112
M. Afri et al. / Chemistry and Physics of Lipids 184 (2014) 105–118
(DCIꢄꢄCH4) m/z: calcd. (12C1713C2H37O3, MH+) 315.2810, obsd.
299.2569. FTIR (KBr) 3061 (vbr, s, OH), 2926, 2845 (s, ꢄꢄCH2ꢄꢄ),
1703 (s, CQO) cmꢄ1
315.2788.
.
2.4.6.6. Methyl 13-oxooctadecanoate (7i). 37% yield, mp: 43 ꢀC. MS
(DCI, CH4) m/z 313.275 (MH+,100%), 281.265 (MH+ꢄꢄMeOH, 6.35%),
197.071 ((CH2)11CO, 78.06%); anal. HRMS (CI): calcd. (C19H37O3, MH
+) 313.2743 obsd. 313.2754. FTIR (KBr) 2983 (w, ꢄꢄCH2ꢄꢄ), 2954
(m, ꢄꢄCH2ꢄꢄ), 2931, 2918 and 2849 (s, ꢄꢄCH2ꢄꢄ), 1738 and 1705
(s, CQO), 1470, 1438, 1415, 1380 and 1321 (m, CꢄꢄH), 1260, 1229,
2.4.7.9. 12-Oxooctadecanoic acid (8h). 84% yield, mp: 110–112 ꢀC.
MS (DCIꢄꢄCH4) m/z: 299.254 (MH+). HRMS (DCIꢄꢄCH4) m/z: calcd.
(C18H35O3, MH+) 299.2586, obsd. 299.2542. FTIR (KBr): 3052
(vbr, s, OH), 2912, 2845 (s,ꢄꢄCH2ꢄꢄ), 1696 (s, CQO) cmꢄ1
.
2.4.7.10. 12-Oxooctadecanoic acid-1,12-13C2
(
13C-8h). 87% yield,
1203 and 1176 (m, CꢄꢄO) cmꢄ1
.
mp: 110–112 ꢀC. MS (DCIꢄꢄCH4) m/z: 301.262 (MH+, 8.62%),
284.252 (MH+ꢄꢄOH, 18.44%), 283.251 (MH+ꢄꢄH2O, 100%), 215.153
2.4.6.7. Methyl 16-oxooctadecanoate (7k). 25% yield. MS (CI, CH4)
m/z 313.272 (MH+, 34.73%), 283.217 ((MHꢄꢄEt)ꢄ, 100%), 281.249
(MH+ꢄꢄMeOH, 61.89%); anal. HRMS (CI): calcd. (C19H37O3, MH+)
313.2743 obsd. 313.2724.
(MH+ꢄꢄC6H14
,
40.82%). HRMS
(DCIꢄꢄCH4) m/z:
calcd.
12
(
C
13C2H35O3, MH+) 301.2653, obsd. 301.2617.
16
2.4.7.11. 13-Oxooctadecanoic acid (8i). 60% yield, mp: 82 ꢀC. MS
(DCI, CH4) m/z 299.25 (MH+, 15.38%), 281.24 (MH+ꢄꢄH2O, 100%),
99.052 (CH3(CH2)4CO,12.13%), 71.07 (CH3(CH2)4, 6.5%); anal. HRMS
(CI): calcd. (C18H35O3, MH+) 299.2586 obsd. 299.2539. FTIR (KBr)
3115 (vbr, s, OH), 2954, 2930, 2916 and 2849 (s, ꢄꢄCH2ꢄꢄ), 1699
(s, CQO), 1469, 1440, 1418 and 1317 (m, CꢄꢄH), 1266, 1236, 1214
2.4.7. General procedure for preparation of keto acid 8
Keto acids 8 were prepared from the corresponding keto esters
7 by saponification according to the procedure of Menger et al.
(1989). The products were crystalline.
(w, CꢄꢄO) cmꢄ1
.
2.4.7.1. 4-Oxooctadecanoic acid (8a). 90% yield, mp: 84 ꢀC. MS
(DCIꢄꢄCH4) m/z: 299.258 (MH+, 23.36%), 281.239 (MH+ꢄꢄH2O,
100%). HRMS (CIꢄꢄCH4) m/z: calcd. (C18H35O3, MH+) 299.2586,
obsd. 299.2585. FTIR (KBr): 3405 (vbr, s, OH), 2919 (s), 2851 (m),
2.4.7.12.14-Oxooctadecanoic acid (8j). 35% yield, mp: 82 ꢀC. MS (CI,
CH4) m/z 299.260 (MH+, 7.71%), 281.248 (MH+ꢄꢄH2O, 100%); anal.
HRMS (CI): calcd. (C18H35O3, MH+) 299.2586 obsd 299.2596. FTIR
(KBr) 3061 (vbr, s, OH), 2912, 2851(s, ꢄꢄCH2ꢄꢄ), 1703
1703 (s, CQO) cmꢄ1
.
(s, CQO) cmꢄ1
.
2.4.7.2. 4-Oxooctadecanoic acid-1,4-13C2 13C-8a). 90% yield, mp:
(
84 ꢀC. 5-Oxooctadecanoic acid (8b):89% yield, mp: 80 ꢀC; MS (EI+)
m/z 298 (M+, 2.4%), 211 (M+ꢄꢄ(CH2)3COOH,15.6%), 84 (C6H12,100%).
2.4.7.13. 16-Oxooctadecanoic acid (8k). 40% yield, mp: 84 ꢀC. MS
(CI, CH4) m/z 299.258 (MH+, 5.45%), 281.252 (MH+ꢄꢄH2O, 100%);
anal. HRMS (CI): calcd. (C18H35O3, MH+) 299.2586 obsd. 299.2583.
FTIR (KBr) 3074 (vbr, s, OH), 2919, 2851 (s,ꢄꢄCH2ꢄꢄ), 1703
2.4.7.3. 6-Oxooctadecanoic acid (8c). 60% yield, mp 84 ꢀC. MS
(DCI, CH4) m/z 299.259 (MH+, 9.8%), 281.243 (MH+ꢄꢄH2O, 100%).
FTIR 3599 (vbr, s, OH), 2976 (m), 2917 (s), 2846 (m), 1715 and 1688
(s, CQ) cmꢄ1
.
(s, CQO), 1473 (m), 1481 (w), 1260 and 1105 (m, CꢄꢄO) cmꢄ1
.
2.5. NMR conditions for preparing correlation graphs and liposomal
samples
2.4.7.4. 7-Oxooctadecanoic acid (8d). 13% yield, mp: 78 ꢀC. MS
(DCI, CH4) m/z 299.259 (MH+, 48.19%), 281.249 (MH+ꢄꢄH2O, 100%),
158.095 ((CH2)10CH3, 18.84%); anal. HRMS (CI): calcd. (C18H34O3,
MH+) 299.2586 obsd. 299.2587. FTIR (KBr) 3105 (vbr, s, OH), 2954,
2928, 2917, 2848 (s, ꢄꢄCH2ꢄꢄ), 1715, 1699 (s, CQO), 1470, 1419 and
For the correlation graph, samples (ca. 10 mg) of ketoesters 7 or
ketoacid 8 were dissolved in 0.6 mL of pure solvent to give a final
concentration of 0.05 M. This is approximately the same concen-
tration as that of the intercalants within the liposomal solution.
The samples in pure solvents were scanned for 20 min. or
1000 scans. Liposomal samples were prepared as described above
in Section 2.3 and were scanned overnight (40,000 scans). D2O
served as the internal lock.
1382 (m, CꢄꢄH), 1250 and 1106 (m, CꢄꢄO) cmꢄ1
.
2.4.7.5. 8-Oxooctadecanoic acid (8e). 82% yield, mp: 79 ꢀC. MS
(DCIꢄꢄCH4) m/z: 299.258 (MH+, 13.22%), 281.261 (MH+ꢄꢄH2O,
100%), 157.084 (MH+ꢄꢄC10H22, 88.61%). HRMS (DCIꢄꢄCH4) m/z:
calcd. (C18H35O3, MH+) 299.2586, obsd. 299.2576. FTIR: 3737 (vbr,
m, OH), 2969, 2939 (s, ꢄꢄCH2ꢄꢄ), 2882 (m), 1749, 1737 (s, CQO),
3. Results and discussion
1541, 1457, 1376 (w), 1217 (w, CꢄꢄO) cmꢄ1
.
3.1. General synthesis of keto esters 7 and keto acids 8
2.4.7.6. 8-Oxooctadecanoic acid-1,8-13C2
(
13C-8e). 62% yield, mp:
As pointed out in the introduction, the first goal of this research
was to synthesize two related families of compounds containing
two carbonyl groups, long chain fatty keto esters 7 and keto acids 8.
Each of these families would be comprised of the same number of
carbons and functional groups, with the ester or acid carbonyls
presumably anchored in the polar region of the membrane. The
only difference between the various members in each set would be
the location of the second ketone carbonyl along the fatty acid
chain.
As outlined in Fig. 3 above, the first step in the synthesis of these
families was the quantitative conversion of dibromoalkanes 1 to
the corresponding dicyanoalkane derivatives 2 using KCN,
followed by basic hydrolysis of 2 to diacids 3. Monoesterification
of 3 to give monoacid monoester 5 proved to be a low-yield
approach. More effective was the initial diesterification of diacid 3
to diesters 4 followed by monohydrolysis to the desired acid esters
79 ꢀC. MS (DCIꢄꢄCH4) m/z: 283.257 (MH+ꢄꢄOH, 0.79%). HRMS
(DCIꢄꢄCH4) m/z: calcd. (12C1613C2H33O2, MH+ꢄꢄOH) 283.2548, obsd.
283.2573.
2.4.7.7. 9-Oxooctadecanoic acid (8f). 95% yield, mp: 74 ꢀC. MS
(DCI, CH4) m/z 298.2 (MH+, 7.22%), 281.247 (MH+ꢄꢄH2O, 100%),
155.108 (CO(CH2)7CO, 21.79%), 125.063 ((CH2)7CO, 12.8%), 98.047
((CH2)7, 21.74%). anal. HRMS (CI): calcd. (C18H34O3, M+) 298.2508
obsd. 298.2437. FTIR (KBr) 3200–3014 (vbr, s, OH), 2955, 2929,
2919 and 2848 (s,ꢄꢄCH2ꢄꢄ), 1717, 1699 (s, CQO), 1470, 1437, 1380,
1306 and 1332 (m, CꢄꢄH), 1106 (w, CꢄꢄO) cmꢄ1
.
2.4.7.8. 10-Oxooctadecanoic acid (8g). 26% yield, mp: 80 ꢀC. MS
(DCIꢄꢄCH4) m/z: 299.257 (MH+, 18.1%), 281.251 (MH+ꢄꢄH2O, 100%).
HRMS (DCIꢄꢄCH4) m/z: calcd. (C18H35O3, MH+) 299.2586, obsd.