 cm³),

was added dropwise to lithium aluminium hydride

J.H.P. Tyman, S.K. Mehet / Chemistry and Physics of Lipids 126 (2003) 177–199

183

(1.52 g, 0.04 mol) in dry THF (30 cm³) cooled

to 0 ^◦C under nitrogen, after which the mixture

was warmed to 50–55 ^◦C for 7 h and then left

at ambient temperature for 16 h. Excess hydride

was decomposed by the addition of ethyl acetate

and after the addition of dilute hydrochloric acid,

the mixture was extracted with diethyl ether. The

combined extracts were washed with saturated

brine (5 × 25 cm³) dried (magnesium sulphate),

and concentrated in vacuo to yield a brown solid

which was recrystallised (light petroleum) to

give cream crystals (1.46 g, 53%), mp 63–65 ^◦C,

lit. (Gulati and Subba Rao, 1964), 65–66 ^◦C;

R_f0.39 (solvent B); ν_max(KBr, cm⁻¹), 3500,

1000 (primary OH), 3150, 1190 (OH, phenol),

traces), anacardic alcohol (0.45), and cardol (0.39);

m/z, M⁺(%), 334.3 (0.7), 332.3 (1.1), 330.4 (0.9),

328.4 (0.7).

2.5.2. Methyl 2-hydroxy-4-pentadecylbenzoate

(7,n = 0, R = Me, R¹= H)

(i) Diazomethane was generated by adding ‘diazald’

(4.3 g, 0.02 mol) in diethyl ether (50 cm³) to

potassium hydroxide (1.38 g, 0.025 mol) in wa-

ter (2 cm³) and ethanol (5 cm³) at 65 ^◦C and

collected in diethyl ether (20 cm³) at 0 ^◦C. This

solution of diazomethane (0.6 g, 0.014 mol) in

diethyl ether was then added to isoanacardic

acid (1.38 g, 0.004 mol) in diethyl ether, until

the solution was pale yellow and nitrogen evo-

lution had ceased. Concentration of the mixture

and crystallisation of the residue from light

petroleum gave cream needles (1.34 g, 93.1%),

mp 45–46.5 ^◦C; R_f0.73 (solvent F). Found, C,

76.16; H, 10.44. C₂₃H₃₈O₃requires C, 76.20;

H, 10.57%; ν_max(KBr, cm⁻¹), 3180, 1220

=

1590 (C C), 1360, 1260 (C–O, phenol and pri-

mary OH); δ_H(CDCl₃), 0.83–1.53 [(CH₂)₁₃, Me,

29H], 2.30–2.80 (CH₂Ar, partially resolved t and

s, HOCH₂Ar, 3H, D₂O exch.), 5.03 (Ar CH₂OH,

s, 2H), 6.80–7.50 (HAr and HOAr, m, 4H, 1H,

D₂O exch.); m/z, M⁺(%), 334 (18.5). C₂₂H₃₈O₂

requires 334.335 (4.4, M⁺+ 1).

=

(OH), 1680 (C O), 1620 (C C), 1340, 1250

(C–O); δ_H(CDCl₃), 0.80–1.52 [(CH₂)₁₃, Me,

m, 26H], 2.40–2.70 (CH₂Ar, t, J 7 Hz, 2H), 3.90

(MeO₂CAr, s, 3H), 6.60–6.70 (HAr, d, J 8 Hz,

1H), 7.21 (HAr, s, 1H), 7.62–7.72 (HAr, d, J

8 Hz, 1H), 10.62 (HOAr, s, 1H, D₂O exch.); m/z,

M⁺(%), 362.4 (100), M⁺+ 1, 363.5 (27.2).

(ii) A mixture of isoanacardic acid (1.82 g, 0.005 mol)

in benzene (20 cm³) containing anhydrous potas-

sium carbonate (3.42 g, 0.025 mol) and dimethyl

sulphate (2.4 cm³, 0.025 mol) was reﬂuxed for

24 h. The cooled mixture was ﬁltered and the ﬁl-

trate was washed with warm water (5 × 25 cm³)

to remove dimethyl sulphate, dried (magnesium

sulphate) and the solvent evaporated to give

a cream solid which was recrystallised (light

petroleum) to afford cream crystals (0.99 g,

52.4%), mp 42–43.5 ^◦C, identical spectroscopi-

cally with the product from method (a).

(ii) Anacardic alcohol (Mehet, 1988) (5): reduc-

tion of anacardic acid Anacardic acid (1)

(43.54 g, 0.126 mol) was reduced in THF by

the same procedure as for the saturated com-

pound with lithium aluminium hydride (14.32 g,

0.189 mol). The crude product was puriﬁed by

dry-column ﬂash chromatography with gradi-

ent elution to give 5 as a viscous brown oil

(33.04 g, 79.1%); R_f0.38 (solvent B); ν_max

(liquid, cm⁻¹), 3400, 1190, 1060 (OH), 1620

=

(C C), 1380 1270 (C–O, phenol and primary

OH); δ_H(CCl₄), 0.73–0.97 (Me, unresolved t),

=

1.1–1.50 [(CH₂)_n, m]1.77–2.17 (CH₂CH CH,

=

m) 2.23–2.87 (CH₂Ar and CH₂(CH CH)₂, m),

3.67–4.0 (HOCH₂Ar, bs, 1H, D₂O exch.), 4.67

=

(HOCH₂Ar, s, 2H), 4.77–5.07 (CH₂CH, m),

=

5.07–5.50 (CH CH, m), 6.17–6.90 (HAr and

HOAr, m, D₂O exch.); m/z, M⁺(%), 334.4 (0.9),

332.4 (2.2), 330.4 (1.2), 328.4 (0.8).

In a similar way natural CNSL (11.00 g) con-

taining anacardic acid (80%), cardol (15%) and 2-

methylcardol/cardanol (5%) was reduced with LiAlH₄

(3.64 g, 0.096 mol) in THF and worked up as before

to give a viscous brown oil (9.45 g, 85.9% recovered);

R_f(solvent B) 0.74 (cardanol), 0.66 (anacardic acid,

2.5.3. Methyl 2-methoxy-4-pentadecylbenzoate

(7, n = 0, R = R¹= Me)

A mixture of isoanacardic acid (0.98 g, 0.003 mol),

3 M sodium hydroxide (4.6 cm³), dimethyl sulphate

(4.8 cm³, 0.006 mol), 40% aqueous tetrabutylam-

monoum hydroxide (0.5 cm³) in water (20 cm³) and

184

J.H.P. Tyman, S.K. Mehet / Chemistry and Physics of Lipids 126 (2003) 177–199

dichloromethane (20 cm³) was vibromixed for 3 h

when TLC (solvent M) indicated dimethylation was

complete. The lower organic layer was separated

and washed with warm water (6 × 50 cm³), dried

and concentrated to give a cream solid which was

crystallised (light petroleum) to afford cream crystals

(0.62 g, 58.5%), mp 29–31 ^◦C; R_f0.39 (solvent F).

Found, C, 76.35; H, 10.89. C₂₄H₄₀O₃requires C,

Reduction of methyl 2-methoxy-4-pentadecylben-

zoate (0.80 g, 0.002 mol) with lithium aluminium

hydride (0.23 g, 0.006 mol) similarly gave the same

product, as cream needles, mp 66.5–67.5 ^◦C, R_f0.66

(solvent C) with similar spectroscopic data as for the

product from reduction of the acid.

2.5.6. Isoanacardic alcohol (9, n = 0, R^ꢀ= H)

76.55; H, 10.71%; ν_max(KBr, cm⁻¹), 1690 (C O),

(2-hydroxymethyl-5-pentadecylphenol)

=

1600 (C C), 1400, 1250, 1240 (C–O); δ_H(CCl₄),

(i) By hydride reduction: 2-Hydroxy-4-pentadecyl-

benzoic acid (1.00 g, 0.001 mol) in THF (20 cm³)

was added dropwise under nitrogen to a sus-

pension of lithium aluminium hydride (0.34 g,

0.009 mol) in THF (10 cm³) cooled to 0 ^◦C. After

the mixture had been reﬂuxed for 2 h and then al-

lowed to stand for 16 h, ethyl acetate (0.50 cm³)

was added, followed by dilute hydrochloric acid.

Ethereal extraction, washing of the combined

extracts with saturated brine, drying (magne-

sium sulphate) and evaporation afforded a cream

solid which was recrystallised (light petroleum)

to give pale cream crystals (0.56 g, 75.2%),

mp 96–97 ^◦C; R_f0.37 (solvent C); ν_max(KBr,

cm⁻¹), 3450, 1000 (OH, primary), 3180, 1220

0.67–1.23 [(CH₂)₁₃, Me, m, 29H], 2.27–2.5 (CH₂Ar,

t, J 7 Hz, 2H), 3.62 (MeO₂CAr, s, 3H), 3.67 (MeOAr,

s, 3H), 6.70–6.67 (HAr, s on d, J 8 Hz, 2H), 7.43–7.60

(HAr, d, J 8 Hz, 1H); m/z, M⁺(%), 376.4 (100),

M⁺+ 1 377.4 (24.3), M⁺–OMe, 345.3 (1.3).

2.5.4. 2-Methoxy-4-pentadecylbenzoic acid

(7, n = 0, R = H, R¹= Me)

Methyl 2-methoxy-4-pentadecylbenzoate (0.50 g,

0.001 mol) in ethanol (10 cm³) was reﬂuxed with

1 M ethanolic KOH (3 cm³) for 1 h. The cooled

mixture was then acidiﬁed with dilute hydrochlo-

ric acid and the solid product collected, dried and

crystallised (light petroleum) to give white needles

(0.45 g, 93.8%), mp 80.5–81.5 ^◦C; R_f0.24 (solvent

C). Found, C, 76.38; H, 10.45. C₂₃H₃₈O₃requires

C, 76.20; H, 10.57%; ν_max(KBr, cm⁻¹), 3230, 1340

=

(OH, phenol), 1630 (C C), 1380, 1290 (C–O);

δ_H(CDCl₃), 0.90–1.50 [(CH₂)₁₃, Me, m, 29H],

2.17 (HOCH₂Ar, s, 1H), 2.43–2.77 (CH₂Ar, t, J

7 Hz, 2H), 4.93 (ArCH₂OH, s, 2H), 6.73–7.23

(HAr, HOAr, m, 4H, 1H, D₂O exch.); m/z, M⁺

(%), 334.6 (34.9). C₂₂H₃₈O₂requires 334.5,

M⁺+ 1 335.6 (8.4).

=

(OH), 1720 (C O), 1610 (C C), 1260 (C–O); δ_H

(CCl₄), 0.73–1.50 [(CH₂)₁₃, Me, m, 29H], 2.47–2.87

(CH₂Ar, t, J 7 Hz, 2H), 4.03 (MeO, s, 3H), 6.73–6.97

(HAr, s on d, J 8 Hz, 2H), 7.67–8.43 (bs, s on d, J

8 Hz, 2H, 1H, D₂O exch.); m/z, M⁺(%), 363.2 (81.4).

(ii) This compound was also prepared by reduction

of the methyl ester.

2.5.5. 2-Hydroxymethyl-5-pentadecylphenyl methyl

ether (9, n = 0, R¹= Me)

2.5.7. Isoanacardic alcohol (9, R^ꢀ= H) (reduction

2-Methoxy-4-pentadecylbenzoic acid (0.36 g,

0.001 mol) and lithium aluminium hydride (0.11 g,

0.001 mol) in the same way as for other reductions,

gave the product as cream needles (0.03 g, 85.7%),

mp 66.5–68 ^◦C; R_f0.66 (solvent C). Found, C, 79.46;

H, 11.58. C₂₃H₄₀O₂requires C, 79.25; H, 11.57%;

of unsaturated methyl isoanacardate)

(i) By hydride reduction: Unsaturated 2-hydroxy-

4-pentadecylbenzoic acid (4.00 g, 0.012 mol),

was methylated with diazomethane (0.50 g,

0.012 mol) in ethereal solution and the methyl

ester obtained as a viscous brown oil (3.50 g,

84.1%); R_f0.35 (solvent N); ν_max(liquid,

ν_max(KBr, cm⁻¹), 3340, 1050 (OH), 1520 (C O),

=

1270 (ArOMe), 1260 (C–O); δ_H(CCl₄) 0.83–1.40

[(CH₂)_n, Me, m, 29H], 2.0–2.67 (CH₂Ar, HOCH₂Ar,

t on bs, 3H, 1H, D₂O exch.), 3.80 (MeO, s, 3H), 4.47

(HOCH₂Ar, s, 2H), 6.50–6.70 (HAr, s on d, J 8 Hz,

2H), 7.0–7.20 (HAr, d, J 8 Hz, 1H); m/z, M⁺(%),

348.4 (100), M⁺+ 1 349.6 (25.5).

cm⁻¹), 3400, 1220 (OH), 3010, 1620 (C C),

=

1670 (C O), 1350 (C–O); δ_H(CCl₄) 0.83–1.03

(unresolved t, Me) 1.13–1.57 [(CH₂)_n, m],

=

1.77–2.27 (CH₂CH CH), 2.60–2.97 [CH₂Ar,

=

CH₂(CH CH)₂, m], 3.93 (MeO, s, 3H),

J.H.P. Tyman, S.K. Mehet / Chemistry and Physics of Lipids 126 (2003) 177–199

185

=

4.77–5.57 (CH₂CH, CH CH, m), 6.47–7.30

(HAr, m, 3H), 10.93 (HOAr, s, D₂O exch.); m/z,

M⁺(%), 362.3 (2.1), 360.2 (14.9), 358.2 (4.0),

356.2 (4.0).

1370, 1270 (C–O, phenol and primary OH);

δ_max(CDCl₃), 0.76–0.94 (Me, t), 1.17–1.36

=

[(CH₂)_n, m], 1.57–2.04 (CH₂CH CH, m),

2.49–2.56 (CH₂Ar, t, J 7 Hz, 2H), 2.60–2.78

=

Methyl isoanacardate (3.14 g, 0.009 mol) in

dry THF (60 cm³) was added dropwise, under

nitrogen, to stirred lithium aluminium hydride

(1.05 g, 0.027 mol) in dry THF (30 cm³) cooled

to 0 ^◦C. After reﬂuxing for 2 h, the mixture was

worked up as for the saturated compound and pu-

riﬁed by chromatography on a silica column with

light petroleum (60–80 ^◦C)/chloroform/ethyl ac-

etate (gradient elution) to give a brown oil (2.56 g,

88.6%); R_f0.38 (solvent B); ν_max(liquid, cm⁻¹),

[CH₂(CH CH)₂, m], 4.78 (HOCH₂Ar, s, 2H),

=

4.89–5.42 (CH₂CH, CH CH, m), 6.64–6.69

(HAr, s on d, 2H), 6.90–6.94 (HAr, d, J 8 Hz,

1H); m/z, M⁺(%), 332.6 (1.6), M⁺–H₂O, 316.5

(2.4), 314.5 (10.1), 312.5 (7.7), 310.5 (7.2).

(iii) By formylation of cardanol (Tyman, 1981) to

8: Ethyl magnesium bromide prepared from

bromoethane (3.8 cm³, 0.05 mol), in dry diethyl

ether (30 cm³) and magnesium turnings (1.44 g,

0.06 mol), in dry ether (20 cm³) was added to a

stirred solution of cardanol (15.35 g, 0.051 mol)

in dry ether (100 cm³) at ambient tempera-

ture. After completion of evolution of ethane

during 16 h, and distillation of the ether, dry

benzene was added, followed by paraformalde-

hyde (5.98 g, 0.13 mol) and hexamethylphos-

phoramide (8.8 cm³, 0.051 mol). The mixture

was stirred and reﬂuxed for 6 h with moni-

toring by TLC (solvent E). After cooling and

acidiﬁcation with dilute sulphuric acid, the mix-

ture was extracted with diethyl ether (200 cm³),

the ethereal extract was washed with saturated

brine (5 × 150 cm³), dried with magnesium

sulphate, ﬁltered and concentrated to afford an

oil which was puriﬁed by column chromatog-

raphy (light petroleum, 40–60 ^◦C/diethyl ether,

gradient elution) to give a golden oil (14.58 g,

86.9%), 2-hydroxy-4-unsaturated pentadecyl-

benzaldehyde; R_f0.69 (solvent E); ν_max(ﬁlm,

=

3350, 1190, 1050 (OH), 1620 (C C), 1390, 1280

(C–O); δ_H(CCl₄) 0.73–1.03 (unresolved t, Me),

=

1.17–1.60 [(CH₂)_n, m], 1.80–2.20 (CH₂CH CH,

=

m), 2.30–2.90 [CH₂Ar, CH₂(CH CH)₂, m],

3.57–4.20 (HOCH₂Ar, s, 1H, D₂O exch.), 4.67

=

(HOCH₂Ar, s, 2H), 4.77–5.13 (CH₂CH, m),

=

5.13–5.53 (CH CH, m), 6.43–7.06 (HAr, m,

3H), 7.30–8.10 (HOAr, s, 1H, D₂O exch.); m/z,

M⁺(%), 334.2 (1.1), 332.2 (2.8), 330.2 (1.6),

328 (0.9).

(ii) By hydroxymethylation: To cardanol (3.04 g,

10 mmol) in methanol (10 cm³) sodium hy-

droxide (0.4 g, 10 mmol) in water (15 cm³) was

added, followed by 37% aqueous formaldehyde

(0.85 g, 10.5 mmol). After reﬂuxing for 4 h,

the mixture was cooled, diethyl ether (50 cm³)

was added and the solution was acidiﬁed with

3 M hydrochloric acid. The ethereal solution

was washed with saturated brine, dried with

magnesium sulphate, ﬁltered and concentrated

in vacuo to give a golden oil (3.36 g). The

crude product (0.85 g) was puriﬁed by prepara-

tive TLC (solvent C) to give ﬁve bands (1) R_f

0.64, 0.36 g (42%), cardanol, (2) R_f0.27, 0.32 g

(37.6%, conversion on cardanol used, 71.2%),

2-hydroxymethyl-5-mixed unsaturated pentade-

cylphenol, unsaturated isoanacardic alcohol, (3)

R_f0.15, 0.03 g (6.7%), which appears to be

4-hydroxymethyl-5-mixed unsaturated pentade-

cylphenol, (4) R_f0.03, 0.06 g (12.2%), from

spectroscopy, 2,4-dihydroxymethyl-5-mixed un-

saturated pentadecylphenol, m/z, 362.5, (5) base-

line, probably polymer; for (band 2): ν_max(ﬁlm,

cm⁻¹), 3200, 1200 (OH), 1660 (C O), 1520

(C C), 1380 (C–O); δ_H(CCl₄), 0.73–1.0 (Me, t),

1.09–1.47[(CH₂)_nm], 1.7–2.17 (CH₂CH CH,

m), 2.37–2.80 [CH₂Ar and CH₂(CH CH)₂, m],

4.67–5.03 (CH₂CH, m), 5.06–5.37 (CH CH,

m), 6.50–6.70 (HAr, s on d, J 8 Hz, 2H),

7.10–7.30 (HAr, d, J 8 Hz, 1H), 9.97 (ArCHO, s,

1H), 10.77 (HOAr, s, D₂O exch.); m/z, M⁺(%),

332.4 (6.8), 330.4 (29.1), 328.4 (16.8), 326.4

(18.0). Attempts to purify the aldehyde by vac-

uum distillation rather than chromatographically

were not successful due to polymerisation.

=

(iv) Borohydride reduction: The aldehyde (10.01 g,

0.03 mol) in methanol (100 cm³) was cooled to

0 ^◦C and then treated with sodium borohydride

cm⁻¹), 3350, 1190, 1020 (OH), 1620 (C C),

=

186

J.H.P. Tyman, S.K. Mehet / Chemistry and Physics of Lipids 126 (2003) 177–199

(2.30 g, 0.06 mol) in small portions while the tem-

The alkyltriphenylphosphonium bromide was pre-

pared by reﬂuxing the 1-bromoalkane (0.50 mol) and

triphenylphosphine (0.50 mol) in o-xylene (200 cm³)

with monitoring by TLC (solvent G). Upon com-

pletion of reaction the solvent was decanted from

the cooled mixture and the product was washed

with 60–80 ^◦C light petroleum (2 × 200 cm³) and

the solvent removed in vacuo to yield the salt as a

viscous oil. The stirred phosphonium salt (0.20 mol)

in dry THF (200 cm³) under nitrogen was treated

with a hexane solution of butyllithium (0.20 mol).

3-Hydroxybenzaldehyde (0.20 mol) in dry THF

(250 cm³) was then added to the phosphoran over

30 min. The reaction mixture changed in colour from

wine-red to yellow and after removal of the solvent in

vacuo, the residual dark yellow viscous oil in ethereal

solution was washed with aqueous sodium metabisul-

phite (2 × 200 cm³) to remove residual aldehyde. The

ethereal solution was dried (magnesium sulphate), ﬁl-

tered, concentrated and the crude product puriﬁed by

dry-column ﬂash chromatography (chloroform/ethyl

acetate with gradient elution) to remove triph-

enylphosphine oxide. The 1-(3-hydroxyphenyl)alk-1-

ene (0.06 mol) in ethanol (200 cm³) was hydrogenated

in the presence of 5% palladium on charcoal (25% of

the weight of alkene) at ambient pressure and tem-

perature with TLC monitoring (solvent H). Removal

of the catalyst by ﬁltration and evaporation of the

solvent in vacuo left the required 3-n-alkylphenol.

perature was maintained at 0 ^◦C. The mixture was

allowed to warm to ambient temperature over

16 h, monitored by TLC (solvent E) and upon

completion of reduction, extracted with diethyl

ether (200 cm³). The ethereal extract was washed

with dilute sulphuric acid (4×150 cm³), then with

saturated brine (5×150 cm³), dried with magne-

sium sulphate, ﬁltered and concentrated to give

an oil which was puriﬁed by dry-column ﬂash

chromatography (chloroform/ethyl acetate with

gradient elution) to afford a waxy solid (8.31 g,

82.5%); R_f0.37 (solvent B), identical chromato-

graphically and spectroscopically with the prod-

uct of methylolation and hydride reduction.

2.5.8. 2-Hydroxymethyl-3-undecylphenol (6)

Anagigantic acid (0.92 g, 0.003 mol) in THF was

reduced by addition to lithium aluminium hydride

(0.35 g, 0.009 mol) in THF as with the previous re-

ductions.

The reaction mixture was worked up as before

and the crude product crystallised (light petroleum)

to give 2-hydroxymethyl-3-undecylphenol as cream

crystals (0.48 g, 55.2%), mp 50.3–51.5 ^◦C; R_f0.28

(solvent B); ν_max(KBr, cm⁻¹), 3500, 1000 (OH, pri-

=

mary OH), 3180, 1210 (OH, phenol), 1620 (C C),

1380, 1260 (C–O); δ_H(CDCl₃), 0.76–1.47 [(CH₂)_n,

Me, m, 21H], 2.67–3.06 (CH₂Ar, HOCH₂Ar, s and t,

1H, D₂O exch.), 4.82 (HOCH₂Ar, s, 2H), 6.50–7.40

(HAr and HOAr, m, 4H, 1H, D₂O exch.); m/z, M⁺

(%), 278.1 (62.0). C₁₈H₃₀O₂requires 278.4, M⁺+ 1

279.1 (10.1).

2.6.2. 3-n-butylphenol (10, R¹= n-Bu)

1-Bromopropane (34.81 g, 0.28 mol) and triph-

enylphosphine (74.24 g, 0.28 mol) formed n-propyltri-

phenylphosphonium bromide (104.20 g, 95.6%)

which in THF was treated with a hexane solution of

n-butyllithium (230 cm³, 0.27 mol) and then with 3-

hydroxybenzaldehyde (33.06 g, 0.27 mol) in THF. The

puriﬁed product, 1-(3-hydroxyphenyl)but-1-ene (17.9,

44.7%), was obtained as a yellow oil; R_f0.80 (solvent

2.6. Synthesis of 1,3-diols from homologous

3-alkylphenols by formylation and reduction of

2-hydroxy-4-alkylbenzaldehydes

2.6.1. Synthesis of 3-alkylphenols

H); ν_max(ﬁlm, cm⁻¹), 3200 (OH), 1590 (C C), 1300,

=

This range of compounds was synthesised by the

Wittig reaction (Maercker, 1965) of 3-hydroxybenzal-

dehyde and the appropriate alkylidenetriphenylphos-

phoran, generated from the phosphonium salt with

butyllithium, to give the corresponding unsaturated

phenol which was hydrogenated to the required 3-

alkylphenol. Formylation followed by sodium boro-

hydride reduction afforded the 1,3-diol in the series of

homologous 2-hydroxymethyl-4-alkylphenols.

=

970 (CH CH); δ_max1-(3-hydroxyphenyl)but-1-ene

(6.70 g, 0.045 mol) was hydrogenated in the presence

of 5% Pd–C (1.70 g) to give a light brown oil (6.47 g,

95.8%) which showed a single band, R_f0.81 (solvent

H, argentation TLC); ν_max(ﬁlm, cm⁻¹), 3300, 1180

=

(OH), 2850–2950 (CH), 1590 (C C), 1490 (CH₂

def.); δ_H(CDCl₃), 0.67–1.73 [(CH₂)₂, Me, m, 7H],

2.30–2.67 (CH₂Ar, t, J 7 Hz, 2H), 6.40–8.20 (HAr

J.H.P. Tyman, S.K. Mehet / Chemistry and Physics of Lipids 126 (2003) 177–199

187

and HOAr, m, with bs, 5H, 1H, D₂O exch.); m/z, M⁺

(%), 150.1 (29.3), M⁺+ 1, 151.1 (3.1), M⁺–CHEt,

108.1 (100), M⁺required for C₁₀H₁₄O, 150.2.

D₂O exch.); m/z, M⁺(%), 220.4 (11.1). Required for

C₁₅H₂₄O, 220.3, M⁺+ 1, 221.4 (1.7), M⁺–C₇H₁₅,

121.2 (8.6), M⁺–C₈H₁₆, 108.2 (100), M⁺–C₈H₁₇,

107.2 (29.5).

2.6.3. 3-n-Octylphenol (10, R¹= C₈H₁₇)

1-Bromoheptane (21.48 g, 0.12 mol) and triph-

enylphosphine (31.44 g, 0.12 mol) formed the phos-

phonium salt heptyltriphenylphosphonium bromide

(47.25 g, 89.3%). The salt (46.60 g, 0.10 mol)

with n-butyllithium (74.44 cm³, 0.10 mol) and 3-

hydroxybenzaldehyde (12.00 g, 0.10 mol), reacted

by the general method, afforded, after puriﬁca-

tion by dry-column ﬂash chromatography, 1-(3-

hydroxyphenyl)oct-1-ene as a yellow oil (11.27 g,

52.3%) showing a single band, R_f0.59 (solvent H).

Hydrogenation of 1-(3-hydroxyphenyl)oct-1-ene

(19.00 g, 0.09 mol) in the presence of 5% Pd–C

(4.75 g) gave 3-n-octylphenol, as a golden oil (8.26 g,

43.0%) showing one band by TLC, R_f0.72 (solvent

H, argentation TLC); ν_max(ﬁlm, cm⁻¹), 3350, 1180

2.6.5. 3-n-Undecylphenol (10, R¹= C₁₁H₂₃)

By the general method, 1-bromodecane (60.00 g,

0.27 mol) with triphenylphosphine (71.26 g, 0.27 mol)

formed the salt, n-decyltriphenylphosphonium

bromide (114.90 g, 87.5%). The salt (100.00 g,

0.21 mol), n-butyllithium (138 cm³, 0.21 mol) and

3-hydroxybenzaldehyde (25.01 g, 0.21 mol) afforded

1-(3-hydroxyphenyl)undec-1-ene, puriﬁed as with

the other compounds to give a golden oil (18.50 g,

36.7%) showing a single band by TLC, R_f0.57

(solvent A).

1-(3-Hydroxyphenyl)undec-1-ene (17.03 g, 0.07

mol) was hydrogenated in the presence of 5% Pd–C

(4.25 g) to give 3-n-undecylphenol as a yellow oil

(10.95 g, 63.8%) having a single band by argenta-

tion TLC, R_f0.58 (solvent A); ν_max(ﬁlm, cm⁻¹),

=

(OH), 2850–2950 (CH), 1590 (C C), 1480 (CH₂

def.); δ_H(CDCl₃), 0.67–1.73 [(CH₂)₆, Me, m, 15H],

2.50 (CH₂Ar, t, J 7 Hz, 2H), 5.57 (HOAr, bs, 1H,

D₂O exch.), 6.43–7.20 (HAr, m, 4H); m/z, M⁺(%),

206.1 (55.7). Required for C₁₄H₂₂O, 206.3, M⁺+ 1,

207.1 (8.9), M⁺–C₄H₉, 149.1 (9.5), M⁺–C₇H₁₄,

108.1 (70.2), M⁺–C₇H₁₅, 107.1 (18.1).

=

3350, 1160 (OH), 2870–2980 (CH ), 1600 (C C),

1490 (CH₂def.), 1380 (C–O); δ_H(CDCl₃), 0.67–1.67

[(CH₂)₉, Me, m, 21H], 2.33–2.67 (CH₂Ar, t, J 7 Hz,

2H), 6.50–7.90 (HAr and HOAr, m, 5H, 1H, D₂O

exch.); m/z, M⁺(%), 248.3 (5.5). Required for

C₁₇H₂₈O, 248.4, M⁺+ 1, 249.3 (1.0), M⁺–C₉H₁₉

121.1 (9.1), M⁺–C₁₀H₂₀, 108.1 (100), M⁺–C₁₀H₂₁,

107.1 (32.3).

2.6.4. 3-n-Nonylphenol (10, R¹= C₉H₁₉)

By the general procedure, 1-bromooctane (100.0 g,

0.518 mol) and triphenylphosphine (135.72 g,

0.518 mol) gave the phosphonium salt, n-octyltriphen-

ylphosphonium bromide (208.0 g, 88.25%). The

salt (90.0 g, 0.198 mol), n-butyllithium (132 cm³,

0.198 mol) and 3-hydroxybenzaldehyde (24.16 g,

0.198 mol), by the general method with ﬁnal puriﬁ-

cation by dry-column ﬂash chromatography, gave 1-

(3-hydroxyphenyl)non-1-ene as a golden oil (20.36 g,

47.2%) having a single band by TLC, R_f0.71

(solvent A).

1-(3-Hydroxyphenyl)non-1-ene (14.40 g, 0.066 mol)

was hydrogenated in the presence of 5% Pd–C (3.63 g)

to afford a golden oil (11.56 g, 79.0%) showing a sin-

gle band, R_f0.71 (solvent A, argentation TLC); ν_max

(ﬁlm, cm⁻¹), 3200, 1170 (OH), 2850–2990 (CH),

2.7. Synthesis of 2-hydroxy-, 3-alkyl-, 4-alkyl- and

5-alkylbenzaldehydes by formylation of 2-, 3-, and

4-alkylphenols, respectively

In a general method, ethyl magnesium bromide

prepared from bromoethane (0.01 mol) in dry diethyl

ether (10 cm³) and magnesium turnings (0.015 mol) in

diethyl ether (10 cm³) was added to a stirred solution

of the alkylphenol (0.01 mol) in diethyl ether (20 cm³)

and the mixture reacted at ambient temperature for

16 h. After removal of the ether, dry benzene (50 cm³)

was added to the phenoxymagnesium bromide, then

paraformaldehyde (0.025 mol) followed by hexam-

ethylphosphoramide, HMPA (0.01 mol). The resulting

mixture was reﬂuxed for 4–6 h with monitoring by

TLC (solvent E). The mixture was cooled, acidiﬁed

with dilute sulphuric acid, extracted with diethyl ether

=

1590 (C C), 1470 (CH₂def.); δ_H(CCl₄), 0.67–1.73

[(CH₂)₇, Me, m, 17H], 2.23–2.63 (CH₂Ar, t, J 7 Hz,

2H), 6.30–8.30 (HAr and HOAr, m and bs, 5H, 1H,

188

J.H.P. Tyman, S.K. Mehet / Chemistry and Physics of Lipids 126 (2003) 177–199

(100 cm³), and the combined extracts washed with

saturated brine (4 × 100 cm³), dried with magnesium

sulphate, and evaporated in vacuo to give the product

which was puriﬁed by column chromatography.

By this methodology, aldehydes were synthe-

sised from 2-n-nonylphenol, 3-n-butylphenol, 3-t-

butylphenol, 2-(1,1,3,3-tetramethylbutyl)phenol, 3-

n-nonylphenol, 3-n-undecylphenol, 4-t-butylphenol,

4-(1,1,3,3-tetramethylbutyl)phenol, 4-n-nonylphenol,

4-(3,5,5-trimethylhexyl)phenol and 2-chloro-4-(1,1,3,

3-tetramethylbutyl)phenol.

2.7.3. 2-Hydroxy-4-n-octylbenzaldehyde

(11, R¹= C₈H₁₇)

3-n-Octylphenoxymagnesium bromide was pre-

pared from bromoethane (1.0 cm³, 0.014 mol), magne-

sium turnings (0.46 g, 0.019 mol) and 3-n-octylphenol.

The addition and reaction with paraformaldehyde

(1.61 g, 0.035 mol) in the presence of HMPA (2.3 cm³,

0.014 mol) gave the product which was puriﬁed as

before to give a yellow oil (1.79 g, 53.6%); R_f0.69

(solvent E); ν_max(ﬁlm, cm⁻¹), 3250, 1210 (OH),

=

1690 (C O), 1590 (C C), 1380 (C–O); δ_H(CDCl₃),

0.72–1.47 [(CH₂)₆, Me, m, 15H], 2.40–2.73 (CH₂Ar,

t, J 7 Hz, 2H), 6.60–7.40 (HAr, m, 3H), 9.63 (CHO,

s, 1H), 10.83 (HOAr, s, 1H, D₂O exch.); m/z, M⁺

(%), 234.3 (7.4), M⁺+ 1, 235.3 (1.3). Required for

C₁₅H₂₂O₂234.3.

2.7.1. 2-Hydroxy-4-alkylbenzaldehydes

2.7.1.1. 2-Hydroxy-4-n-butylbenzaldehyde

(11, R¹= n-Bu). 3-n-Butylphenoxymagnesium bro-

mide was prepared by the general method from

bromoethane (1.5 cm³, 0.02 mol) magnesium turn-

ings (0.60 g, 0.025 mol), and 3-n-butylphenol (3.00 g,

0.02 mol). Paraformaldehyde (2.30 g, 0.05 mol) and

HMPA (3.5 cm³) were added and reaction afforded the

product which was puriﬁed by column chromatogra-

phy on silica gel G (60–80 ^◦C light petroleum/diethyl

ether with gradient elution to give a yellow oil (1.81 g,

50.8%); R_f0.65 (solvent E); ν_max(ﬁlm, cm⁻¹), 3200,

2.7.4. 2-Hydroxy-4-n-nonylbenzaldehyde

(11, R¹= C₉H₁₉)

3-n-Nonylphenoxymagnesiumbromide

obtained

from bromoethane (0.37 cm³, 0.005 mol) magnesium

turnings (0.24 g, 0.01 mol) and 3-nonylphenol (1.00 g,

0.005 mol) was treated with paraformaldehyde (0.58 g,

0.013 mol) and HMPA (0.90 cm³, 0.005 mol) and

reacted to afford the crude product which was puri-

ﬁed by dry-column ﬂash chromatography (40–60 ^◦C,

light petroleum/diethyl ether, with gradient elution),

to give a yellow oil (0.61 g, 54.0%); R_f0.72 (solvent

=

1180 (OH), 1690 (C O), 1590 (C C), 1380 (C O);

δ_H(CCl₄) 0.70–1.76 [(CH₂)₂, Me, m, 7H], 2.40–2.70

(CH₂Ar, t, J 7 Hz, 2H), 6.53–7.40 (HAr, m, 3H), 9.70

(CHO, s, 1H), HOAr, s, 1H, D₂O exch.); m/z, M⁺

(%), 178.4 (39.7), M⁺+ 1, 179.4 (5.4). M⁺, required

for C₁₁H₁₄O₂, 178.2.

E); ν_max(ﬁlm, cm⁻¹), 3300, 1220 (OH), 1680 (C O),

=

1580 (C C), 1390 (C–O); δ_H(CCl₄), 0.73–1.47

[(CH₂)₇, Me, m, 17H], 2.3–2.63 (CH₂Ar, t, J 7 Hz,

2H), 6.57–7.17 (HAr, m, 3H), 9.57 (CHU, s, 1H),

10.47 (OH, s, D₂O exch.); m/z, M⁺(%), 248.4 (30.9),

M⁺+ 1 (249.4 (3.5). Required for C₁₆H₂₄O₂, 248.4.

2.7.2. 2-Hydroxy-4-t-butylbenzaldehyde

(11, R¹= t-Bu)

3-t-Butylphenoxymagnesium bromide was pre-

pared from bromoethane (5.3 cm³, 0.07 mol), magne-

sium turnings (1.80 g, 0.075 mol) and 3-t-butylphenol

(10.00 g, 0.07 mol). Formylation was effected with

paraformaldehyde (7.71 g, 0.175 mol) and HMPA

(11.7 cm³, 0.07 mol) and the crude product was puri-

ﬁed as before to afford a yellow oil (9.34 g, 78.7%);

R_f0.66 (solvent E); ν_max(ﬁlm, cm⁻¹), 3200, 1190

2.7.5. 2-Hydroxy-4-n-undecylbenzaldehyde

(11, R¹= C₁₁H₂₃)

3-n-Undecyl phenoxy magnesium bromide was

prepared from bromoethane (1.0 cm³, 0.014 mol)

magnesium turnings (0.46 g, 0.019 mol) and 3-n-

undecylphenol (3.50 g, 0.014 mol). Treatment with

paraformaldehyde (1.61 g, 0.035 mol) and HMPA

(2.3 g, 0.014 mol) gave, upon reaction, the crude prod-

uct which was recrystallised from light petroleum, to

give cream needles (2.05 g, 52.7%); R_f0.74 (solvent

=

(OH), 1690 (C O), 1620 (C C), 1380 (C–O); δ_H

(CCl₄) 1.26 (Me₃C, s, 9H), 6.77–7.33 (HAr, m, 3H),

9.67 (CHO, s, 1H), 10.77 (HOAr, s, 1H, D₂O exch.);

m/z, M⁺(%), 178.5 (49.3). Calculated for C₁₁H₁₄O₂,

178.2.

E); ν_max(ﬁlm, cm⁻¹), 3300, 1210 (OH), 1690 (C O),

=

1590 (C C), 1390 (C–O); δ_H(CCl₄), 0.83–1.37

[(CH₂)₉, Me, m, 21H], 2.57 (CH₂Ar, t, J 7 Hz,

J.H.P. Tyman, S.K. Mehet / Chemistry and Physics of Lipids 126 (2003) 177–199

189

2H), 6.67–7.47 (HAr, m, 3H), 9.83 (CHO, s, 1H),

10.93 (HO, s, 1H, D₂O exch.); m/z, M⁺(%), 276.0

(11.1), M⁺+ 1 277.0 (3.6). Required for C₁₈H₂₈O₂,

276.2.

88–100 ^◦C/1.0 mmHg, which was crystallised (light

petroleum) to afford white platelets, mp 38–40 ^◦C

(50.98 g, 27.7%); R_f0.63 (solvent E); ν_max(KBr disc,

cm⁻¹), 3540, 1190 (OH, phenol), 1610 (C C), 1370

=

(C–O), 760 (CH, 1,2-disubstituted ring); δ_H(CDCl₃),

0.77 (Me₃CH₂–, s, 9H), 1.43 (Me₂CAr–, s, 6H),

1.90 (CH₂CMe₂–, s, 2H), 4.67 (HOAr, s, 1H, D₂O

exch.), 6.27–7.17 (HAr, m, 4H); m/z, M⁺(%) 206.3

(7.6), M⁺+ 1 207.3, 1.1). Calculated for C₁₄H₂₂O,

206.1670. Found, 206.1669.

2.8. 2-Alkylphenols

2.8.1. 2-n-Nonylphenol (13)

In the same way as for 3-alkylphenols, 2-nonyl-

phenol was synthesised by the Wittig reaction.

1-Bromooctane (50.00 g, 0.259 mol) and triphenyl-

phosphine (67.86 g, 0.259 mol) formed n-octyltriphen-

ylphosphonium bromide (116.32 g, 98.7%). The salt

(75.00 g, 0.165 moll), n-butyllithium (103.2 cm³,

0.165 mol), and 2-hydroxybenzaldehyde (20.13 g,

0.165 mol) were reacted to give, after puriﬁcation by

dry-column ﬂash chromatography (60–80 ^◦C, light

petroleum/chloroform and gradient elution), a yellow

oil, 1-(2-hydroxyphenyl)non-1-ene (20.45 g, 56.8%);

R_f0.88 (solvent A).

1-(2-Hydroxyphenyl)non-1-ene (20.00 g, 0.092

mol) was hydrogenated in the presence of 10% Pd–C

(2.50 g) to afford a yellow oil, 2-n-nonylphenol,

showing, after puriﬁcation, a single band (16.26 g,

80.6%); R_f0.55 (solvent A, argentation TLC); ν_max

(ﬁlm, cm⁻¹), 3400, 1170 (OH), 2850–2990 (CH),

2.9. 2-Hydroxy-3-alkylbenzaldehydes

2.9.1. 2-Hydroxy-3-n-nonylbenzaldehyde (14)

2-n-Nonylphenoxy magnesium bromide was pre-

pared from bromoethane (1.3 cm³, 0.017 mol),

magnesium turnings (0.53 g, 0.022 mol), and 2-n-

nonylphenol (3.80 g, 0.017 mol) and formylated by

reaction with paraformaldehyde (1.95 g, 0.0425 mol)

and HMPA (2.80 cm³, 0.017 mol) to give the product

which was puriﬁed by dry-column ﬂash chromatog-

raphy (40–60 ^◦C, light petroleum/diethyl ether with

gradient elution), to give a yellow oil (1.80 g, 42.0%);

R_f0.68 (solvent E); ν_max(ﬁlm, cm⁻¹), 3200, 1220

=

(OH), 1690 (C O), 1590 (C C), 1390 (C–O); δ_H

(CCl₄), 0.67–1.53 [(CH₂)₇, Me, m, 17H], 1.93–2.27

(CH₂Ar, t, J 7 Hz, 2H) (HAr, m, 3H), 9.50 (CHO, s,

1H), 11.1 (HOAr, s, 1H, D₂O exch.); m/z, M⁺(%),

248.2 (3). Calculated for C₁₆H₂₄O₂, 248.4.

=

1600 (C C), 1470 (CH₂def.), 1370 (C–O); δ_H

(CDCl₃) 0.70–1.50 [(CH₂)₇, Me, m, 17H], 1.77–2.27

(CH₂Ar, t, J 7 Hz, 2H), 6.30–7.93 (HAr and HOAr,

m, 5H, 1H, D₂O exch.); m/z, M⁺(%), 220.4 (11.6).

Required for C₁₅H₂₄O, 220.3, M⁺+ 1, 211.4

(7.6).

2.9.2. 2-Hydroxy-3-(1,1,3,3-tetramethylbutyl)

benzaldehyde (17)

2-(1,1,3,3-Tetramethylbutyl)phenoxymagnesium

bromide obtained from bromoethane (0.75 cm³,

0.011 mol), magnesium turnings (0.38 g, 0.016 mol)

2.8.2. 2-(1,1,3,3-Tetramethylbutyl)phenol (Laan and

Ward, 1987) (16)

To melted phenol (104.45 g, 1.11 mol) at 41 ^◦C,

aluminium turnings (1.04 g, 1%) were added. Hydro-

gen evolution occurred and a rise in temperature to

165 ^◦C after which the mixture was cooled to 100 ^◦C

and treated with 2,4,4-trimethylpent-1-ene (99.86 g,

0.89 mol). The colour changed to red-brown and the

temperature was maintained at 100–110 ^◦C during

TLC monitoring. After no further change the cooled

mixture was diluted with water (50 cm³) and ex-

tracted with chloroform (100 cm³). The extract was

washed with dilute sulphuric acid (3 × 50 cm³), then

with dilute NaOH (3 × 50 cm³), dried, ﬁltered and

concentrated in vacuo to give a viscous yellow oil, bp

and

2-(1,1,3,3-tetramethylbutyl)phenol

(2.00 g,

0.011 mol) was formylated by the addition of

paraformaldehyde (1.27 g, 0.027 mol) and HMPA

(1.91 cm³, 0.011 mol) to give after reaction the prod-

uct as a yellow oil (1.27 g, 55.9%), which was pu-

riﬁed as before; R_f0.71 (solvent E); ν_max(ﬁlm,

cm⁻¹), 3400, 1250 (OH), 1710 (C O), 1600 (C C),

1390 (C–O); δ_H(CCl₄), 0.67 (Me₃C, s, 9H), 1.37

(Me₂CAr–, s, 6H), 1.90 (CH₂, s, 2H), 6.37–7.37

(HAr, m, 3H), 9.50 (CHO, s, 1H), 11.53 (OH, s,

1H, D₂O exch.); m/z, M⁺(%) 234.2 (4.3). Calcu-

lated for C₁₆H₂₄O₂, 248.4, 2-hydroxy-3-(1,1,3,3-

tetramethylbutyl)phenol.

=

190

J.H.P. Tyman, S.K. Mehet / Chemistry and Physics of Lipids 126 (2003) 177–199

(ﬁlm, cm⁻¹), 3300, 1210 (OH), 1680 (C O), 1590

2.10. 2-Hydroxy-5-alkylbenzaldehtdes

=

(C C), 1380 (C–O); δ_H(CCl₄), 0.79–1.68 [(CH₂)₇,

2.10.1. 2-Hydroxy-5-t-butylbenzaldehyde

(18, R = t-Bu)

Me, m, 17H], 2.50–2.68 (CH₂Ar, t, J 7 Hz, 2H),

6.73–7.43 (HAr, m, 3H), 9.75 (CHO, s, 1H), 10.95

(OH, s, 1H, D₂O exch.); m/z, M⁺(%), 248.4 (3.2),

M⁺+ 1, 249.4 (3.9). Calculated for C₁₆H₂₄O₂,

248.4.

4-t-Butylphenoxymagnesium bromide was pre-

pared from bromoethane (4.9 cm³, 0.066 mol), magne-

sium turnings (1.70 g, 0.071 mol) and 4-t-butylphenol

(10.00 g, 0.066 mol). Formylation by reaction with

paraformaldehyde (7.59 g, 0.165 mol) and HMPA

(11.5 cm³, 0.066 mol) afforded the product which

was puriﬁed by dry-column ﬂash chromatography, as

before, to give a yellow oil (9.90 g, 83.5%), R_f0.75

(solvent E); ν_max(ﬁlm, cm⁻¹), 3200, 1180 (OH),

2.10.4. 2-Hydroxy-5-(3,5,5-trimethylhexyl)

benzaldehyde (18, R = t-C₉H₁₉)

(i) 4-(3,5,5-Trimethylhexyl)phenoxymagnesium

bromide obtained from the reaction of bro-

moethane (3.4 cm³, 0.045 mol), magnesium

turnings (1.20 g, 0.05 mol) and 4-(3,5,5-trimethyl-

hexyl)phenol (10.00 g, 0.045 mol) was formy-

lated by reaction with paraformaldehyde (5.18 g,

0.09 mol) and HMPA (7.8 cm³, 0.045 mol). The

crude product was puriﬁed by column chro-

matography on silica gel G to give a pale yel-

low oil (8.26 g, 73.3%), R_f0.69 (solvent E);

ν_max(ﬁlm, cm⁻¹), 3200, 1180 (OH), 1680

=

1680 (C O), 1590 (C C), 1380 (C–O); δ_H(CCl₄),

1.23 (Me₃C, s, 9H), 6.50–7.30 (HAr, m, 3H), 9.47

(CHO, s, 1H), 10.37 (OH, s, D₂O exch.); m/z, M⁺

(%), 178.3 (22.8), M⁺+ 1 179.3 (3.0). Calculated for

C₁₁H₁₄O₂, 178.2.

2.10.2. 2-Hydroxy-5-(1,1,3,3-tetramethylbutyl)

benzaldehyde (18, R = t-C₈H₁₇)

4-(1,1,3,3-Tetramethylbutyl)phenoxymagnesium

bromide was obtained from bromoethane (8.9 cm³,

0.12 mol), magnesium turnings (3.00 g, 0.125 mol) and

4-(1,1,3,3-tetramethylbuytl)phenol (25.00 g, 0.12 mol)

and formylated by reaction with paraformaldehyde

(13.8 g, 0.30 mol) and HMPA (20.9 cm³, 0.12 mol)

to afford the crude product which was puriﬁed on

silica gel G by column chromatography, to give a

yellow oil (21.15 g, 74.5%), R_f0.71 (solvent E);

=

(C O), 1590 (C C), 1380 (C–O); δ_H(CCl₄),

0.67–2.20 (C₉H₁₉, m, 19H), 6.50–7.30 (HAr,

M, 3H), 9.47 (CHO, s, 1H), 10.40 (OH, s,

1H, D₂O exch.); m/z, M⁺(%), 248.3 (5.4),

M⁺+ 1, 249.1 (1.3). Required for C₁₆H₂₄O₂,

248.4.

(ii) This compound was also obtained by the acid

hydrolysis of the commercial reagent, Acorga (2-

hydroxy-5-(3,5,5-trimethylhexyl)benzaldoxime).

A 50:50 mixture of the oxime and nonylphenol

(30.0 g) and 20% aqueous sulphuric acid was

stirred and warmed at 60–65 ^◦C over 16 h, with

monitoring by TLC (solvent F). Upon comple-

tion of reaction, the cooled mixture was extracted

with diethyl ether (200 cm³).

ν_max(ﬁlm, cm⁻¹), 3200, 1190 (OH), 1680 (C O),

=

1590 (C C), 1370 (C–O); δ_H(CCl₄) (Me₃C, s,

9H), 1.23 (Me₂CAr–, s, 6H), 1.57 (CH₂, s, 2H),

6.50–7.47 (HAr, m, 3H), 9.53 (CHO, s, 1H), 1.47

(HO, s, 1H, D₂O exch.); m/z, M⁺(%), 234.5 (7.0),

M⁺+ 1 235.5 (1.1). Calculated for C₁₅H₂₂O₂,

234.3.

2.10.3. 2-Hydroxy-5-n-nonylbenzaldehyde

(18, R = n-C₉H₁₉)

The ethereal extract was washed with saturated

brine (4 × 100 cm³), dried (magnesium sulphate),

concentrated and the residue puriﬁed dry-column

ﬂash chromatography (light petroleum/diethyl ether

with gradient elution) to give 2-hydroxy-5-(3,5,5-

trimethylhexyl)benzaldehyde as a yellow oil (11.20 g,

79,2%) based on a 50% oxime/nonylphenol composi-

tion. The product was chromatographically and spec-

troscopically identical with the formylation product

(18).

4-n-Nonylphenoxy magnesium bromide was pre-

pared from bromoethane (0.67 cm³, 0.009 mol),

magnesium turnings (0.34 g, 0.014 pmol) and 4-

nonylphenol (2.00 g, 0.009 mol) and formylated by

reaction with paraformaldehyde (1.04 g, 0.023 mol)

and HMPA (1.6 cm³, 0.009 mol). The crude product

was puriﬁed by dry-column ﬂash chromatography

to give a yellow oil (1.86 g, 82.7%), R_f0.73; ν_max

J.H.P . T y man, S.K. Mehet / Chemistry and Physics of Lipids 126 (2003) 177–199

191

2.10.5. 2-Hydroxy-3-chloro-5-(1,1,3,3-

ethereal solution was washed with dilute sulphuric

acid (4 × 100 cm³), dried (magnesium sulphate) ﬁl-

tered and concentrated in vacuo to afford the crude

product which was puriﬁed either by column chro-

matography or recrystallisation.

tetramethylbutyl)benzaldehyde (20, R = t-C₈H₁₇)

Firstly, Scheme 3 (b), 4-(1,1,3,3-tetramethylbutyl)

phenol (15.01 g, 0.073 mol) in carbon tetrachloride

(300 cm³) was chlorinated at ambient temperature over

4 h (TLC monitoring, solvent J, to avoid dichlorina-

tion). After completion of reaction, air was admitted to

remove excess chlorine and the HCl formed. Concen-

tration gave a yellow oil (16.80 g, 96.0%). 2-Chloro-

4-(1,1,3,3-tetramethylbutyl)phenoxymagnesium bro-

mide was formed from the addition of ethyl magne-

sium bromide [prepared from bromoethane (8.72 cm³,

0.08 mol), in diethyl ether (75 cm³) and magnesium

turnings (2.88 g, 0.12 mol) in diethyl ether (50 cm³)] to

2-chloro-4-(1,1,3,3-tetramethylbutyl)phenol (19.46 g,

0.08 mol) in diethyl ether (100 cm³) and the stirred

reaction mixture was left at ambient temperature

for 16 h, after which the ether was removed by

distillation and replaced with benzene (100 cm³).

Paraformaldehyde (9.20 g, 0.20 mol) and HMPA

(13.9 cm³, 0.08 mol) were added and the mixture was

reﬂuxed for 6 h with TLC monitoring (solvent E).

The cooled mixture was acidiﬁed with dilute sul-

phuric acid, extracted with diethyl ether (200 cm³)

and the ethereal extract was washed with saturated

brine (5 × 150 cm³), dried with magnesium sulphate,

ﬁltered and concentrated in vacuo to give the crude

product. This was puriﬁed by column chromatography

on silica gel G (chloroform/60–80 ^◦C, light petroleum

with gradient elution). The product was obtained as

a yellow oil (18.05 g, 83.1%); R_f0.72 (solvent E);

2.11.1. 2-Hydroxymethyl-5-n-butylphenol

(12, R¹= n-Bu)

2-Hydroxy-4-n-butyl benzaldehyde (1.81 g, 0.01

mol) and sodium borohydride (0.76 mol), by the

general method, gave the crude product which was

recrystallised (60–80 ^◦C light petroleum) to afford

white needles, mp 66.7–67.6 ^◦C (1.10 g, 60.1%); R_f

0.15 (solvent C). Found, C, 73.29; H, 9.27. Required

for C₁₁H₁₆O, C, 73.30; H, 9.95%; ν_max(KBr disc,

cm⁻¹), 3440, 1000 (OH, pr. alc.), 3180, 1250 (OH,

=

phenol), 1620 (C C), 1410, 1280 (C–O); δ_H(CDCl₃),

0.86–1.80 [(CH₂)₂, Me, m, 7H], 2.0–2.67 (CH₂Ar,

HOCH₂, t on bs, 3H, D₂O exch.), 4.80 (HOCH₂Ar,

s, 2H), 6.57–6.97 (HAr, m, 3H), 7.20 (HOAr, s, 1H,

D₂O exch.); m/z, M⁺(%), 180.4 (18.4), M⁺+ 1,

181.4 (2.1), M⁺–H₂O, 162.4 (7.8).

2.11.2. 2-Hydroxymethyl-5-t-butylphenol

(12, R¹= t-Bu)

By the general procedure, 2-hydroxy-4-t-butylben-

zaldehyde (9.34 g, 0.05 mol) and sodium borohydride

(3.97 g, 0.10 mol) afforded the crude product which

was recrystallised (60–80 ^◦C light petroleum/benzene)

to give white ﬂuffy crystals, mp 95.9–96.3 ^◦C (6.51 g,

68.9%); R_f0.17 (solvent C). Found, C, 73.27; H,

8.67. Required for C₁₁H₁₆O, C, 73.30; H, 8.95%; ν_max

(KBr disc, cm⁻¹), 3350, 1000 (OH, pr. alc.), 3250,

ν_max(ﬁlm, cm⁻¹), 3420, 1180 (OH), 1670 (C O),

=

1610 (C C), 1370 (C–O); δ_H(CCl₄), 0.77 (Me₃C, s,

=

9H), 1.35 (CH₂, s, 2H), 7.3,7.3 (HAr, 2s, 2H), 9.60

(ArCHO, s, 1H), 10.83 (HOAr, s, 1H, D₂O exch.);

m/z, M⁺(%), 268.2 (5.2), 270.2 (1.7).

1210 (OH, phenol), 1590 (C C), 1360, 1290 (C–O);

δ_H(CDCl₃) 1.27 (Me₃C, s, 9H), 2.0 (HOCH₂Ar, bs,

1OH, D₂O exch.), 4.80 (HOCH₂Ar, s, 2H), 6.83–7.06

(HAr, m, 3H), 7.17 (HOAr, s, 1H, D₂O exch.); m/z,

M⁺(%), 180.2 (15.0), M⁺+ 1, 181.2 (1.4%).

2.11. Reduction of 2-hydroxy-3-, 4- and

5-alkylbenzaldehydes

2.11.3. 2-Hydroxymethyl-5-n-octylphenol

In a general method, a stirred solution of the alde-

hyde (0.005 mol) in methanol (30 cm³), cooled to

below 0 ^◦C (ice–salt bath), was slowly treated with

sodium borohydride (0.01 mol) while the reaction

temperature was kept below 0 ^◦C. The reaction mix-

ture was allowed to warm to ambient over 16 h and

completion of reduction monitored by TLC (solvent

E). After the addition of diethyl ether (100 cm³), the

(12, R¹= n-C₈H₁₇)

2-Hydroxy-4-n-benzaldehyde (0.93 g, 0.004 mol)

and sodium borohydride (0.30 g, 0.008 mol) gave the

crude product which was crystallised (40–60 ^◦C light

petroleum/diethyl ether) to give white needles, mp

85.8–86.6 ^◦C (0.50 g, 53.2%); R_f0.22 (solvent C).

Found, C, 76.38; H, 9.95. Required for C₁₅H₂₄O, C,

76.23; H, 10.24%; ν_max(KBr disc, cm⁻¹), 3440, 1000

192

J.H.P. Tyman, S.K. Mehet / Chemistry and Physics of Lipids 126 (2003) 177–199

C, 76.75; H, 10.47%; ν_max(ﬁlm, cm⁻¹), 3350 (OH),

=

(OH, pr. alc.), 3240, 1210 (OH, phenol), 1600 (C C),

1390, 1280; δ_H(CDCl₃), 0.86–1.53 [(CH₂)₆, Me, m,

15H], 2.13 (CH₂Ar, t, J 7 Hz, 2H), 2.50 (HOCH₂, bs,

1H, D₂O exch.), 4.70 (HOCH₂Ar, s, 2H), 6.63–7.17

(HAr, HO, m, 4H, 1H, D₂O exch.); m/z, M⁺(%),

235.9 (8.2), M⁺–H₂O, 218.0 (5.2).

=

1220, 1020 (OH, phenol, pr. alc.), 1600 (C C), 1380,

1260 (C–O); δ_H(CDCl₃), 0.83–1.45 [(CH₂)₇, Me, m,

17H], 2.15–2.23 (CH₂Ar, t, J 7 Hz, 2H), 2.25 (HO,

s, HOCH₂Ar, D₂O exch.), 4.77 (HOCH₂Ar, s, 2H),

6.07–7.33 (HAr, m, 3H), 7.52 (HOAr, s, 1H, D₂O

exch.); m/z, M⁺(%), 250.2 (20.3), M⁺+ 1, 251.2

(3.4), M⁺–H₂O, 232.2 (18.0).

2.11.4. 2-Hydroxymethyl-5-n-nonylphenol

(12, R¹= n-C₉H₁₉)

2-Hydroxy-4-n-nonyl benzaldehyde (1.86 g, 0.007

mol) and sodium borohydride (0.57 g, 0.014 mol) af-

forded the crude product which was recrystallised as

for the octyl compound to give white needles, mp

88.7–89.1 ^◦C (1.53 g, 81.8%); R_f0.35 (solvent E).

Found, C, 76.77; H, 10.38. Required for C₁₄H₂₆O,

C, 76.77; H, 10.47%; ν_max(KBr disc, cm⁻¹), 3440,

1000 (OH, pr. alc.), 3180, 1220 (OH, phenol), 1595

2.11.7. 2-Hydroxymethyl-6-(1,1,3,3-tetramethylbutyl)

phenol (15, R¹= t-C₈H₁₇)

2-Hydroxy-3-(1,1,3,3-tetramethylbutyl)benzaldeh-

yde (0.94 g, 0.004 mol), and sodium borohydride

(0.30 g, 0.008 mol) gave the crude product which was

puriﬁed by dry-column ﬂash chromatography (light

petroleum, diethyl ether with gradient elution) to give

white needles, mp 74.1–75.1 ^◦C (0.65 g, 68.7%), R_f

0.64 (solvent E). Found, C, 76.22; H, 10.52. Re-

quired for C₁₅H₂₄O, C, 76.23; H, 10.24%; ν_max(KBr

disc, cm⁻¹), 3400, 1090 (OH, pr. alc), 3180, 1250

=

(C C), 1410, 1280 (C–O); δ_H(CDCl₃) 0.87–1.45

[(CH₂)₇, Me, m, 17H], 1.56 (HOCH₂Ar, bs, 1H),

2.44–2.62 (CH₂Ar, t, J 7 Hz, 2H), 4.77 (HOCH₂Ar, s,

2H), 6.59–7.21 (HAr, HOAr, m, 4H, 1H, D₂O exch.);

m/z, M⁺(%), 250.1 (16.4), M⁺+ 1, 251.1 (2.1),

M⁺–H₂O, 232.0 (8.9).

=

(OH, phenol), 1620 (C C), 1410, 1280 (C–O, phenol

and pr. alc.); δ_H(CCl₄), 0.73 [ArCMe₂CH₂C(Me)₃,

s, 9H], 1.40 (ArCMe₂, s, 6H), 1.87 (HOCH₂Ar, s,

1H, D₂O exch.), 1.93 (ArCMe₂CH₂, s, 2H), 4.67

(HOCH₂Ar, s, 2H), 6.47–7.07 (HAr, m, 3H), 7.40

(HOAr, s, 1H, D₂O exch.); m/z, M⁺(%), 235.9 (6.7),

M⁺+ 1, 236.9 (1.0).

2.11.5. 2-Hydroxymethyl-5-n-undecylphenol

(12, R¹= n-C₁₁H₂₃)

2-Hydroxy-4-n-undecylbenzaldehyde

(2.05 g,

0.007 mol) and sodium borohydride (0.53 g, 0.014 mol)

gave the crude product which was recrystallised to ob-

tain white needles, mp 90.4–91.4 ^◦C (1.42 g, 68.9%);

R_f0.22 (solvent C). Found, C, 77.84; H, 10.86. Re-

quired for C₁₈H₃₀O, C, 77.66; H, 10.86%; ν_max(KBr

disc, cm⁻¹), 3450, 1000 (OH, pr. alc.), 3060, 1210

2.11.8. 2-Hydroxymethyl-4-t-butylphenol

(19, R = t-Bu)

2-Hydroxy-5-t-butylbenzaldehyde (9.90 g, 0.055

mol) and sodium borohydride (4.16 g, 0.10 mol) gave

the crude product which was recrystallised to give

white needles, mp 85.3–86.1 ^◦C (6.71 g, 67.6%); R_f

0.26 (solvent E). Found, C, 73.05; H, 8.70. Required

for C₁₁H₁₆O, C, 73.30; H, 8.95%; ν_max(KBr disc,

cm⁻¹), 3350, 1000 (OH, pr. alc.), 3250, 1200 (OH,

=

(OH, phenol), 1590 (C C), 1410, 1260 (C–O); δ_H

(CDCl₃) 0.87–1.74 [(CH₂)₉, Me, m, 21H], 2.34–2.61

(CH₂Ar, HOCH₂, t on bs, 3H, 1H, D₂O exch.), 4.76

(HOCH₂Ar, s, 2H), 6.57–7.10 (HAr HOAr, m, 4H,

1H, D₂O exch.); m/z, M⁺(%), 278.0 (36.6), M⁺+ 1,

279.1 (8.1).

=

phenol), 1590 (C C), 1380, 1290 (C–O); δ_H(CDCl₃),

1.23 (Me₃C, s, 9H), 2.0–2.23 (HOCH₂Ar, bs, 1H, D₂O

exch.), 4.63 (HOCH₂Ar, s, 2H), 6.47–7.03 (HAr and

HOAr, m, 4H, 1H, D₂O exch.); m/z, M⁺(%), 180.3

(19.6), M⁺+ 1, 181.3 (2.0), M⁺–H₂O, 162.3 (21.5).

2.11.6. 2-Hydroxymethyl-6-n-nonylphenol

(15, R¹= n-C₉H₁₉)

2-Hydroxy-3-n-nonylbenzaldehyde (1.17 g, 0.005

mol) and sodium borohydride (0.38 g, 0.01 mol) were

reacted by the general method and the crude product

puriﬁed by dry-column ﬂash chromatography to give

a pale yellow oil (0.91 g, 77.1%), R_f0.50 (solvent E).

Found, C, 76.87; H, 9.93. Required for C₁₆H₂₆O₂,

2.11.9. 2-Hydroxymethyl-4-(1,1,3,3-tetramethylbutyl)

phenol (19, R = t-C₈H₁₇)

2-Hydroxy-5-(1,1,3,3-tetramethyl)benzaldehyde

(15.46 g, 0.066 mol) with sodium borohydride (4.91 g,

J.H.P. Tyman, S.K. Mehet / Chemistry and Physics of Lipids 126 (2003) 177–199

193

0.13 mol) gave the crude product which was recrys-

tallised (40–60 ^◦C light petroleum/diethyl ether) to af-

ford white crystals, mp 83.5–84.4 ^◦C (12.73, 81.6%);

R_f0.20 (solvent E); ν_max(KBr disc, cm⁻¹), 3530,

1000 (OH, pr. alc.), 3260, 1180 (OH, phenol), 1610

(ii) From hydroxymethylation: To 4-(3,5,5-trimethyl-

hexyl)phenol (11.44 g, 0.052 mol), stirred and

heated to 60 ^◦C, 3 M sodium hydroxide (1 cm³)

was added, to raise the pH to 10–11, and then

37% aqueous formaldehyde (5.4 cm³, 0.067 mol)

The reaction mixture was stirred and heated

for 24 h, cooled, extracted with diethyl ether

(100 cm³) and the extract washed with dilute HCl

(2 × 100 cm³), saturated brine (3 × 100 cm³),

dried (magnesium sulphate), ﬁltered and con-

centrated to give the crude product which was

puriﬁed by dry-column ﬂash chromatography

(40–60 ^◦C, light petroleum/diethyl ether with gra-

dient elution) to afford a pale yellow oil (3.90 g,

30.0%) consisting of 2-hydroxymethyl-4-(3,5,5-

trimethylhexyl)phenol; R_f0.29 (solvent C); ν_max

=

(C C), 1380, 1270 (C–O); δ_H(CCl₄), 0.70 (Me₃C,

s, 9H), 1.27 (–Me₂CAr, s, 6H), 1.60 (–CH₂Me₂CAr,

s, 2H), 3.27 (HOCH₂Ar, bs, 1H, D₂O exch.), 4.57

(HOCH₂Ar, s, 2H), 6.43–7.0 (HAr, m, 3H), 7.33

(HOAr, bs, 1H, D₂O exch.). Found, M⁺, 236.1777.

Required for C₁₅H₂₄O, 236.1776; m/z, M⁺(%), 236.8

(34.5), M⁺+ 1, 237.9 (4.1).

2.11.10. 2-Hydroxymethyl-4-n-nonylphenol

(19, R = n-C₉H₁₉)

2-Hydroxy-5-n-nonylbenzaldehyde (0.61 g, 0.002

mol) and sodium borohydride (0.18 g, 0.004 mol) af-

forded the crude product which was recrystallised

(40–60 ^◦C, light petroleum/diethyl ether) to give

white platelets, mp 97.4–97.9 ^◦C (0.35 g, 57.4%); R_f

0.27 (solvent E). Found, C, 76.88; H, 10.68. Required

for C₁₆H₂₆O, C, 76.75; H, 10.47%; ν_max(KBr disc,

cm⁻¹), 3440, 1130 (OH, pr. alc.), 3170, 1220 (OH,

(ﬁlm, cm⁻¹), 3350 (OH), 1620 (C C), 1390,

=

1260 (C–O); δ_H(CCl₄), 0.37–1.57 (C₉H₁₉, m,

19H), 3.10–3.87 (HOCH₂Ar, bs, 1H, D₂O exch.),

4.50 (HOCH₂Ar, s, 2H), 6.33–6.93 (HAr and

HOAr, m, 4H, 1H, D₂O exch.); m/z, M⁺(%),

250.4 (19.8), M⁺+ 1, 251.4 (3.2). Calculated for

C₁₆H₂₆O₂, 250.1933. Found, 250.1932.

=

phenol), 1595 (C C), 1390, 1280 (C–O); δ_H(CDCl₃),

2.11.12. 2-Hydroxymethyl-6-chloro-4-(1,1,3,3-

tetramethylbutyl)phenol (21, R = t-C₈H₁₉)

0.77–1.67 [(CH₂)₇, Me, m, 17H], 1.83 (HOCH₂Ar,

s, 1H, D₂O exch.), 2.23–2.53 (CH₂Ar, t, J 7 Hz, 2H),

4.63 (HOCH₂Ar, s, 2H), 6.47–6.93 (HO and HOAr,

4H, 1H, D₂O exch.); m/z, M⁺(%), 250.1 (30.8),

M⁺+ 1, 251.1 (3.9), M⁺–H₂O, 232.1 (22.4).

2-Hydroxy-3-chloro-5-(1,1,3,3-tetramethylbutyl)

benzaldehyde (9.42 g, 0.035 mol) and sodium boro-

hydride (2.65 g, 0.07 mol), by the general method, af-

forded (TLC monitoring, solvent E) the crude product

which was puriﬁed by dry-column ﬂash chromatog-

raphy to give a pale yellow oil (7.34 g, 77.3%); R_f

0.35 (solvent E); ν_max(ﬁlm, cm⁻¹), 3340 (OH), 1610

2.11.11. 2-Hydroxymethyl-4-(3,5,5-trimethylhexyl)

phenol (19: R = t-C₉H₁₉)

=

(i) From reduction: 2-Hydroxy-5-(3,5,5-trimethy-

lhexyl)benzaldehyde (11.20 g, 0.045 mol) re-

acted with sodium borohydride (3.80 g, 0.90 mol)

afforded the crude product which was puri-

ﬁed by dry-column ﬂash chromatography (light

petroleum/diethyl ether with gradient elution)

to give a pale yellow oil (8.13 g, 63.7%); R_f

0.32 (solvent E); ν_max(ﬁlm, cm⁻¹), 3350 (OH),

1190 (OH, phenol), 1010 (OH, pr. alc.), 1260

(C C), 1370, 1260 (C–O), 1180, 1020 (OH, pr. alc.);

δ_H(CDCl₃) 0.73 (Me₃C, s, 9H), 1.27 (Me₂C–, s,

6H), 1.62 (CH₂CMe₂C–, s, 2H), 3.53 (HOCH₂Ar, s,

1H, D₂O exch.), 4.60 (HOCH₂Ar, s, 2H), 6.88–7.05

(HAr and HOAr, 3s, 3H, 1H, D₂O exch.); m/z, M⁺

(%), 270.3 (13.0), 272.4 (4.2). Found, M⁺, 270.1389.

Calculated for C₁₅H₂₃O₂Cl, 270.1386.

2.12. Synthesis of 2-hydroxymethyl-3-n-alkylphenols

from ethyl 2-methoxy-6-alkylbenzoates

=

(C C), 1390, 1620 (C–O); δ_H(CDCl₃), 0.43–1.83

(C₉H₁₉, m, 19H), 2.63 (HOCH₂Ar, bs, 1H, D₂O

exch.), 4.77 (HOCH₂Ar, s, 2H), 6.60–7.23 (HAr

and HOAr, m, 4H, 1H, D₂O exch.); m/z, M⁺(%),

250.1 (9.5), M⁺+ 1, 251.1 (1.2). Found, M⁺,

250.1934. Required for C₁₆H₂₆O, 250.1933.

2.12.1. Ethyl 2-methoxy-6-alkylbenzoates (22)

To lithium diisopropylamide (LDA), prepared

from diisopropylamine (0.14 mol) and n-butyllithium

(0.12 mol) in dry THF (40 cm³), under nitrogen, ethyl

194

J.H.P. Tyman, S.K. Mehet / Chemistry and Physics of Lipids 126 (2003) 177–199

2H), 6.3–6.96 (HAr, m, 3H); m/z, M⁺(%), 236.2

(38.9), M⁺+ 1, 237.2 (6.3). Required for C₁₄H₂₀O₃,

236.3.

Demethylation afforded a crude product which was

puriﬁed by dry-column ﬂash chromatography to give a

golden brown oil (1.49 g, 58.7%), ethyl 2-hydroxy-6-

n-butylbenzoate and a solid (white needles from 40 to

60 ^◦C, light petroleum), 2-hydroxy-6-n-butylbenzoic

acid, mp 114.2–115.0 ^◦C (0.51 g, 23.0%); for the es-

ter, R_f0.49 (solvent F); ν_max(ﬁlm, cm⁻¹), 3400,

2-methoxy-6-methylbenzoate (0.1 mol) in dry THF

(60 cm³) was added at −70 ^◦C. After reaction to com-

plete formation of the anion (deep red coloration)

during 30 min, HMPA (10% v/v of the total volume)

and the bromoalkane (0.13 mol) in dry THF (20 cm³)

were added at −70 ^◦C. The reaction mixture was left

for 4 h and then allowed to warm to ambient temper-

ature. To the now golden-brown solution, methylated

spirit (60 cm³) was added and after stirring for 6 h, the

mixture was acidiﬁed with excess 3 M sulphuric acid

and extracted with diethyl ether (2 × 200 cm³) fol-

lowed by ethyl acetate (2 × 200 cm³). The combined

extracts were washed with saturated sodium hydrogen

carbonate (2 × 200 cm³), then with saturated brine

(4 × 200 cm³), dried (magnesium sulphate), ﬁltered

and the ﬁltrate concentrated to afford the crude prod-

uct which was puriﬁed by column chromatography.

=

1220 (OH), 1650 (C O), 1600 (C C); δ_H(CDCl₃),

0.53–1.70 [(CH₂)₂, 2Me, 10H], 2.25–2.90 (CH₂Ar, t, J

7 Hz, 2H), 4.10–4.47 (OCH₂, q, J 7 Hz, 2H), 6.35–7.20

(HAr, m, 3H), 11.20 (HOAr, s, 1H, D₂O exch.); m/z,

M⁺(%), 222.2 (34.5), M⁺+ 1, 223.3 (6.4). Required

for C₁₃H₁₈O₃, 222.3; for the acid, R_f0.01 (solvent

F); ν_max(KBr disc, cm⁻¹), 3400, 1220 (OH), 2600,

=

1600 (OH, acid with internal H-bonding), 1650 (C O),

2.12.2. Ethyl 2-hydroxy-6-n-alkylbenzoates (23)

(ethyl 6-n-alkylsalicylates)

1440, 1310 (C–O); δ_H(CCl₄), 0.50–1.77 [(CH₂)₂, Me,

m, 7H], 2.53–2.93(CH₂Ar, t, J 7 Hz, 2H), 6.23–7.10

(HAr, m, 3H), 10.87 (OH, HO₂C, s, 2H, D₂O exch.);

m/z, M⁺(%), 194.1 (33.7), M⁺+ 1, 195.1 (4.4). Re-

quired for C₁₁H₁₄O₃, 194.2.

The alkylmethoxy derivatives (0.01 mol) in dry

dichloromethane (50 cm³) were demethylated at

−78 ^◦C with boron tribromide (0.02 mol) in dichlo-

romethane (20 cm³) and the mixture then allowed

to warm to ambient temperature over 16 h. The ex-

cess reagent was hydrolysed with water (25 cm³)

and the phenolic product extracted with diethyl ether

(100 cm³). The ethereal extract was washed with sat-

urated brine (3 × 100 cm³) until neutral, dried with

magnesium sulphate, ﬁltered and the solvent evap-

orated in vacuo. The crude product was puriﬁed by

column chromatography.

2.12.5. Ethyl 2-hydroxy-6-n-octylbenzoate

(23, R = n-C₇H₁₅)

By the general procedure, ethyl 2-methoxy-6-meth-

ylbenzoate (8.00 g, 0.041 mol) and 1-bromoheptane

(8.2 cm³, 0.052 mol) reacted to give the crude product

which was puriﬁed by dry-column ﬂash chromatogra-

phy to give a golden oil (5.93 g, 49.25%); ν_max(ﬁlm,

cm⁻¹), 1730 (C O), 1600 (C C), 126-, 1250 (C O,

ether and ester); δ_H(CDCl₃), 0.79–1.67 [(CH₂)₆,

2Me, m, 18H], 2.27–2.76 (CH₂Ar, t, J 7 Hz, 2H),

3.76 (MeO, s, 3H), 4.22–4.49 (OCH₂, q, J 7 Hz, 2H),

6.64–7.30 (HAr, m, 3H); m/z, M⁺(%), 292.1 (18.1),

M⁺+1, 293.1 (2.7), M⁺–OEt, 247.0 (24.7). Required

for C₁₈H₂₈O₃, 292.2.

=

2.12.3. 2-Hydroxymethyl-3-n-alkylphenols (24)

Ethyl 2-hydroxy-6-methylbenzoate and ethyl 2-

methoxy-6-methylbenzoate were prepared as de-

scribed (Hauser and Pogany, 1980).

2.12.4. Ethyl 2-hydroxy-6-n-butylbenzoate

(23, R = n-Pr)

Demethylation gave a cream coloured solid which

was puriﬁed by dry-column ﬂash chromatography

(60–80 ^◦C, light petroleum/chloroform with gradi-

ent elution to afford a yellow oil (3.10 g, 54.9%)

consisting of 2-hydroxy-6-n-octylbenzoate and 2-

hydroxy-6-n-octylbenzoic acid, mp 92.4–93.6 ^◦C

(1.57 g, 30.9%); for the ester, R_f0.44 (solvent F); ν_max

Ethyl 2-methoxy-6-n-butylbenzoate (4.00 g, 0.02

mol) and 1-bromopropane (2.4 cm³) gave the crude

product which was puriﬁed by dry-column ﬂash chro-

matography to give a golden oil (3.24 g, 66.5%); R_f

0.33 (solvent F); ν_max(ﬁlm, cm⁻¹), 1730 (C O),

=

1600 (C C), 1270, 1250 (C–O); δ_H(CCl₄), 0.83–1.37

[(CH₂)₂, 2Me, m, 10H], 2.26–2.50 (CH₂Ar, t, J 7 Hz,

2H), 3.6 (OMe, s, 3H), 3.9–4.26 (OCH₂, q, J 7 Hz,

(ﬁlm, cm⁻¹), 3400, 1220 (OH), 1650 (C O), 1600

=

(C C), 1320, 1250 (C–O); δ_H(CDCl₃), 0.80–1.63

J.H.P. Tyman, S.K. Mehet / Chemistry and Physics of Lipids 126 (2003) 177–199

195

[(CH₂)₆, 2Me, m, 18H], 2.53–2.97 (CH₂Ar, t, J 7 Hz,

2.13.2. 2-Hydroxymethyl-3-n-butylphenol

(24, R = n-Pr)

2H), 4.27–4.54 (OCH₂, q, 2H), 6.50–7.33 (HAr,

m, 3H), 11.13 (HOAr, s, 1H, D₂O exch.); m/z, M⁺

(%), 278.2 (17.9), M⁺–OEt, 232.2 (21.4). Required

for C₁₇H₂₆O₃, 278.4; for the acid, R_f0.04 (sol-

vent F); ν_max(KBr disc, cm⁻¹), 3400, 1220 (OH),

By the general method, ethyl 2-hydroxy-6-n-

butylbenzoate (1.91 g, 0.009 mol) and LAH (0.29 g,

0.03 mol) afforded the crude product. Similarly, 2-

hydroxy-6-n-butylbenzoic acid (0.51 g, 0.003 mol)

and LAH (0.98 g, 0.009 mol) gave the same prod-

uct which was puriﬁed by dry-column ﬂash chro-

matography (chloroform/ethyl acetate, with gradient

elution) to give white crystals (from 40 to 60 ^◦C,

light petroleum), mp 54.9–55.7 ^◦C (1.59 g, 96.5%);

R_f0.29 (solvent C). Found, C, 73.05; H, 8.70. Re-

quired for C₁₁H₁₆O₂, C, 73.30; H, 8.95%; ν_max(KBr

disc, cm⁻¹), 3300 (OH), 1210, 1030 (OH, phenol

=

2600, 1610 (OH, acid H-bonding), 1650 (C O), 1600

=

(C C), 1440, 1310 (C–O); δ_H(CDCl₃), 0.87–1.68

[(CH₂)₆, Me, m, 15H], 2.87–3.05 (CH₂Ar, t, J 7 Hz,

2H), 6.68–7.42 (HAr, m, 3H), 9.75–12.75 (HOAr

and HO₂C, 2H, D₂O exch.); m/z, M⁺(%), 250.2

(33.1), M⁺+ 1, 251.1 (4.6). Required for C₁₅H₂₂O₃,

250.3.

=

2.13. Reduction of ethyl 6-n-alkylsalicylates to

and pr. alc.), 1600 (C C), 1345, 1290 (C–O); δ_H

2-hydroxymethyl-3-n-alkylphenols (24)

(CDCl₃), [(CH₂)₂, Me, m, 7H], 2.09–2.73 (CH₂Ar, t,

J 7 Hz, 2H), 2.63–4.0 (HOCH₂Ar, s, 1H, D₂O exch.),

4.53–4.77 (HOCH₂Ar, s, 2H), 6.27–7.03 (HAr and

HOAr, m, 4H, 1H, D₂O exch.); m/z, M⁺(%), 180.1

(82.9), M⁺+ 1, 181.0 (9.4), M⁺–H₂O, 162.0 (49.3).

General method: The ethyl 2-hydroxy-6-n-

alkylbenzoate (0.01 mol) in dry THF (30 cm³) was

treated with an ice-cold suspension of lithium alu-

minium hydride (0.03 mol) in dry THF (20 cm³)

under nitrogen. After completion of reaction (TLC

monitoring) the excess reagent was destroyed with

ethyl acetate (ca. 1 cm³), the mixture was then acid-

iﬁed with 3 M HCl and extracted with diethyl ether

(100 cm³). The extract was washed with saturated

brine until neutral, dried (anhydrous sodium sulphate),

ﬁltered and concentrated to give a crude product

which was puriﬁed by dry-column ﬂash chromatogra-

phy. The method was also used for the corresponding

acid.

2.13.3. 2-Hydroxymethyl-3-n-octylphenol

(24, R = n-C₇H₁₅)

By the general procedure, ethyl 2-hydroxy-6-n-

octylbenzoate (3.10 g, 0.011 mol) and LAH (1.25 g,

0.033 mol), and similarly 2-hydroxy-6-n-octylbenzoic

acid (1.57 g, 0.006 mol) and LAH 0.68 g, 0.018 mol)

together gave the crude product. Puriﬁcation by dry-

column ﬂash chromatography gave a clear viscous

oil (combined batches, 2.79 g, 67.9%); R_f0.31 (sol-

vent C). Found, C, 76.08; H, 10.54. Required for

C₁₅H₂₄O₂, C, 76.23; H, 10.24%; ν_max(KBr disc,

cm⁻¹), 3300 (D₂O); m/z, M⁺(%), 236.1 (26.1),

M⁺+ 1, 237.1 (3.7), M⁺–H₂O, 218.2 (9.2) (OH),

2.13.1. 2-Hydroxymethyl-3-methylphenol

(24, R = H)

=

1190, 1040 (OH, phenol and pr. alc.), 1590 (C C),

By the general method ethyl 2-hydroxy-6-

methylbenzoate (1.70 g, 0.009 mol) and lithium alu-

minium hydride (1.02 g, 0.027 mol) gave a crude

product which was recrystallised (light petroleum)

to yield white crystals, mp 105.6–106.6 ^◦C (0.73 g,

56.1%); R_f0.23 (solvent C). Found, C, 69.25; H,

7.22. Calculated for C₈H₁₀O₃, C, 69.55; H, 7.10%;

ν_max(KBr disc, cm⁻¹), 3300 (OH), 1210, 1040 (OH,

1350, 1250 (C–O); δ_H(CDCl₃), [(CH₂)₆, Me, m,

15H], 2.44–2.62 (CH₂Ar and HOCH₂Ar, t, J 7 Hz,

2H and 1H, D₂O exch.), 4.85 (HOCH₂Ar, s, 2H),

6.60–7.20 (HAr and HOAr, m, 4H, 1H exch.).

3. Results and discussion

=

phenol and pr. alc.), 1600 (C C), 1330, 1290 (C–O);

3.1. Sources of phenolic lipids

δ_H(CDCl₃), 2.20 (MeAr, s, 3H), 2.45 (HOCH₂Ar, bs,

1H, D₂O exch.), 4.75 (HOCH₂Ar, s, 2H), 6.33–7.03

(HAr, m, 3H), 7.45 (HOAr, bs, 1H, D₂O exch.); m/z,

M⁺(%), 138.1 (46.2), M⁺+1, 139.1 (4.3), M⁺–H₂O,

120.0 (63.4).

The phenolic lipids (Fig. 1), from Anacardiaceae

sources all require puriﬁcation before semi-synthetic

usage (Tyman, 1995). Of the variety of methods avail-

able, the process of phase separation (Tyman et al.,

196

J.H.P. Tyman, S.K. Mehet / Chemistry and Physics of Lipids 126 (2003) 177–199

1992) is applicable to both the isolation of anacardic

acid and of cardanol, respectively, from natural and

technical CNSL since it is essentially a mild ambient

temperature method in which the highly unsaturated

constituents are preserved intact. Additionally, the

remaining component, namely cardol, is also simul-

taneously recoverable whereas in chemical or purely

thermal methods it is lost. Technical CNSL is avail-

able commercially but with natural CNSL, although

the technology exists to cut shells, while leaving the

edible nut uncontaminated, the subsequent solvent ex-

traction stage, or high pressure extrusion, has not yet

been achieved on a commercial scale (M. Grimminger,

Buhler-Miag Co., private communication). In a similar

way, urushiol is processed in Japan and China but not

generally available elsewhere. Thitsiol, the 4-alkenyl

analogue (Tyman, 1973, 1979) of the 3-alkenyl-1,2-

diol, urushiol, was unfortunately not available for

study as a borate complexant in the present work.

However, although synthesis of all the constituents

of these phenolic lipids has been achieved (Kozubek

and Tyman, 1999; Tyman, 2001; Niimura et al., 1998),

natural sources remain the source of supply.

yields of 88.6 and 79.1%, respectively. Nevertheless,

the additional step of esteriﬁcation, either by the less

attractive use of diazomethane, or more conveniently

by esteriﬁcation, offset this slight gain.

3.4. Homologous 2-hydroxymethyl-3-alkylphenols

Homologous

2- hydroxymethyl- 3- alkylphenols

were synthesised as shown in Scheme 2. Alkylation

(Tyman and Visani, 1997; Carpenter et al., 1984)

of ethyl 2-methoxy-6-methylbenzoate (Hauser and

Pogany, 1980) afforded the required 6-alkyl deriva-

tive which was demethylated with boron tribromide

(Durrani and Tyman, 1980) to give the corresponding

salicylate. Reduction with lithium aluminium hydride

furnished the methylol.

Certain of the homologous 2-hydroxymethyl-3-

alkylphenols (24, R = H, n-C₃H₇and n-C₇H₁₅) were

synthesised by the alkylation of ethyl 2-methoxy-6-

methylbenzoate as depicted in Scheme 2 since the

lower anacardic acids are not available from natu-

ral sources. The alkylation stage to give (22) was

followed by demethylation with boron tribromide

producing (23) and reduction of the ester with lithium

aluminium hydride, as in Scheme 1, to afford the

three compounds represented by 24.

As well as the natural aromatic diols and semi-

synthetic o-hydroxymethylols described in the present

study, the unsaturated side chains of methylated phe-

nolic lipids have been polyhydroxylated (Durrani

et al., 1982) to afford potential borate complexants.

3.5. Synthesis of 2-hydroxymethyl-4-alkylphenols

3.2. Synthesis of 1,3-diols (2-hydroxymethylols)

Homologous

2 - hydroxymethyl- 4- alkylphenols

were synthesised as shown in Scheme 3 from the

appropriate 4-alkylphenol in the form of the phenoxy-

magnesiobromide by reaction with paraformaldehyde

(Casiraghi et al., 1978) and reduction of the aldehyde

product with sodium borohydride.(b) (iii), (iv) as in

(a), respectively.

The synthesis of certain homologous members of

this group is shown in Scheme 3 (a) consisting of

(19, R = t-Bu, t-C₈H₁₇, n-C₉H₁₉, t-C₉H₁₉). Apart

from the n-nonyl member the 4-alkyl-substituted

phenols were all from petrochemical sources. Al-

though as with the anacardic acids in Scheme 1,

the methylols could be formed by hydride reduction

of a carboxylic or carbethoxy substituent, we had

found that either formylation (Casiraghi et al., 1978;

Tyman, 1981) (J.H.P. Tyman and S.J.A. Iddenten,

unpublished work) and reduction with sodium boro-

hydride or, direct methylolation, were two alternative

The Schemes 1–6 depict the essence of the present

work namely to semi-synthesise and synthesise ho-

mologous members of the four structural isomers,

namely 2-hydroxymethyl derivatives of 3-alk(en)yl-,

4-alkyl-, 5-alk(en)yl- and 6-alkylphenols in order to

compare their relative borate complexation.

3.3. Anacardic alcohols, 2-hydroxymethyl-3-alk

(en)ylphenols

Lithium aluminium hydride reduction of C₁₁, anagi-

gantic and C₁₅, anacardic acids (2) and (1), afforded

the corresponding anacardic alcohols (6) and (5, n =

0, 2, 4, 6), respectively, as shown in Scheme 1.

Generally, the use of methyl esters afforded slightly

better yields than reduction of the corresponding acids.

Thus, the methyl ester of (1) and the acid (1) gave

J.H.P. Tyman, S.K. Mehet / Chemistry and Physics of Lipids 126 (2003) 177–199

197

procedures. In the case of the parent phenol (R = t-

nonyl) monoformylation proceeded regiospeciﬁcally

and borohydride reduction gave an overall 46.7%

yield whereas hydroxymethylolation, which resulted

in some disubstitution (2,6-dihydroxymethyl-4-3,5,5-

trimethylhexylphenol, 42.4%), gave 30.0% of the

monohydroxymethyl compound, although the direct-

ness of the latter method is an advantage (this work

with A. Ninagawa, will be reported elsewhere). In (b)

Scheme 3, the synthesis of the chloro-derivative (21),

OCS, namely, 2-hydroxymethyl-6-chloro-4-(1,1,3,4-

tetramethylutyl)phenol is shown. Monochlorination of

t-octylphenol in carbon tetrachloride at ambient tem-

perature gave a 96% yield of 2-chloro-4-t-octylphenol

which was formylated to give 2-hydroxy-3-chloro-5-

(1,1,3,3-tetramethylbutyl)benzaldehyde (20) in 83.1%

yield, sodium borohydride reduction of which gave

21 in 77.3% yield, in pure form. It appears that

previous preparations of this extractant (Brown and

Sanderson, 1978b), were impure and were employed

contained both the starting material 4-t-octylphenol

and its 2-methylol.

Bu., n-C₈H₁₇, n-C₉H₁₉and n-C₁₁H₂₃is shown. Wittig

reaction (Maercker, 1965) of 3-hydroxybenzaldehyde

with the required alkyltriphenylphosphonium bro-

mide followed by catalytic hydrogenation of the re-

spective alkene formed, gave the 3-alkylphenol (10).

Formylation in the usual way of the phenoxymagne-

sium bromide and reaction with paraformaldehyde

afforded the respective aldehyde (11) and thence by

sodium borohydride reduction, the required product.

Alternative procedures (Caplin and Tyman, 1982;

Tyman et al., 2002) to 3-alkylphenols by reaction of

3-hydroxybenzaldehyde with 1-bromoalkanes in THF

containing lithium, followed by catalytic hydrogenol-

ysis, also afford excellent yields.

3.8. Synthesis of 2-hydroxymethyl-6-alkylphenols

The synthesis of two homologous 2-hydroxymethyl-

6-alkylphenols is depicted in Scheme 6 (a and b).

2-n-Nonylphenol (13), obtained by a Wittig reaction

with salicylaldehyde followed by catalytic hydrogena-

tion, was formylated as the phenoxymagnesium bro-

mide by reaction with paraformaldehyde to afford the

aldehyde (14) which was reduced by sodium borohy-

dride to give 2-hydroxymethyl-6-n-nonylphenol (15,

R¹= n-C₉H₁₉). The t-octyl analogue (15, R¹= t-

C₈H₁₇) was synthesised by t-octylation of phenol to

give 16, followed by formylation and reduction of the

aldehyde product (17 ) with sodium borohydride.

Alternative methods for formation of methylols

by catalytic hydrogenation with copper chromite

(Adkins, 1954), rhenium catalysts (Broadbent and

Bartley, 1963) and by electrolytic reduction Riﬁ and

Covitz, 1974) are available, but were not examined in

this present exploratory work.

3.6. 2-hydroxymethyl-5-alk(en)ylphenols

The parent C₁₅2-hydroxymethyl-5-alk(en)ylphenol,

isoanacardic alcohol (9) was synthesised as depicted

in Scheme 4, either, by the Kolbe carboxylation of

cardanol to give isoanacardic acid (Durrani et al.,

1980) (7) followed by lithium hydride reduction

or, from isoanacardic aldehyde (8), available from

the reaction of cardanoxymagnesium bromide with

paraformaldehyde in the presence of HMPT, followed

by reduction of (8) with sodium borohydride, or

by hydroxymethylation in aqueous alkaline solution

with formaldehyde. Hydroxymethylation of cardanol

with formaldehyde in aqueous alkaline solution af-

forded isoanacardic alcohol (9) (37.3%), recovered

cardanol (42.4%), together with small proportions of

the 4-isomer (3.5%), the 2,4-disubstituted compound

(7.1%) and less than 10% of more complex material.

Based on the cardanol reacted, the conversion to the

monomethylol was 71.2%.

3.9. Solvent extraction properties of 1,2- and

1,3-diols

The complexation and solvent extraction of borate

leading to the recovery of boric acid by compounds

described in this account will be described in detail

elsewhere. Unsaturated anacardic alcohol (5) appears

to be a superior extractant to its iso-analogue (9) over a

wide pH range. By contrast, OCS (21) and its dechloro

analogue (19, R = C₈H₁₇) and the 4-t-nonylphenol

analogue (19, R = C₉H₁₉) are only more effective

at a higher pH but rapidly decline and are inferior

3.7. Synthesis of homologous 2-hydroxymethyl-5-n-

alkylphenols

In Scheme 5, the synthesis of certain homologous

2-hydroxymethyl-5-alkylphenols (12, R¹= n-Bu, t-

198

J.H.P. Tyman, S.K. Mehet / Chemistry and Physics of Lipids 126 (2003) 177–199

Durrani, A.A., Goh, C.S., Tyman, J.H.P., 1982. Synthesis of

oxidative degradation products from methylated component

phenols of Anacardium occidentale. Lipids 17, 561–

569.

Folkestad, F.E., Loeiten, K.O., Mejdell, G.T., Gloer, T., Torvund,

A., 1972. Removing boric acid and its salts from magnesium

chloride solutions. Norway Patent 124026 (21 February).

Gulati, A.S., Subba Rao, B.C., 1964. Drug analogues from the

phenolic constituents of cashew nut-shell liquid. Indian J.

Chem. 2, 337–338.

Hauser, F.M., Pogany, S.F., 1980. 2-Hydroxy-6-methylbenzoic acid

derivatives. Synthesis 814–815.

Havighorst, C.R., 1963. New process separates borates from ore

by extraction. Chem. Eng. 70, 228–232.

Klopfenstein, R.R., Arnold, D.S., 1966. Recent developments in

solvent extraction technology. J. Met. 18, 1195–1197.

Kozubek, A., Tyman, J.H.P., 1999. Resorcinolic lipids, the natural

non-isoprenoid phenolic amphiphiles: their biological activity.

Chem. Rev. 99, 1–26.

at normal (neutral) pH values. Urushiol (4) is less

effective over the whole pH range. However, in the

presence of Aliquat 336 (tri-t-octylamine), the perfor-

mance of unsaturated anacardic alcohol, isoanacardic

alcohol, the 4-t-nonylphenol analogue and urushiol

is enhanced, but again unsaturated anacardic alcohol

and its iso analogue are the most effective of the

semi-synthetic series of lipidic diols. The usage of

diols from natural replenishable sources would enable

fossil fuels to be employed preferentially for energy

rather than for chemical uses. It is also relevant that

certain phenolic lipid products from natural sources

have been found to be more biodegradable than their

petrochemical analogues (Tyman and Bruce, 1992;

Tyman and Bruce, 2003).

Laan, I.A.M., Ward, J.P., 1987. Selective monoortho-alkylation of

phenol with an aluminium catalyst. Chem. Ind. 34–35.

Lam, S.K., Tyman, J.H.P., 1982. The conversion of anacardic

acid into urushiol, J. Chem. Soc., Perkin Trans. 1942–

1952.

Acknowledgements

Borax Research are thanked for partial ﬁnancial

support and for laboratory facilities.

Maercker, A., 1965. The Wittig reaction. Org. React. 14, 270–

490.

Matthews, A.J., Tyman, J.H.P., 1982. Compositional studies on

Japanese lac (Rhus vernicifera) by chromatography and mass

spectrometry. J. Chromatogr. 235, 149–164.

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Article Doi

The separation and synthesis of lipidic 1,2- and 1,3-diols from natural phenolic lipids for the complexation and recovery of boron

DOI: 10.1016/j.chemphyslip.2003.08.004

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