Synthesis of surfactants based on pentaerythritol. I. Cationic and zwitterionic gemini surfactants

Article abstract of DOI:10.1021/jo9018107

(Chemical Equation Presented) Simple strategies for the synthesis of five series of cationic gemini surfactants and one series of zwitterionic gemini surfactants from pentaerythritol have been developed. Two lipophilic groups were introduced onto pentaery

Full text of DOI:10.1021/jo9018107

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Synthesis of Surfactants Based on Pentaerythritol. I. Cationic and
Zwitterionic Gemini Surfactants
Nusrat Jahan,† Nawal Paul,† Christian J. Petropolis,†,‡ D. Gerrard Marangoni,*,‡ and
T. Bruce Grindley*,†
†Department of Chemistry, Dalhousie University, Halifax, NS, Canada B3H 4J3, and ‡Department
of Chemistry, St. Francis Xavier University, Antigonish, NS, Canada B2G 2W5
bruce.grindley@dal.ca; gmarango@stfx.ca
Received July 14, 2009
Simple strategies for the synthesis of five series of cationic gemini surfactants and one series of
zwitterionic gemini surfactants from pentaerythritol have been developed. Two lipophilic groups
were introduced onto pentaerythritol by alkylation of the known compound, O-benzylidenepentaery-
thritol, with 1-bromooctane, 1-bromodecane, 1-bromododecane, and 1-bromotetradecane. Hydroge-
nolysis of the benzylidene acetals gave diols which were converted into three different series of
trimethylammonium derivatives. The diiodides derived from the diols could be displaced by dimethy-
lamine, even though they are adjacent to a quaternary carbon atom. Alkylation with methyl iodide gave
the first series. The iodides were easily displaced by cyanide ion and the resulting dinitriles were
hydrolyzed, converted to N,N-dimethylamides, and reduced to give a second series. Oxidation of the
diols to dialdehydes under Swern conditions followed by Horner-Wadsworth-Emmons reactions with
diethyl N,N-dimethylcarbamoylmethylphosphonate followed by two-stage reduction gave a third series.
The dialkoxides derived from the four di-O-alkylpentaerthritol diols were reacted with 2-dimethylami-
noethyl chloride and 3-dimethylaminopropyl chloride in neighboring-group assisted double Williamson
ether syntheses to give precursors to two more series. As expected because the neighboring group
participation occurs through a four-membered-ring intermediate, considerably more vigorous condi-
tions were required for the reactions with 3-dimethylaminopropyl chloride. 2-Diethylaminoethyl
bromide was found to be less reactive than 2-dimethylaminoethyl chloride. The products were alkylated
with methyl iodide and, in some cases, other alkyl halides to give cationic gemini surfactants. Alkylation
of one series with ethyl bromoacetate followed by anion exchange resin catalyzed ester hydrolysis gave
zwitterionic gemini surfactants. The members of all series have superior surfactant properties.
Introduction
is applied to compounds having two or more lipophilic units
connected at or close to the polar head groups. Gemini
surfactants display critical micellization concentrations that
Gemini surfactants have attracted considerable atten-
tion1-9 since the creation of the term by Menger.10 This term
(5) Alami, E. O.;Holmberg, K.Adv. ColloidInterface Sci. 2003, 100, 13–46.
(6) Yao, Z. G.; Li, G. Z.; Dong, F. L.; Hu, A. X. Prog. Chem. 2004, 16,
349–364.
(7) Shukla, D.; Tyagi, V. K. J. Oleo Sci. 2006, 55, 215–226.
(8) Shukla, D.; Tyagi, V. K. J. Oleo Sci. 2006, 55, 381–390.
(9) Bombelli, C.; Giansanti, L.; Luciani, P.; Mancini, G. Curr. Med.
Chem. 2009, 16, 171–183.
*To whom correspondence should be addressed. Phone:1-902-494-2041
(T.B.G.) and 1-902-867-2324 (D.G.M.).
(1) Menger, F. M.; Keiper, J. S. Angew. Chem., Int. Ed. 2000, 39, 1907–
1920.
(2) Zana, R. Adv. Colloid Interface Sci. 2002, 97, 205–253.
(3) Rosen, M. J. Cosmet. Toiletries 1998, 113, 49–55.
(4) Wettig,S.D.;Verrall,R.E.;Foldvari, M. Curr. GeneTher. 2008, 8, 9–23.
(10) Menger, F. M.; Littau, C. A. J. Am. Chem. Soc. 1991, 113, 1451–
1452.
7762 J. Org. Chem. 2009, 74, 7762–7773
Published on Web 09/16/2009
DOI: 10.1021/jo9018107
r
2009 American Chemical Society

Jahan et al.
JOCArticle
are 1 to 2 orders of magnitude lower than those of the
corresponding conventional surfactants with only a single
head group and also are much more efficient at lowering
surface tensions of aqueous solutions. There has been con-
siderable interest in exploring how structural variations
influence surfactant properties, particularly in how head
group spacing influences these properties.11-21
SCHEME 1. Synthetic Strategy for the Synthesis of Cationic
Gemini Surfactants Based on Pentaerythritol
Pentaerythritol is a convenient starting material for the
preparation of gemini surfactants as will be shown herein.
Two previous reports22,23 have described surfactants pre-
pared from pentaerythritol. Those of type 1 had poor
solubility in water.22
SCHEME 2. Synthesis of Di-O-alkylpentaerythritols (9-12)
Compounds 2 and 3 had quite low CMCs but only the two
compounds shown and a disulfated derivative were pre-
pared.23 This publication will describe the synthesis of a
comprehensive set of pentaerythritol-based cationic gemini
surfactants designed to determine how the structure of the
surfactant influences its properties.
synthesis of the three series that contain variable numbers
of methylene groups between the pentaerythritol quaternary
center and the cationic center is shown in Scheme 1.
This simple strategy was selected because it can be used to
prepare a wide variety of structures that will allow the
thorough investigation of structure-function relationships.
These investigations will be reported elsewhere.24 Protection
of two of the four pentaerythritol hydroxyls allows the
incorporation of a variety of lipophilic groups through
alkylation of the remaining two hydroxyls with use of alkyl
halides. Here only linear alkyl halides were employed but
other lipophilic groups could be used. Deprotection of the
remaining two hydroxyls then allows their transformation
into units bearing charged groups, trialkylammonium
groups in this publication.
Synthesis of Alkylated Diols. As in the synthetic route used
by Murguı
´
a and Grau,23 a pentaerythritol derivative with
Results and Discussion
Cationic Gemini Surfactants Derived from Pentaerythritol
with Branching Chains Only Containing Carbon Atoms. Syn-
thetic Strategy. The synthetic strategy adopted for the
two of the four hydroxyl groups protected was employed as
the starting material, in this case, the readily available mono-
O-benzylidenepentaerythritol (4).25 This starting material
was converted into di-O-alkylpentaerythritols (9-12) by
double Williamson ether syntheses with linear alkyl bro-
mides. If the reaction temperatures were kept close to 0 °C,
the amounts of elimination byproducts from the alkyl bro-
mides were negligible. Hydrogenolysis removed the benzyli-
dene acetals in excellent yields, as shown in Scheme 2. In our
hands, hydrogenolysis of the benzylidene acetals provided
cleaner diols from benzylidene acetals 5 to 8 than did mild
(11) Zana, R.; Benrraou, M.; Rueff, R. Langmuir 1991, 7, 1072–1075.
(12) Bhattacharya, S.; Haldar, J. Colloids Surf., A 2002, 205, 119–126.
(13) Zana, R. J. Colloid Interface Sci. 2002, 248, 203–220.
(14) Ali, H. E. S. Tenside, Surfactants, Deterg. 2007, 44, 281–286.
(15) Cao, X. L.; Li, Z. Q.; Song, X. W.; Cui, X. H.; Wei, Y. P.; Cheng, F.;
Wang, J. J. Surfactants Deterg. 2009, 12, 165–172.
(16) Borse, M.; Sharma, V.; Aswal, V. K.; Goyal, P. S.; Devi, S. J. Colloid
Interface Sci. 2005, 284, 282–288.
(17) Ao, M. Q.; Huang, P. P.; Xu, G. Y.; Yang, X. D.; Wang, Y. J. Colloid
Polym. Sci. 2009, 287, 395–402.
(18) Van Biesen, G.; Bottaro, C. S. J. Chromatogr., A 2008, 1180, 171–
178.
acid hydrolysis. Murguı
´
a and Grau23 had used acid hydro-
lysis of cyclohexylidene acetals.
(19) Chen, Q. B.; Zhang, D. Z.; Li, R.; Liu, H. L.; Hu, Y. Thin Solid Films
2008, 516, 8782–8787.
(20) Chen, L. F.; Li, Y.; Xie, H. Q. J. Dispersion Sci. Technol. 2008, 29,
1098–1102.
(21) Klijn, J. E.; Stuart, M. C. A.; Scarzello, M.; Wagenaar, A.; Engberts,
J. B. F. N. J. Phys. Chem. B 2006, 110, 21694–21700.
(22) Menger, F. M.; Migulin, V. A. J. Org. Chem. 1999, 64, 8916–8921.
(24) Karpichev, Y.; Jahan, N.; Paul, N.; Tran, T.; Grindley, T. B.;
Petropolis, C. J.; Marangoni, D. G. Langmuir, in preparation.
(25) Issidorides, C. H.; Gulen, R. C. Monobenzalpentaerythritol. In
Organic Syntheses; Rabjohn, N., Ed.; John Wiley and Sons: New York,
1963; Collect. Vol. IV, pp 679-681.
(23) Murguıa, M. C.; Grau, R. J. Synlett 2001, 1229–1232.
´
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SCHEME 3. Synthesis of the Shortest Series of Cationic
Gemini Surfactants (Series 1)
SCHEME 4. Synthesis of Cationic Gemini Surfactants by Dis-
placement with Pyrrolidine
SCHEME 5. Neighbouring Group Participation in Displace-
ments of Alkoxyneopentyl Iodides
An alternative approach for the synthesis of diols 9-12
will be described later.26
This publication describes the synthesis of five series of
cationic pentaerythritol-based gemini surfactants. The series
are numbered based on the distance the ionic group is from
the quaternary carbon originating in pentaerythritol with the
series having the shortest distance being series 1. All com-
pounds in each series are numbered with the series number
followed by the number of the compound in the series (see
schemes below).
SCHEME 6. Synthesis of the Second Series of Cationic Gemini
Surfactants (Series 2)
Synthesis of Series 1-3. The synthesis of the first series
commenced with the conversion of the diols into diiodides
with iodine, triphenylphosphine, and imidazole27,28 in ex-
cellent yields as shown in Scheme 3. Even though the iodine
atoms are attached to primary carbons adjacent to quatern-
ary centers, they can be displaced by nucleophiles. Linear
nucleophiles, such as cyanide (see Scheme 6) or azide, also
displaced iodide easily. Dimethylamine displaced iodide
slowly at elevated temperatures in a sealed tube but we
were unable to find conditions where the more branched
nucleophiles, trimethylamine or sodium sulfite, could per-
form this displacement. The displacement products with
dimethylamine were isolated as hydrochlorides in reasonable
yields for the two steps (68-75%). The iodides can also be
displaced with pyrrolidine (Scheme 4). These tertiary amines
were alkylated with methyl iodide to give surfactant series
1 as shown in Schemes 3 and 4.
These nucleophilic displacements probably proceed by
an SN2 mechanism,29-31 even though SN2 displacements of
halides and tosylates in neopentyl derivatives are known to
occur slowly32 and mechanisms involving single electron
transfer (SRN1) are often considered for displacement of
neopentyl halides,33 particularly iodides.34,35 It is probable
that SN2 displacements in pentaerythritol systems are faster
(26) Tran, T.; Jahan, N.; Marangoni, D. G.; Grindley, T. B. J. Org.
Chem., in preparation.
(27) Garegg, P. J.; Johansson, R.; Ortega, C.; Samuelsson, B. J. Chem.
Soc., Perkin Trans. 1 1982, 681–683.
(28) Lubineau, A.; Malleron, A.; Le Narvor, C. Tetrahedron Lett. 2000,
41, 8887–8891.
(29) Anderson, P. H.; Stephenson, B.; Mosher, H. S. J. Am. Chem. Soc.
1974, 96, 3171–3177.
(32) Streitwieser, A. Solvolytic displacement reactions; McGraw-Hill:
New York, 1962.
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(33) Rossi, R. A.; Pierini, A. B.; Penenory, A. B. Chem. Rev. 2003, 103,
(30) DePuy, C. H.; Gronert, S.; Mullin, A.; Bierbaum, V. M. J. Am.
Chem. Soc. 1990, 112, 8650–8655.
(31) Vayner, G.; Houk, K. N.; Jorgensen, W. L.; Brauman, J. I. J. Am.
Chem. Soc. 2004, 126, 9054–9058.
71–167.
(34) Ashby, E. C.; Argyropoulos, J. N. J. Org. Chem. 1985, 50, 3274–
3283.
(35) Ashby, E. C.; Welder, C. O. J. Org. Chem. 1997, 62, 3542–3551.
7764 J. Org. Chem. Vol. 74, No. 20, 2009

Jahan et al.
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SCHEME 7. Synthesis of Cationic Surfactants via Horner-Wadsworth-Emmons Reactions
than those in neopentyl systems because of neighboring group
participation as shown in Scheme 5. Although participation
by oxygen through four-membered-ring intermediates does
not normally provide significant rate enhancement,36-39
when branching on the intervening atoms is present, signifi-
cant rate enhancements have been observed.40,41 Dale and
Fredriksen suggested that displacements of bromides
by alkoxides from 2-bromo-2-methyl-1,3-dibromopropane
proceed via four-membered-ring bromonium ion intermedi-
ates.42 We believe that the iodide displacements here follow
the SN2 mechanism both because neighboring group partici-
pation is possible and also because the dependency of ease of
reaction on the steric bulk of the nucleophile fits what is
expected for an SN2 mechanism.
A second series of pentaerythritol-based cationic gemini
surfactants with greater distances between head groups was
synthesized as shown in Scheme 6. Cyanide displacement of
the diiodides was followed by hydrolysis of the cyanides with
sodium hydroxide in 2-propanol and conversion to the N,N-
dimethylamides. Reduction and alkylation gave cationic
surfactant series 2.
with the anion of diethyl N,N-dimethylcarbamoylmethyl-
phosphonate. The latter compound was made by the reac-
tion of triethyl phosphite with bromo-N,N-dimethyl-
acetamide as performed by Barlett et al. with trimethyl
phosphite.44 Horner-Wadsworth-Emmons reactions using
ylides stabilized by acetamido groups have been performed
on a number of occasions,45-49 but never with dialdehydes,
as far as we are aware. The conjugated amides were obtained
exclusively as trans alkenes, as established from the magni-
3
tudes of the JH,H values across the alkene (16 Hz).
The alkenes were hydrogenated over 10% palladium/C
then further reduced to tertiary amines with lithium
aluminum hydride. Alkylation with methyl iodide yielded
quaternary ammonium salts, the third series of gemini
surfactants.
Cationic Gemini Surfactants Derived from Pentaerythritol
Having Branching Chains Incorporating Ether Linkages. Two
series of cationic gemini surfactants having ether linkages in
the chains were prepared by Williamson ether syntheses. The
dialkoxides derived from diols 9-12 react readily (50 °C) in
DMF with 2-dimethylaminoethyl chloride because of neigh-
boring group participation through three-membered-ring in-
termediates39 to give dimethylamino derivatives, isolated as the
hydrochlorides (see Scheme 1). Monosubstitution products
were often present as minor impurities but were minimized by
extending reaction times. Alkylation of the products with
methyl iodide yielded cationic gemini surfactants of series 4.
A third series of cationic surfactants was synthesized as
shown in Scheme 7. The diols 9-12 were oxidized under
Swern conditions43 and the unstable dialdehydes were im-
mediately used in Horner-Wadsworth-Emmons reactions
(36) Jursic, B.; Ladika, M.; Sunko, D. E. Gazz. Chim. Ital. 1988, 118, 613–
616.
(37) Winstein, S.; Henderson, R. B. J. Am. Chem. Soc. 1943, 65, 2196–
2200.
(44) Bartlett, P. A.; Carruthers, N. I.; Winter, B. M.; Long, K. P. J. Org.
Chem. 1982, 47, 1284–1291.
ꢀ~
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(45) Ordonez, M.; Hernandez-Fernandez, E.; Montiel-Perez, M.;
Bautista, R.; Bustos, P.; Rojas-Cabrera, H.; Fernandez-Zertuche, M.;
(38) Winstein, S.; Ingraham, L. L. J. Am. Chem. Soc. 1952, 74, 1160–1164.
(39) Capon, B.; McManus, S. P. Neighbouring Group Participation;
Plenum: New York, 1976; Vol. 1.
ꢀ
Garcıa-Barradas, O. Tetrahedron: Asymmetry 2007, 18, 2427–2436.
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(40) Eliel, E. L.; Clawson, L.; Knox, D. E. J. Org. Chem. 1985, 50, 2707–
2711.
(46) Schauer, D. J.; Helquist, P. Synthesis 2006, 3654–3660.
(47) Kojima, S.; Hidaka, T.; Ohba, Y. Heteroatom Chem. 2004, 15, 515–
(41) McManus,S.P.;Karaman,R.M.;Sedaghatherati,R.;Neamatimazraeh,
N.; Hovanes, B. A.; Paley, M. S.; Harris, J. M. J. Org. Chem. 1987, 52, 2518–
2522.
523.
(48) Beck, B.; Picard, A.; Herdtweck, E.; Domling, A. Org. Lett. 2004, 6,
39–42.
(42) Dale, J.; Fredriksen, S. B. Acta Chem. Scand. 1992, 46, 278–282.
(43) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651–1660.
(49) Petrova, J.; Momchilova, S.; Vassilev, N. G. Phosphorus Sulfur
Silicon 2000, 164, 87–94.
J. Org. Chem. Vol. 74, No. 20, 2009 7765

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SCHEME 8. Synthesis of Pentaerythritol-Based Cationic Gemini Surfactants of Series 4 by Neighbouring-Group Assisted Double
Williamson Ether Synthesis with 2-Dimethylaminoethyl Chloride
SCHEME 9. Synthesis of Pentaerythritol-Based Cationic Gemini Surfactants of Series 4 by Neighbouring-Group Assisted Double
Williamson Ether Synthesis with 2-Diethylaminoethyl Bromide
SCHEME 10. Alkylation of Compound 4.3
dialkoxides 1-4 with 3-dimethylaminopropyl chloride in DMF
(Scheme 11). Here, neighboring group participation39 involves
four-membered-ring intermediates, which are known51-54 to be
less effective for amines than the three-membered-ring inter-
mediates used in the previous series. As a result, reaction
temperatures had to be raised and reaction times increased.
Reaction for shorter periods gave monosubstitution products.
Zwitterionic Gemini Surfactants. The normal procedures
for the preparation of carboxymethyl derivatives of amines
(betaines) use haloacetates or haloacetic acid as electrophiles.
Attempts to perform these reactions on bisamines 4.1 to 4.4
always resulted in inseparable mixtures. It was found that the
two-step procedure of Souiriti and Baboulene55,56 using ethyl
ꢁ
Unfortunately, the Krafft temperatures of the longer
chain members of these trimethylammonium derivatives
were found to be greater than room temperature.24 It is
known that triethylammonium derivatives have lower Krafft
temperatures than their trimethylammonium analogues.50
Triethylammonium derivatives were synthesized in the same
way as shown in Scheme 2 except that it was found necessary
to run the Williamson ether syntheses at slightly higher
temperatures, even though the leaving group in 2-diethyla-
minoethyl bromide is better than the chloride employed in
Scheme 8. The diethylamino group must be a poorer neigh-
boring group participator, probably because the larger
group finds it more difficult to achieve the correct three-
membered-ring geometry for participation.
bromoacetate as the electrophile resulted in pure surfactants,
particularly when the ester hydrolysis was performed with an
anion exchange resin as shown in Scheme 12.
All five series of cationic gemini surfactants as well as the series
of zwitterionic gemini surfactants had good solubilities in water
and had outstanding surfactant properties. These properties will
be discussed in detail elsewhere.24 CMCs of the compounds with
C12 tails, 1.11, 2.19, 3.15, 4.11, 5.7, and 6.7, were 0.053, 0.041,
0.028, 0.054, 0.016, and 0.016 mM, respectively, as measured from
the change in surface tension with concentration with a KRUSS
K8 tensiometer. These CMCs are 1 to 2 orders of magnitude lower
than most cationic gemini surfactants (see Table 1 in the review by
Zana57). C20 values for these compounds are also promising.
An alternative approach to lowering the Krafft tempera-
ture was to alkylate the intermediate dimethylamines from
the synthesis shown in Scheme 8 with different alkyl halides,
as shown in Scheme 10.
A series of cationic surfactants with greater distances be-
tween head groups (series 5) was prepared by reacting the diol
(51) Freundlich, H.; Kroepelin, H. Z. Phys. Chem. 1926, 122, 39–48.
(52) Dewey, C. S.; Bafford, R. A. J. Org. Chem. 1967, 32, 3108–3110.
(53) Bird, R.; Knipe, A. C.; Stirling, C. J. J. Chem. Soc., Perkin Trans. 2
1973, 1215–1220.
(54) Detar, D. F.; Luthra, N. P. J. Am. Chem. Soc. 1980, 102, 4505–4512.
ꢁ
(56) Souirti, S.; Baboulene, M. Can. J. Chem. 2001, 79, 1153–1158.
(55) Souirti, S.; Baboulene, M. Synth. Commun. 2001, 31, 9–18.
ꢁ
(57) Zana, R. Gemini Surfactants in Water. In Gemini surfactants:
Synthesis, Interfacial and Solution-phase Behaviour, and Applications; Zana,
R., Xia, J., Eds.; Marcel Dekker: New York, 2004; pp 109-140.
(50) Davey, T. W.; Ducker, W. A.; Hayman, A. R.; Simpson, J. Langmuir
1998, 14, 3210–3213.
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SCHEME 11. Synthesis of Pentaerythritol-Based Cationic Gemini Surfactants of Series 5 by Neighbouring-Group Assisted Double
Williamson Ether Synthesis with 3-Dimethylaminopropyl Chloride
SCHEME 12. Synthesis of Zwitterionic Surfactants
Experimental Section
2,2-Bis(octyloxymethyl)-1,3-propanediol (9). To a solution of
compound 5 (10.02 g, 22.3 mmol) in ethyl acetate (100 mL) was
added 10% Pd/C (Degussa type, 0.2 g). The mixture was stirred
vigorously under atmospheric pressure of H2(g) for 1 h. More
10% Pd/C (Degussa type, 0.5 g) was added and the solution was
stirred until uptake of H2(g) ceased (2 h). The mixture was
filtered and the residue was washed with dichloromethane
(50 mL), then dichloromethane containing 20% methanol (2 ꢀ
50 mL). The filtrate and washings were concentrated to a color-
less solid: yield 6.89 g, 85%. Crystallization from 2-propanol
gave colorless crystals: Rf 0.40 (dichloromethane: methanol
96:4); mp 35 °C; 1H NMR δ 0.88 (t, 6H, J = 6.9 Hz, 2 ꢀ Me),
1.20-1.36 (br m, 20H, 10 ꢀ CH2), 1.56 (pentet, 4H, J = 6.8 Hz,
2 OCH2CH2), 2.82 (t, 2H, J = 6.1 Hz, OH), 3.42 (t, 4H, J = 6.5
Hz, octyl OCH2), 3.50 (s, 4H, OCH2C), 3.65 (d, 4H, CH2OH);
13C NMR δ 73.1 (CCH2OCH2CH2), 72.2 (CH2CH2OC), 65.5
(CH2OH), 44.7 (q C), 31.9 (CH2CH2CH3), 29.64 (OCH2CH2),
29.50, 29.35 (2 octyl CH2), 26.3 (CH2CH2CH2O), 22.8
(CH2CH3), 14.2 (Me); LR ESI MS m/z calcd for C21H45O4
361.33, found 361.1. Anal. Calcd for C21H44O4: C, 69.95; H,
12.30. Found: C, 69.62; H, 12.68.
1,3-Diiodo-2,2-bis(octyloxymethyl)propane (13). Iodine(10.2g,
0.0415 mol, 2.5 equiv), imidazole (2.73 g, 0.0415 mol, 2.5 equiv),
and triphenylphosphine (8.94 g, 0.0353 mol, 2.2 equiv) were
added to a solution of compound 9 (5.80 g, 0.0161 mol) in
anhydrous toluene (200 mL) and the reaction mixture was
refluxed for 3 h. More iodine was then added to consume excess
triphenylphosphine and reflux was continued for 1 h. The cooled
reaction mixture was stirred for 10 min each with saturated
sodium bicarbonate (100 mL) and 10% aqueous sodium thio-
sulfate (200 mL) solutions. The organic layer was washed with
water (3 ꢀ 50 mL), dried (MgSO4), and concentrated. The resi-
due was taken up in hexanes and the solution was passed through
a short silica gel column. Concentration gave the title com-
pound as a colorless oil: 7.89 g, 86%; Rf 0.34 (98:2 hexanes:
dichloromethane); 1H NMR δ 0.89 (t, 6H, J = 6.3 Hz, 2 ꢀ Me),
1.22-1.36 (br s, 20H, 10 ꢀ CH2), 1.55 (pentet, 4H, J = 6.1 Hz, 2
OCH2CH2), 3.33 (s, 4H, CH2I), 3.35 (s, 4H, OCH2C), 3.42 (t, 4H,
5,50-Bis(octyloxymethyl)-2-phenyl-1,3-dioxane (5). A hex-
anes-washed sodium hydride oil dispersion (60% oil dispersion,
8.6 g, 0.22 mol, 2.0 equiv) was added in portions slowly to a
stirred solution of mono-O-benzylidenepentaerythritol25 (4)
(24.11 g, 0.1076 mol) in dry DMF (600 mL) under a nitrogen
atmosphere. The stirred reaction mixture was cooled with an ice
water bath for 1 h, then dried 1-bromooctane (46.76 mL, 51.90 g,
0.268 mol, 2.5 equiv) was added dropwise over 2 h. After the
reaction mixture had been stirred 12 h at 0 °C, another addition
of sodium hydride (4.5 g, 0.11 mol, 1.0 equiv) and 1-bromooc-
tane (20 mL, 0.11 mol, 1.0 equiv) was made. If after the reaction
mixture had been stirred a further 12 h at 0 °C TLC showed that
some mono-O-octyl product was present, another identical
addition was made. When all of the mono-O-octyl derivative
had been consumed, the reaction mixture was quenched by the
addition of methanol dropwise until foaming ceased. The reac-
tion mixture was filtered and the solid was washed with dichlor-
omethane (∼150 mL). The combined filtrate and washings were
concentrated and the residue was extracted with hexanes
(300 mL, then 200 mL). The combined extracts were concen-
trated to an oily residue that was passed through a short silica gel
column with hexanes, then 5% ethyl acetate/95% hexanes
as eluents. The title compound (5) was a colorless oil (44.71 g,
1
85%): Rf 0.46 (hexanes:ethyl acetate 94:6); H NMR (500.13
MHz) δ 0.88, 0.89 (2 t, 6H, J = 6.5 Hz, 2 ꢀ Me), 1.20-1.35 (br
m, 20H, 10 ꢀ CH2), 1.54, 1.57 (2 pentet, 4H, J = 6.8 Hz,
2 OCH2CH2), 3.22 (s, 2H, eq CCH2O), 3.35 (t, 2H, J = 6.5 Hz,
eq octyl OCH2), 3.45 (t, 2H, J = 6.6 Hz, ax octyl OCH2), 3.71 (s,
2H, ax OCH2C), 3.88, 4.09 (2d, 4H, J = 11.5 Hz, H-4,H-40, H-6,
H-60), 5.42 (s, 1H, acetal H), 7.31-7.49 (m, 5H, Ph); 13C NMR δ
138.5 (q Ph), 128.8 (para Ph), 128.3 (2C, mPh), 126.1 (2C, oPh),
101.7 (acetal C), 71.8 (eq OCH2CH2), 71.7 (ax OCH2CH2), 70.8
(eq OCH2C), 70.2 (C-4 and C-6), 69.4 (ax OCH2C), 38.9 (q C),
2 ꢀ 31.89 (CH2CH2CH3), 29.68, 29.54, 29.51, 29.45, 2 ꢀ 29.34
(6 octyl CH2), 26.22, 26.19 (CH2CH2CH2O), 2 ꢀ 22.70
(CH2CH3), 14.3 (Me); HR ESI MS m/z calcd for C28H48O4Na
(M þ Na) 471.3445, found 471.3448.
J. Org. Chem. Vol. 74, No. 20, 2009 7767

Jahan et al.
JOCArticle
octyl OCH2); 13C NMR δ 71.7 (CH2CH2OC), 70.9 (CCH2-
OCH2C), 41.7 (q C), 32.0 (CH2CH2CH3), 29.69, 29.56, 29.47
(3 octyl CH2), 26.3 (CH2CH2CH2O), 22.8 (CH2CH3), 14.3 (Me),
12.1 (CH2I); HR ESI MS m/z calcd for C21H43I2O2 (M þ H)
581.1353, found 581.1351.
nitrogen for 48 h, allowed to cool to rt, then filtered. The solid
was washed with dichloromethane (2 ꢀ 10 mL) and the filtrate
and washings were combined and diluted with dichloromethane
(100 mL). The resulting solution was washed with water (3 ꢀ 100
mL), dried (MgSO4), and concentrated at 30 °C to give crude
1,3-bis(1-azacyclopentyl)-2,2-bis(octyloxymethyl)propane
(1.13): yield 14.20 g. This product was taken up in dichloro-
methane (100 mL) and the resulting solution was shaken with
ice cold 2 M HCl (100 mL). The aqueous layer was extracted
with dichloromethane (2 ꢀ 100 mL), then the combined organic
layers were washed with water (20 mL), dried (MgSO4), and
concentrated to give the title compound as a light yellow crystal-
line solid that was recrystallized from hexanes:ethyl acetate 2:1
to give colorless crystals: yield 12.5 g, 75%; mp 124-125 °C,
Rf 0.22 on basic alumina (hexanes:ethyl acetate:methanol
N,N,N0,N0-Tetramethyl-2,2-bis(octyloxymethyl)-1,3-propane-
diaminium Dichloride (1.5). Compound 13 (9.98 g, 17.2 mmol),
dimethylamine in THF (2 M, 87 mL, 0.17 mol, 10 equiv), and
potassium carbonate (5.9 g, 43 mmol, 2.5 equiv) were added to a
sealed tube with the aid of THF (10 mL). The reaction mixture
was stirred at 160-170 °C. After one week, all of the starting
material had been consumed and the reaction mixture was
filtered and the solvent was removed in vaccuo at 35-40 °C
to give a yellow oil, N,N,N0,N0-tetramethyl-2,2-bis(octyloxy-
methyl)-1,3-propanediamine (1.1). The crude oil was taken up
in dichloromethane (50 mL) and the resulting solution was
shaken with ice cold 2 M HCl (75 mL). The aqueous layer was
extracted with dichloromethane (2 ꢀ 50 mL), then the combined
organic layers were washed with water (20 mL), dried (MgSO4),
and concentrated to give the title compound as a light yellow
crystalline solid that was recrystallized from ethyl acetate:acet-
one 15:1 to give clear rectangular crystals: yield 5.62 g, 67%; mp
145 °C; Rf 0.29 on basic alumina (hexanes:ethyl acetate:metha-
nol 96:4:0.4); 1H NMR δ 0.88 ppm (t, 6H, J = 6.9 Hz, 2 ꢀ Me),
1.26 -1.33 (br s, 20H, 10 ꢀ CH2), 1.56 (pentet, 4H, J = 6.6 Hz,
2 OCH2CH2), 2.97 (s, 12H, 2 ꢀ N(CH3)2), 3.47 (t, 4H, J =
6.6 Hz, octyl OCH2), 3.68 (s, 4H, OCH2C), 3.79 (s, 4H, CH2N),
11.78 (br s, HN); 13C NMR δ 71.7 (CH2CH2OC), 66.9
(CCH2OCH2C), 58.6 (CH2N), 47.5 (N(CH3)2), 44.5 (q C),
31.8 (CH2CH2CH3), 29.5, 29.3, 29.2 (3 octyl CH2), 26.2
(CH2CH2CH2O), 22.6 (CH2CH3), 14.1 (Me); HR ESI MS m/z
calcd for C25H55N2O2 (M - H - 2Cl) 415.4264, found 415.4260.
N,N,N,N0,N0,N0-Hexamethyl-2,2-bis(octyloxymethyl)-1,3-
propanediammonium Diiodide (1.9). An aqueous NaOH solution
(2 M, 30 mL) was added to salt 1.5 (4.44 g, 9.1 mmol) and the
resulting mixture was extracted with dichloromethane (3 ꢀ
50 mL). The combined extracts were washed with water and
dried (MgSO4) and concentrated to a colorless syrup, N,N,N0,
N0-tetramethyl-2,2-bis(octyloxymethyl)-1,3-propanediamine
(1.1): yield 2.45 g, 65%; Rf 0.39 on basic alumina (hexanes:ethyl
1
96:4:0.4); H NMR δ 0.88 ppm (t, 6H, J = 6.9 Hz, 2 ꢀ Me),
1.26-1.31 (br s, 20H, 10 ꢀ CH2), 1.55 (pentet, 4H, J = 6.6 Hz,
2 OCH2CH2), 2.06 (YY0 part of AA0BB0XX0YY0 pattern, 4H,
1
/
pattern, 4H,
of 2 N(CH2CH2)2), 2.25 (XX0 part of AA0BB0XX0YY0
2
1
/
of 2 N(CH2CH2)2), 3.21 (BB0 part of
2
1
AA0BB0XX0YY0 pattern, 4H,
J = 6.6 Hz, octyl OCH2), 3.59 (s, 4H, OCH2C), 3.84 (s, 4H,
CH2N), 3.91 (AA0 part of AA0BB0XX0YY0 pattern, 4H, /2 of
/
2
of 2 N(CH2)), 3.46 (t, 4H,
1
2 N(CH2)), 11.51 (br s, HN); 13C NMR δ 71.5 (CH2CH2OC),
67.5 (CCH2OCH2CH2), 57.8 (NCH2), 56.9 (CH2N), 44.3 (q C),
31.7 (CH2CH2CH3), 29.41, 29.25, 29.18 (3 octyl CH2), 26.2
(CH2CH2CH2O), 23.5(NCH2CH2), 22.6 (CH2CH3), 14.0 (Me);
HR ESI MS m/z calcd for C29H59N2O2 (M - H - 2Cl) 467.4577,
found 467.4578.
1,3-Bis(1-methyl-1-azoniacyclopentyl)-2,2-bis(octyloxymethyl)-
propane Diiodide (1.21). An aqueous 2 M NaOH solution
(50 mL) was added to compound 1.17 (12.5 g, 23.2 mmol) and
the resulting mixture was extracted with dichloromethane (3 ꢀ
50 mL). The combined extracts were washed with water and
dried (MgSO4), then concentrated to give the free base, 1,3-
bis(1-azacyclopentyl)-2,2-bis(octyloxymethyl)propane (1.13) as
a light yellow syrup: yield 10.3 g, 72%; Rf 0.32 on basic alumina
(hexanes:ethyl acetate:methanol 96:4:0.4); 1H NMR δ 0.88 ppm
(t, 6H, J = 6.8 Hz, 2 ꢀ Me), 1.27-1.34 (br s, 20H, 10 ꢀ CH2),
1.53 (pentet, 4H, J = 6.7 Hz, 2 OCH2CH2), 1.68 (m, 8H,
2NCH2CH2), 2.48 (s, 4H, CH2N), 2.56 (m, 8H, 2N(CH2)2),
1
acetate:methanol 96:4:0.4); H NMR δ 0.88 ppm (t, 6H, J =
6.9 Hz, 2 ꢀ Me), 1.26 -1.32 (br s, 20H, 10 ꢀ CH2), 1.54 (pentet,
4H, J = 7.0 Hz, 2 OCH2CH2), 2.26 (s, 12H, 2 ꢀ N(CH3)2), 3.26
(s, 4H, 2 ꢀ NCH2), 3.26 (s, 4H, OCH2C), 3.33 (t, J = 6.5 Hz,
4H, octyl OCH2); 13C NMR δ 71.2 (CH2CH2OC), 70.8 (CCH2-
OCH2C), 59.9 (CH2N), 48.7 (N(CH3)2), 45.8 (q C), 32.0 (CH2-
CH2CH3), 29.9, 29.6, 29.5, (3 octyl CH2), 26.5 (CH2CH2CH2O),
22.8 (CH2CH3), 14.2 (Me).
3.27 (s, 4H, OCH2C), 3.32 (t, 4H, J = 6.4 Hz, octyl OCH2); 13
C
NMR δ 71.7 (CCH2OCH2CH2), 71.1 (CH2CH2OC), 56.81
(CH2N), 56.84 (NCH2), 45.7 (q C), 31.9 (CH2CH2CH3),
29.87, 29.55, 29.43 (3 octyl CH2), 26.4 (CH2CH2CH2O), 24.3
(NCH2CH2), 22.8 (CH2CH3), 14.1 (Me).
Methyl iodide (13.3 g, 21.3 mmol, 10 equiv) was added to a
stirred solution of compound 1.13 (9.90 g, 21.3 mmol) in dry
THF (50 mL). The resulting mixture was refluxed under nitro-
gen for 48 h, then concentrated. The title compound, a light
brown crystalline solid, was recrystallized from ethyl acetate
to give colorless crystals: yield 13 g, 81%; mp 92 °C; Rf 0.69
on basic alumina (chloroform:acetone:methanol:ammonia
Methyl iodide (3.6 mL, 57.9 mmol, 10.0 equiv) was added to a
stirred solution of compound 1.1 (2.4 g, 5.79 mmol) in dry THF
(15 mL) and the resulting solution was refluxed for 24 h, then
concentrated. The title compound, a light yellow crystalline
solid, was recrystallized from ethyl acetate and acetone to give
colorless crystals: yield 3.01 g, 75%; mp 160-162 °C; Rf on basic
alumina 0.53 (chloroform:acetone:methanol 2:1:1); 1H NMR δ
0.88 ppm (t, 6H, J = 6.9 Hz, 2 ꢀ Me), 1.27-1.29 (br s, 20H, 10 ꢀ
CH2), 1.60 (pentet, 4H, J = 6.6 Hz, 2 OCH2CH2), 3.51 (t, 4H,
J = 6.7 Hz, octyl OCH2), 3.65 (s, 18H, 6 ꢀ CH3), 3.91 (s, 4H,
OCH2C), 4.45 (s, 4H, CH2N); 13C NMR δ 72.2 (CH2CH2OC),
68.2 (CCH2OCH2C), 67.7 (CH2N), 56.5 (N(CH3)3), 49.1(q C),
31.9 (CH2CH2CH3), 29.7, 29.4, 29.3, (octyl CH2), 26.4
(CH2CH2CH2O), 22.7 (CH2CH3), 14.2 (Me); HR ESI MS m/z
calcd for C27H60N2IO2 (M - I) 571.3700, found 571.3702; calcd
for C54H120N4I3O4 (2M - I) 1269.6444, found 1269.6443.
1,3-Bis(1-azacyclopentyl)-2,2-bis(octyloxymethyl)propane Di-
hydrochloride (1.17). A stirred solution of compound 13 (18.0 g,
31.0 mmol) in pyrrolidine (100 mL) containing potassium
carbonate (10.7 g, 31.0 mmol, 2.5 equiv) was refluxed under
1
2:2:1:0.5); H NMR δ 0.89 ppm (t, 6H, J = 6.9 Hz, 2 ꢀ Me),
1.26-1.30 (br s, 20H, 10 ꢀ CH2), 1.57 (pentet, 4H, J = 6.5 Hz,
2 OCH2CH2), 2.18 (YY0 part of AA0BB0XX0YY0 pattern, 4H,
1
/
of 2 2 N(CH2CH2)2), 2.38 (XX0 part of AA0BB0XX0YY0
2
pattern, 4H, 1/2 of 2 2 N(CH2CH2)2)), 3.46 (s, 6H, 2 NCH3), 3.49
(t, 4H, J = 6.6 Hz, octyl OCH2), 3.96 (s, 4H, OCH2C), 4.04 (m,
8H, 2 N(CH2)2), 4.63 (s, 4H, 2 CH2N); 13C NMR δ 71.9
(CH2CH2OC), 68.3 (CCH2OCH2CH2), 66.9 (NCH2), 65.4
(CH2N), 48.5 (CH3N), 48.4 (q C), 31.8 (CH2CH2CH3), 29.5,
29.3, 29.2 (3 octylCH2), 26.3 (CH2CH2CH2O), 22.6 (CH2CH3),
21.1 (NCH2CH2), 14.1 (Me); HR ESI-MS m/z calcd for
C31H64IN2O2 623.4013 (M - I), found 623.4011.
3,3-Bis(octyloxymethyl)pentanedinitrile (2.1). Potassium cya-
nide (0.80 g, 12.0 mmol, 3.0 equiv) was added to a stirred
solution of compound 13 (2.4 g, 4.1 mmol) in dry DMF
7768 J. Org. Chem. Vol. 74, No. 20, 2009

Jahan et al.
JOCArticle
(25 mL). The resulting mixture was stirred at 80 °C for 24 h, and
then allowed to cool to rt. A solid was deposited and the solution
was decanted. The solid was washed with dichloromethane (2 ꢀ
10 mL). The combined solution and washings were concentrated
to yellow oil that was taken up in dichloromethane (30 mL). The
resulting solution was washed with water (3 ꢀ 25 mL), dried
(MgSO4), and concentrated to give the title compound as a light
yellow oil: yield 1.3 g, 83%; Rf 0.42 (hexanes:ethyl acetate 9:1);
1H NMR δ 0.88 (t, 6H, J = 6.9 Hz, 2 ꢀ Me), 1.23-1.33 (br s,
20H, 10 ꢀ CH2), 1.55 (pentet, 4H, J = 7.0 Hz, 2 OCH2CH2),
2.57 (s, 4H, CH2CN), 3.42 (s, 4H, OCH2C), 3.44 (t, J = 6.5 Hz,
4H, octyl OCH2); 13C NMR δ 116.7 (CN), 71.9 (CH2CH2OC),
70.8 (CCH2OCH2C), 41.3 (q C), 32.9 (CH2CH2CH3), 29.45,
29.34 (2 octyl CH2), 29.47 (OCH2CH2), 26.2 (CH2CH2CH2O),
22.7 (CH2CH3), 21.7 (CH2CN), 14.2 (Me); HR ESI MS m/z
calcd for C23H42N2O2Na (M þ Na) 401.3138, found 401.3152.
3,3-Bis(octyloxymethyl)pentanedioic Acid (2.5). A mixture of
compound 2.1 (2.5 g, 5.61 mmol) in 1-propanol (40 mL) contain-
ing 35% NaOH (10 mL) was refluxed for 36 h. The reaction
mixture was concentrated then the resulting aqueous reaction
mixture was refluxed for another 24 h. The reaction mixture was
cooled to 10 °C, then acidified by adding a dilute HCl solution
until the pH was 5 (pH paper). The mixture was extracted with
ethyl acetate (2 ꢀ 50 mL) and the combined organic layers were
washed with water (2 ꢀ 30 mL) and brine (20 mL), dried
(Na2SO4), and concentrated to give the crude product (2.5).
The product was purified by flash column chromatography on
silica gel, using a gradient changing from 5% EtOAc in hexanes
to 15% EtOAc in hexanes as eluent. The product was obtained
as a thick colorless syrup: yield 1.75 g (63%); Rf 0.5 (EtOAc:
hexanes 1:1); 1H NMR (CDCl3) δ 0.88 (t, 6H, J = 6.5 Hz, CH3),
1.24-1.31 (m, 20H, 10 ꢀ CH2), 1.53 (pentet, 4H, J = 6.5 Hz,
OCH2CH2), 2.61 (s, 4H, COCH2), 3.40 (t, 4H, J = 6.5, OCH2),
3.46 (s, 4H, OCH2), 10.92 (br s, 2H, COOH); 13C NMR (CDCl3)
δ 176.8 (COOH), 73.2 (CCH2O), 71.8 (OCH2CH2), 41.1 (q C),
37.5 (HOOCCH2), 32.0 (CH2CH2CH3), 29.60, 29.55, 29.42
(3 octyl CH2), 26.3 (OCH2CH2CH2), 22.8 (CH3CH2), 14.2
(CH3); HR ESI MS m/z calcd for C23H43O6 (M - 1) 415.3065,
found 415.3042.
General Procedure for Formation of N,N-Dimethyl Amides: N,
N,N0,N0-Tetramethyl-3,3-bis(octyloxymethyl)pentanediamide
(2.9). 1-Hydroxybenzotriazole (HOBT, 1.03 g, 7.69 mmol)
and N-(3-dimethylamino-propyl)-N0-ethylcarbodiimide.hydro-
chloride (EDC.HCl, 1.54 g, 8.07 mmol) were added to a stirred
solution of diacid 2.5 (1.6 g, 3.9 mmol) and the reaction mixture
was stirred for 1 h. Dimethylamine hydrochloride (1.25 g, 15.4
mmol) and triethylamine (2.7 g, 27 mmol) were added and the
reaction mixture was stirred for another 24 h, then diluted with
dichloromethane (50 mL). This mixture was washed with water
(2 ꢀ 30 mL) and brine (20 mL), dried (Na2SO4), and concen-
trated. The residue was purified by flash column chromatogra-
phy, using a gradient of 15% to 30% EtOAc in hexanes as
eluent, yielding 2.9 as a viscous liquid: yield 1.63 g (91%); Rf 0.5
(ethyl acetate:hexanes 2:1); 1H NMR (CDCl3) δ 0.88 (t, 6H, J =
6.5 Hz, CH3), 1.26-1.30 (m, 20 H, 10 ꢀ CH2), 1.51 (pentet, 4H,
J = 6.5 Hz, OCH2CH2), 2.65 (s, 4H, COCH2), 2.89 (s, 6H,
NCH3), 3.03 (s, 6H, NCH3), 3.36 (t, 4H, J = 6.5 Hz, OCH2),
3.53 (s, 4H, OCH2); 13C NMR (CDCl3) δ 172.4 (CO), 72.7
(CCH2O), 71.4 (OCH2CH2), 42.1 (qC), 37.9 (NCH3), 35.5
(NCH3), 33.6 (NCOCH2), 32.0 (CH2CH2CH2), 29.87, 29.63,
29.51 (2 ꢀ 3 octyl CH2), 26.4 (OCH2CH2CH2), 22.8 (CH3CH2),
14.2 (CH3); HR ESI MS m/z calcd for C27H54N2O4Na (M þ Na)
493.3976, found 493.3966.
by water (0.3 mL), then 1 M NaOH (0.3 mL). The mixture was
filtered on a bed of Celite that was washed with hot ethyl acetate.
The combined filtrate and washings were dried (Na2SO4),
filtered, and concentrated to a residue that was purified by flash
column chromatography. Elution with a gradient of 5% to 15%
MeOH in dichloromethane gave 2.13 as a light brown liquid:
yield 0.67 g (80%); Rf on basic alumina 0.46 (dichloromethane:
1
methanol 96:4); H NMR (CDCl3) δ 0.88 (t, 6H, J = 7.0 Hz,
CH3), 1.22-1.38 (m, 20 H, 10 ꢀ CH2), 1.43-1.54 (m, 8H,
NCH2CH2, OCH2CH2), 2.21 (s, 12H, NCH3), 2.27 (t, 4H,
J = 8.0 Hz, NCH2), 3.19 (s, 4H, OCH2), 3.34 (t, 4H, J = 6.5
Hz, OCH2); 13C NMR (CDCl3) δ 73.8 (CCH2O), 71.5 (OCH2-
CH2), 54.5 (NCH2), 45.8 (NCH3), 40.2 (qC), 32.0 (CH3-
CH2CH2), 30.3 (NCH2CH2), 29.89, 29.64, 29.50 (2 ꢀ 3 octyl
CH2), 26.5 (OCH2CH2CH2), 22.8 (CH3CH2), 14.3 (CH3); ESI
MS m/z calcd for C27H58N2O2 (M þ 1) 443.4571, found
443.4558.
N,N,N,N0,N0,N0-Hexamethyl-3,3-bis(octyloxymethyl)-1,5-
pentanediammonium Diiodide (2.17). A solution of methyl iodide
(1.6 g, 11 mmol) and diamine 2.13 (0.50 g, 1.1 mmol) in THF
(20 mL) was refluxed for 36 h, then concentrated. The solid
residue was purified by flash column chromatography with 10%
methanol in dichloromethane as eluent to give the title product
as an off-white solid: yield 0.70 g (85%); mp 223-225 °C; Rf 0.5
on basic alumina (8% methanol in dichloromethane); 1H NMR
(CDCl3) δ 0.88 (t, 6H, J = 7.0 Hz, CH3), 1.22-1.28 (m, 20 H,
10 ꢀ CH2), 1.45 (t, 4H, J = 6.0 Hz, OCH2CH2), 1.83 (AA0 part
of AA0XX0 pattern, 4H, NCH2CH2), 3.13 (s, 4H, OCH2), 3.15
(s, 18H, NCH3), 3.18 (t, 4H, J= 7.0 Hz, OCH2), 3.73 (XX part
of AA0XX0 pattern, 4H, NCH2); 13C NMR (CDCl3) δ 71.7
(CCH2O), 71.5 (OCH2CH2), 62.8 (CH2N(CH3)3), 54.2 (NCH3),
41.6 (qC), 32.0 (CH2CH2CH2), 29.82, 29.58, 29.50 (3 octyl
CH2), 26.6 (OCH2CH2CH2), 24.6 (NCH2CH2), 22.8 (CH3-
CH2), 14.3 (CH3); HR ESI MS m/z calcd for C29H64IN2O2
(M - I) 599.4007, found 599.3993.
N,N,N0,N0-Tetramethyl-4,4-bis(octyloxymethyl)-2,5-hepta-
dienediamide (3.1). A solution of dry dimethyl sulfoxide
(DMSO) (0.47 g, 6.11 mmol) in dichloromethane (2 mL) was
added dropwise to a stirred solution of oxalyl chloride (0.38 g,
3.0 mmol) in dichloromethane (5 mL) at -78 °C. After the
reaction mixture had been stirred for 30 min, a solution of diol
9 (0.50 g, 1.4 mmol) was added and the reaction mixture was
stirred for 1.5 h at -78 °C, then Et3N (0.98 g, 9.7 mmol) was
added slowly. The reaction mixture was stirred for 30 min,
allowed to warm to rt, then quenched by addition of a saturated
NH4Cl solution (10 mL). The reaction mixture was extracted
with dichloromethane (3 ꢀ 50 mL), and the combined organic
layers were washed with 2 M HCl (5 mL), water (2 ꢀ 5 mL), and
brine (5 mL), then dried (Na2SO4) and concentrated to give 2,2-
bis(octyloxymethyl)propanedial (17) as a colorless viscous oil:
yield 0.47 g, 95%; Rf 0.56 (hexanes:ethyl acetate 8:2); 1H NMR δ
0.88 (t, 6H, J = 7.0 Hz, 2 ꢀ Me), 1.26-1.32 (br s, 20H, 10 ꢀ
CH2), 1.51 (p, 4H, J = 7.2 Hz, 2 OCH2CH2), 3.42 (t, 4H, J =
6.5 Hz, decyl OCH2), 3.87 (s, 4H, OCH2C), 9.74 (s, 2H,CHO);
13C NMR δ 199.4 (CHO), 72.3 (CH2CH2OC), 68.6 (OCH2C),
43.8 (q C), 31.7 (CH2CH2CH3), 29.76, 29.62, 29.48, 29.44, 29.37
(5 decyl CH2), 26.12 (CH2CH2CH2O), 22.8 (CH2CH3), 14.2
(Me); LR ESI m/z calcd for C21H40O4Na MeOH 411.31, found
3
411.3; for C21H40O4Na 2MeOH 443.33, found 443.3; for
3
2 C21H40O4 þ Na þ H2O 753.54, found 753.6.
Diethyl N,N-dimethylcarbamoylmethylphosphonate44,58
(4.1 g, 18 mmol) in THF (10 mL) was added in portion to a
stirred suspension of NaH (0.45 g, 18 mmol) in THF (80 mL) at
rt and the reaction mixture was stirred for 2 h, then cooled to
0 °C. A solution of dialdehyde 17 (1.6 g, 4.5 mmol) in THF
N,N,N0,N0-Tetramethyl-3,3-bis(octyloxymethyl)-1,5-pentane-
diamine (2.13). Diamide 2.9 (0.9 g, 1.91 mmol) was added
dropwise to a stirred suspension of LiAlH4 (0.29 g, 7.65 mmol)
in THF (50 mL) at 0 °C, then the reaction mixture was stirred at
rt for 6 h. Ethyl acetate (50 mL) was added dropwise, followed
(58) Lomakina, V. I.; Mandel’baum, Y.; Mel’nikov, N. N. Zh. Obshch.
Khim. 1966, 36, 447–449.
J. Org. Chem. Vol. 74, No. 20, 2009 7769

Jahan et al.
JOCArticle
(10 mL) was added and the reaction mixture was stirred for 24 h
at rt. A saturated aqueous ammonium chloride solution (20 mL)
was added to the reaction mixture and then the volatile organic
components were removed by concentration. The resulting
solution was extracted with ethyl acetate (3 ꢀ 30 mL). The
combined organic layers were washed with water (2 ꢀ 20 mL)
and brine (20 mL), dried (Na2SO4), filtered, and concentrated.
The residue was purified by flash column chromatography,
using a gradient of 80% to 90% EtOAc in hexanes as eluent,
yielding 3.1 as a viscous liquid: yield 1.4 g (63%); Rf 0.35
(dichloromethane:methanol 94:6); 1H NMR δ 0.88 (t, 6H,
J = 7 Hz, 2 ꢀ Me), 1.26-1.34 (br s, 20H, 10 ꢀ CH2), 1.53
(pentet, 4H, J = 7 Hz, 2 OCH2CH2), 2.99 (s, 3H, NCH3), 3.05 (s,
3H, NCH3), 3.39 (t, 4H, J = 6.5 Hz, decyl OCH2), 3.49 (s, 4H,
OCH2C), 6.36 (d, 2H, J = 16 Hz, COCHCH), 6.86 (d, 2H,
J = 16 Hz, COCHCH); 13C NMR δ 166.8 (CdO), 145.3
(CHdCHC), 121.9 (COCHd), 72.9 (CH2CH2OC), 71.9 (OC-
H2C), 48.9 (q C), 37.5 (NCH3), 35.8 (NCH3), 32.0 (CH2-
CH2CH3), 29.77, 29.61, 29.45 (3 octyl CH2), 26.4 (CH2CH2-
CH2O), 22.8 (CH2CH3), 14.2 (Me); HR ESI MS m/z calcd for
C29H54N2O4Na (M þ Na) 517.3976, found 517.3971.
solid: yield 0.75 g (94%); mp 233-236 °C; Rf 0.5 on basic
alumina (7% methanol in dichloromethane); 1H NMR
(CDCl3) δ 0.88 (t, 6H, J = 7.0 Hz, CH3), 1.23-1.31 (m, 20 H,
10 ꢀ CH2), 1.43 (m, 4H, J = 8.2 Hz NCH2CH2CH2), 1.51
(pentet, 4H, J = 6.5 Hz, 2 ꢀ OCH2CH2), 1.88 (m, 4H, NCH2-
CH2), 3.21 (s, 4H, OCH2), 3.36 (t, 4H, J = 6.5 Hz, OCH2), 3.44
(s, 18H, NCH3), 3.73 (m, 2H, NCH2); 13C NMR (CDCl3)
δ 72.5 (CCH2O), 71.6 (OCH2), 67.8 (NCH2), 54.5 (NCH3),
41.4 (qC), 32.0 (CH2CH2CH3), 29.82, 29.62, 29.53 (octyl
CH2), 26.7 (CCH2), 26.5 (OCH2CH2CH2), 22.8 (CH3CH2),
17.8 (NCH2CH2), 14.3 (Me); HR ESI MS m/z calcd for
C31H68IN2O2 (M - I) 627.4320, found 627.4267.
N,N,N0,N0-Tetramethyl-5,5-bis(octyloxymethyl)-3,7-dioxa-
1,9-nonanediaminium Dichloride (4.5). Sodium hydride (3.36 g,
0.14 mol, 10 equiv) was added slowly to a stirred solution of 2,2-
dioctyloxymethyl-1,3-propanediol (1) (5.05 g, 0.014 mol) in
DMF (500 mL) under nitrogen gas at rt and the mixture was
stirred vigorously for 1 h. 2-(Dimethylamino)ethyl chloride
hydrochloride (8.08 g, 0.05 mol, 4 equiv) was added and the
reaction mixture was stirred at 50 °C under an N2 atmosphere
for 12 h, then quenched with methanol. The mixture was filtered
and concentrated. The residue was taken up in diethyl ether
(50 mL) and the resulting solution was washed with brine
(50 mL), dried (MgSO4), and concentrated at 30-35 °C to give
N,N,N0,N0-tetramethyl-5,5-bis(octyloxymethyl)-3,7-dioxa-1,9-
nonanediamine (4.1) as a orange oil. The crude product was
taken up in dichloromethane (50 mL) and the resulting solution
was shaken with ice cold 2 M HCl (30 mL). The aqueous layer
was diluted with brine and this solution was extracted with
dichloromethane (5 ꢀ 30 mL). The combined organic layers
were dried (MgSO4) and concentrated to give the title com-
pound (4.5) as a light yellow solid that was crystallized from
ethyl acetate and acetone to give colorless crystals: yield 4.90 g,
61%; mp 150-152 °C; Rf on basic alumina 0.47 (dichloro-
N,N,N0,N0-Tetramethyl-4,4-bis(octyloxymethyl)heptanediamide
(3.5). A mixture of 3.1 (0.5 g, 1.0 mmol) and 10% Pd/C wet
Degusa type catalyst (50 mg) in ethyl acetate (50 mL) was stirred
under H2 at atmospheric pressure for 24 h. The reaction mixture
was filtered with a Celite bed and the filtrate was concentrated to
give compound 3.5 as a colorless liquid: yield 0.46 g (91%); Rf 0.5
1
(dichloromethane:methanol 95:5); H NMR δ 0.88 (t, 6H, J =
6.5 Hz, 2 ꢀ Me), 1.25-1.31 (br s, 20H, 10 ꢀ CH2), 1.50 (pentet,
4H, J = 7 Hz, 2 OCH2CH2), 1.61 (4H, AA0XX0 pattern, CCH2),
2.32 (4H, AA0XX0 pattern, COCH2), 2.99 (s, 3H, NCH3), 3.07
(s, 3H, NCH3), 3.22 (s, 4H, OCH2C), 3.34(t, 4H, J=6.5Hz, decyl
OCH2); 13C NMR δ 173.8 (CdO), 73.9 (CH2CH2OC), 71.7
(OCH2C), 40.6 (qC), 37.4 (NCH3), 35.6 (NCH3), 32.0
(CH2CH2CH3), 29.90, 29.64, 29.48 (3 octyl CH2), 28.04, 27.94
(COCH2CH2, COCH2), 26.5 (CH2CH2CH2O), 22.8 (CH2CH3),
14.3 (Me); HR ESI MS m/z calcd for C29H58N2O4Na (M þ Na)
521.4289, found 521.4278.
N,N,N0,N0-Tetramethyl-4,4-bis(octyloxymethyl)-1,7-heptane-
diamine (3.9). Diamide 3.5 (0.6 g, 1.2 mmol) was added dropwise
to a stirred suspension of LiAlH4 (0.18 g, 4.8 mmol) in THF at
0 °C. The reaction mixture was stirred at rt for 6 h, then the
excess of LAH was decomposed by dropwise addition of ethyl
acetate (50 mL), water (0.3 mL), then 1 M NaOH (0.3 mL) at
10 °C. The mixture was filtered on a bed of Celite, which was
then washed with hot ethyl acetate. The combined filtrate and
washings were dried (Na2SO4), then concentrated to a residue
that was purified by flash column chromatography. Elution
with a gradient of 5% to 15% MeOH in dichloromethane gave
the title compound as a light brown liquid: yield 0.45 g (80%);
Rf on basic alumina 0.71 (dichloromethane:methanol 94:6); 1H
NMR (CDCl3) δ 0.88 (t, 6H, J = 7.0 Hz, CH3), 1.21-1.33 (m, 24
H, 10 octyl CH2, 2 CCH2), 1.37-1.43 (m, 4H, NCH2CH2), 1.51
(pentet, 4H, J = 7 Hz, OCH2CH2), 2.201 (t, 4H, J = 7.5 Hz,
NCH2), 2.206 (s, 12H, NCH3), 3.17 (s, 4H, OCH2), 3.33 (t, 4H,
J = 6.5 Hz, OCH2); 13C NMR (CDCl3) δ 73.5 (CCH2O), 71.5
(OCH2), 60.9 (NCH2), 45.7 (NCH3), 41.0 (qC), 32.0
(CH2CH2CH3), 29.85, 29.76, 29.65, 29.50 (3 octyl CH2, CCH2),
26.5 (OCH2CH2CH2), 22.8 (CH2CH3), 21.45 (NCH2CH2), 14.3
(Me); HR ESI MS m/z calcd for C29H63N2O2 (M þ 1) 471.4884,
found 471.4885.
1
methane:ethanol 96:4); H NMR δ 0.88 (t, 6H, J = 6.8 Hz,
2 ꢀ Me), 1.27 (br s, 20H, 10 ꢀ CH2), 1.50 (pentet, 4H, J =
6.3 Hz, 2 OCH2CH2), 2.92 (s, 12H, 2 ꢀ N(CH3)2), 3.33 (t, 4H,
J = 6.7 Hz, octyl OCH2), 3.34 (s over broad pattern, 8H,
octylOCH2C and OCH2CH2N), 3.51 (s, 4H, N(CH2)2OCH2C),
3.90 (XX0 part of AA0XX0 pattern, 4H, OCH2CH2N), 12.0 (br s,
2H, NH); 13C NMR δ 71.7 (CH2CH2OC), 70.6 (CCH2O
(CH2)2N), 69.5 (CCH2O octyl), 65.8 (OCH2CH2N), 56.7
(NCH2CH2), 45.1 (q C), 43.6 (N(CH3)2), 32.0 (CH2CH2CH3),
29.7, 29.5, 29.3 (octyl CH2), 26.2 (CH2CH2CH2O), 22.7
(CH2CH3), 14.2 (Me); HR ESI MS m/z calcd for C29H63N2O4
(M þ H) 503.4788, found 503.4784.
N,N,N,N0,N0,N0-Hexamethyl-5,5-bis(octyloxymethyl)-3,7-
dioxa-1,9-nonanediammonium Diiodide (4.9). Salt 4.5 (4.1 g,
7.1 mmol) was dissolved in a NaOH solution (2 M, 30 mL)
and the resulting mixture was extracted with diethyl ether (2 ꢀ
30 mL). The combined extracts were washed with brine (10 mL),
dried (MgSO4), and concentrated to give a light yellow syrup,
N,N,N0,N0-tetramethyl-5,5-bis(octyloxymethyl)-3,7-dioxa-1,9-
nonanediamine (4.1): yield 3.20 g, 89%; Rf on basic alumina
1
0.44 (chloroform:ethanol 98:2); H NMR δ 0.88 (t, 6H, J =
6.9 Hz, 2 ꢀ Me), 1.25-1.33 (br m, 20H, 10 ꢀ CH2), 1.51 (pentet,
4H, J = 6.8 Hz, 2 ꢀ OCH2CH2), 2.26 (s, 12H, 2 ꢀ N(CH3)2),
2.49 (t, 4H, J = 5.8 Hz, OCH2CH2N), 3.35 (t, 4H, J = 6.5 Hz,
octyl OCH2), 3.36 (s, 4H, octylOCH2C), 3.39 (s, 4H,
NCH2CH2OCH2C), 3.49 (t, 4H, J = 6.0 Hz, OCH2CH2N);
13C NMR δ 71.9 (CH2CH2OC), 70.5 (NCH2CH2OCH2), 70.3
(OCH2CH2N), 69.8 (CCH2O octyl), 58.8 (OCH2CH2N), 46.1
(N(CH3)2), 45.6 (q C), 32.0 (CH2CH2CH3), 29.70, 29.57, 29.54
(3 octyl CH2), 29.40 (OCH2CH2), 26.3 (CH2CH2CH2O), 22.8
(CH2CH3), 14.2 (Me); LR ESI MS m/z calcd for C29H63N2O4
(M þ H) 503.47, found 503.4; calcd for M þ Na 525.46, found
525.5.
N,N,N,N0,N0,N0-Hexamethyl-4,4-bis(octyloxymethyl)-1,7-
heptanediammonium Diiodide (3.13). Methyl iodide (1.51 g,
10.6 mmol) was added to a stirred solution of amine 3.9 (0.5 g,
1.0 mmol) in THF (30 mL). The reaction mixture was refluxed
for 12 h, then concentrated. The solid residue was purified by
flash column chromatography with 10% methanol in dichloro-
methane as eluent to give the title compound as an off-white
7770 J. Org. Chem. Vol. 74, No. 20, 2009

Jahan et al.
JOCArticle
Compound 4.1 (7.49 g, 0.0149 mol) was shaken with methyl
iodide (8.28 g, 0.0584 mol, 4 equiv) for 2 min, then dichloro-
methane (100 mL) was added and shaking was continued for
5 min. The reaction mixture was concentrated to a yellow solid,
which was washed with acetone, then crystallized from toluene:
ethanol 10:1 to give colorless crystals: yield 10.17 g, 87%;
recrystallized from ethyl acetate:methanol; Rf on basic alumina
0.54 (butanol:water:methanol 20:5:2); mp softens 180 °C, melts
(s, 4H, CCH2O(CH2)2N), 3.47 (t, J = 6.3 Hz, 4H, 2 OCH2CH2);
13C NMR δ 71.6 (CH2CH2OC), 70.4 (CCH2O(CH2)2N), 70.4
(CH2CH2N), 69.8 (CCH2O octyl), 52.1 (NCH2CH2), 47.8
(NCH2CH3), 45.4 (q C), 32.0 (CH2CH2CH3), 29.8, 29.6, 29.5,
29.3 (octyl CH2), 26.3 (CH2CH2CH2O), 22.8 (CH2CH3), 14.2
(Me), 12.1 (CH2CH3).
Ethyl bromide (98%, 2.78 mL, 37.3 mmol, 20.0 equiv) was
added to a stirred solution of compound 4.13 (1.04 g, 1.86 mmol)
in a mixture of THF and ethanol (6 mL) (2:1). Potassium
carbonate (0.5 g, 3.7 mmol, 2 equiv) was added and the resulting
mixture was refluxed for 26 h, cooled to rt, and filtered, then the
filtrate was concentrated to give the title compound (4.21) as a
colorless sticky solid (1.92 g). The salt precipitated from ethyl
acetate containing a few drops of methanol: yield 1.13 g, 78%;
mp 157 °C; Rf 0.53 on basic alumina (butanol:water:methanol
20:5:2); 1H NMR δ 0.88 (t, 6H, J = 6.9 Hz, 2 ꢀ Me), 1.28 (br s,
20H, 10 ꢀ CH2), 1.41 (t, J = 7.2 Hz, 12H, 6 ꢀ Me), 1.51 (pentet,
4H, J = 6.5 Hz, 2 OCH2CH2), 3.28 (s, 4H, octyl OCH2C), 3.33
(t, J = 6.6 Hz, 4H, octyl OCH2), 3.47 (s, 4H, CCH2O(CH2)2N),
3.4 7 (q, 12H, J = 7.2 Hz, 2 N(CH2CH3)2), 3.79 (AA0 part of
AA0BB0 pattern, 4H, 2 NCH2CH2), 3.94 (BB0 part of AA0BB0
pattern, 4H, 2OCH2CH2); 13C NMR δ 71.9 (CH2CH2OC),
71.1(CCH2O(CH2)2N), 69.5 (CCH2O octyl), 65.1 (OCH2-
CH2N), 57.8 (NCH2CH2), 54.4 (NCH2CH3), 45.3 (q C), 31.9
(CH2CH2CH3), 29.7, 29.6, 29.4 (octyl CH2), 26.3 (CH2-
CH2CH2O), 22.7 (CH2CH3), 14.2 (Me), 8.4 (CH2CH3); HR
ESI MS m/z calcd for C37H80N2O4/2 (M - 2Br)/2 308.3054,
found 308.3038.
5,5-Bis(dodecyloxymethyl)-N,N0-diethyl-N,N,N0,N0-dimethyl-
3,7-dioxa-1,9-nonanediammonium dibromide (4.25). Ethyl bro-
mide (2.3 mL, 31 mmol, 10 equiv) then sodium bicarbonate
(1.30 g, 15.5 mmol, 5.0 equiv) were added to a stirred solution of
compound 4.3 (2.13 g, 3.10 mmol) in THF (30 mL) and the
resulting mixture was refluxed for 12 h, cooled to rt, and filtered,
then the filtrate was concentrated to give the title compound as a
colorless solid. Crystallization from ethyl acetate and acetone
gave colorless granules: yield 2.37 g, 91.1%; mp 185 °C; Rf on
basic alumina 0.45 (butanol:water:methanol 20:5:2); 1H NMR
δ 0.88 ppm (t, 6H, J = 6.9 Hz, 2 ꢀ Me), 1.27-1.31 (br s, 36H,
18 ꢀ CH2), 1.45 (t, J = 7.2 Hz, 6H, 2 ꢀ NCH2CH3) 1.51 (pentet,
4H, J = 6.2 Hz, 2 OCH2CH2), 3.28 (s, 4H, dodecyl OCH2C),
3.32 (t, J = 6.6 Hz, 4H, dodecyl OCH2), 3.43 (s, 12H, 2 ꢀ
N(CH3)2), 3.47 (s, 4H, CCH2O(CH2)2N), 3.81 (q, 4H, J = 7.3
Hz, 2 ꢀ N(CH2CH3)2), 3.92 (AA0 part of AA0BB0 pattern, 4H,
2 OCH2CH2N), 3.97 (BB0 part of AA0BB0 pattern, 4H,
2 NCH2CH2O); 13C NMR δ 71.8 (CH2CH2OC), 70.9 (CCH2O-
(CH2)2N), 69.4 (CCH2Ododecyl), 65.3 (OCH2CH2N), 63.1
(NCH2CH2O), 61.0 (NCH2CH3), 51.3 (N(CH3)2), 45.1 (q C),
31.9 (CH2CH2CH3), 29.7, 29.7, 29.5, 29.4 (dodecyl CH2), 26.3
(CH2CH2CH2O), 22.7 (CH2CH3), 14.2 (Me), 8.9 (NCH2CH3);
HR ESI MS m/z calcd for C41H88BrN2O4 (M - Br) 751.5927,
found 751.5922.
1
188-189 °C; H NMR δ 0.89 (t, 6H, J = 6.9 Hz, 2 ꢀ Me),
1.28 -1.32 (br s, 20H, 10 ꢀ CH2), 1.51 (pentet, 4H, J = 6.3 Hz,
2 OCH2CH2), 3.30 (s, 4H, octylOCH2C), 3.33 (t, 4H, J = 6.6
Hz, octyl OCH2), 3.51 (s, 4H, N(CH2)2OCH2C), 3.54 (s, 18H,
2 ꢀ N(CH3)3), 3.94 (br s, 4H, OCH2), 4.02 (br m, 4H, CH2N);
13C NMR δ 71.8 (CH2CH2OC), 70.9 (CCH2O(CH2)2N), 69.4
(CCH2Ooctyl), 65.8 (CH2N), 65.4 (OCH2CH2N), 54.9
(N(CH3)3), 45.2 (q C), 31.9 (CH2CH2CH3), 29.66, 29.41, 29.32
(3 octyl CH2), 29.46 (OCH2CH2), 26.2 (CH2CH2CH2O), 22.7
(CH2CH3), 14.2 (Me); LR ESI MS m/z calcd for C31H68N2O4I
(M - I) 659.45, found 659.1. Anal. Calcd for C31H68N2O4I2: C,
47.33; H, 8.71; N, 3.56. Found: C, 47.34; H, 8.51; N, 3.29.
N,N,N0,N0-Tetraethyl-5,5-bis(octyloxymethyl)-3,7-dioxa-1,9-
nonanediaminium Dihydrochloride (4.17). Sodium hydride
(6.10 g, 0.15 mol, 10 equiv) was added slowly to a stirred solution
of 2,2-dioctyloxymethyl-1,3-propanediol (9) (5.50 g, 0.015 mol)
in THF (500 mL) under N2 gas at rt. When foaming ceased, the
mixture was stirred vigorously at 60 °C for 1 h. The reaction
mixture was cooled to rt, then 2-bromo-N,N-diethylethylamine
hydrobromide (15.95 g, 0.061 mol, 4.0 equiv) was added. The
reaction mixture was stirred at 60 °C under N2 gas for 12 h, then
quenched with methanol. The reaction mixture was filtered and
the filtrate concentrated to a syrupy residue. The residue was
taken up in diethyl ether (50 mL) and the resulting solution was
washed with brine (50 mL), dried (MgSO4), and concentra-
ted at 30-35 °C to give crude N,N,N0,N0-tetraethyl-5,5-bis-
(octyloxymethyl)-3,7-dioxa-1,9-nonanediamine (4.13). The
crude product was taken up in dichloromethane (50 mL) and
the resulting solution was shaken with ice cold 2 M HCl (30 mL).
The aqueous layer was diluted with brine (20 mL) and this
solution was extracted with dichloromethane (5 ꢀ mL). The
combined organic layers were dried (MgSO4) and concentrated
to give the title compound (4.17) as a colorless solid, which was
crystallized from ethyl acetate and acetone to give colorless
granules: yield 7.20 g, 75%; mp 155 °C; Rf 0.5 (dichloromethane:
ethanol 96:4); 1H NMR δ 0.88 (t, 6H, J = 6.8 Hz, 2 ꢀ Me), 1.27
(br s, 20H, 10 ꢀ CH2), 1.42 (t, 12H, J = 7.2 Hz, 4 ꢀ Me), 1.51
(pentet, 4H, J = 6.3 Hz, 2 OCH2CH2), 3.21 (very br AB part of
ABX3 pattern, 8H, NCH2CH3), 3.26 (br t, 4H, NCH2CH2O),
3.31 (s, 4H, octyl OCH2C), 3.33 (t, 4H, J = 6.6 Hz, octyl OCH2),
3.44 (s, 4H, N(CH2)2OCH2C), 3.91 (t, 4H, J = 4.3 Hz, OCH2-
CH2N), 12.0 (br s, 2H, NH); 13C NMR δ 71.7 (CH2CH2OC),
70.6 (CCH2O(CH2)2N), 69.4 (CCH2O octyl), 65.8 (OCH2-
CH2N), 50.9 (NCH2CH2), 47.3 (NCH2CH3), 45.1 (q C),
32.0 (CH2CH2CH3), 29.6, 29.5, 29.3 (octyl CH2), 26.2
(CH2CH2CH2O), 22.7 (CH2CH3), 14.1 (Me), 8.8 (Me); HR
ESI MS m/z calcd for C33H72N2O4/2 (M þ 2H/2) 280.2741,
found 280.2741.
5,5-Bis(dodecyloxymethyl)-N,N,N0,N0-dimethyl-3,7-dioxa-N,
N0-dipropyl-1,9-nonanediammonium Dibromide (4.26). 1-Bromo-
propane (5.4 mL, 59 mmol, 10 equiv) then sodium bicarbo-
nate (2.47 g, 29.4 mmol, 5.0 equiv) were added to a stirred
solution of compound 4.3 (4.05 g, 5.89 mmol) in THF (50 mL)
and the resulting mixture was refluxed for 26 h, cooled to rt, and
filtered, then the filtrate was concentrated to give the title
compound as a colorless solid. Crystallization from ethyl acetate
and acetone gave colorless crystals: yield 4.83 g, 95.5%; mp 62
°C; Rf on basic alumina 0.50 (butanol:water:methanol 20:5:2);
1H NMR δ 0.88 ppm (t, 6H, J = 6.7 Hz, 2 ꢀ Me), 1.05 (t, J =
7.3 Hz, 6H, 2 ꢀ N (CH2)2CH3) 1.26-1.31 (br s, 36H, 18 ꢀ CH2),
1.51 (pentet, 4H, J = 6.2 Hz, 2 OCH2CH2), 1.86 (AA0 part
of AA0XX0 pattern, 4H, 2 x NCH2CH2CH3), 3.28 (s, 4H,
dodecylOCH2C), 3.32 (t, J = 6.6 Hz, 4H, dodecyl OCH2),
3.44 (s, 12H, 2 ꢀ N(CH3)2), 3.48 (s, 4H, CCH2O(CH2)2N), 3.63
N,N,N,N0,N0,N0-Hexaethyl-5,5-bis(octyloxymethyl)-3,7-
dioxa-1,9-nonanediammonium Dibromide (4.21). Salt 4.17 (1.44
g, 2.28 mmol) was dissolved in a NaOH solution (2 M, 15 mL).
The resulting mixture was extracted with diethyl ether (3 ꢀ
5 mL) to yield a colorless syrup of N,N,N0,N0-tetraethyl-5,5-
bis(octyloxymethyl)-3,7-dioxa-1,9-nonanediamine (4.13), yield
1.08 g, 85%; Rf 0.43 on basic alumina (dichloromethane:ethanol
98:2); 1H NMR δ 0.88 (t, 6H, J = 6.8 Hz, 2 ꢀ Me), 1.03 (t, J =
7.2 Hz, 12H, 4 ꢀ Me) 1.28 (br s, 20H, 10 ꢀ CH2), 1.51 (pentet,
4H, J = 6.8 Hz, 2 OCH2CH2), 2.57 (q, 8H, J = 7.1 Hz, 2 ꢀ
N(CH2CH3)2), 2.65 (t, 4H, J = 6.2 Hz, 2NCH2CH2), 3.35 (t,
J = 6.5 Hz, 4H, octyl OCH2), 3.35 (s, 4H, decylOCH2C), 3.38
J. Org. Chem. Vol. 74, No. 20, 2009 7771

Jahan et al.
JOCArticle
(XX0 part of AA0XX0 pattern 4H, 2 ꢀ NCH2CH2CH3), 3.93
(AA0 part of AA0BB0 pattern, 4H, 2, OCH2CH2N), 3.99 (BB0
part of AA0BB0 pattern, 4H, 2,NCH2CH2O); 13C NMR δ 71.8
(CH2CH2OC), 70.9 (CCH2O(CH2)2N), 69.5 (CCH2Ododecyl),
67.1 (NCH2CH2CH3), 65.4 (OCH2CH2N), 63.6 (NCH2CH2O),
51.9 (N(CH3)2), 45.2 (q C), 31.9 (CH2CH2CH3), 29.7, 29.7, 29.5,
29.4 (dodecyl CH2), 26.2 (CH2CH2CH2O), 22.7 (CH2CH3),
16.5 (NCH2CH2CH3), 14.2 (Me), 10.8 (N(CH2)2CH3); HR
ESI MS m/z calcd for C43H92BrN2O4 (M - Br) 779.6235, found
779.6209.
(1.6 g, 11 mmol) was added to a stirred solution of amine 5.1
(0.6 g, 1.1 mmol) in THF (50 mL) and the reaction mixture was
stirred for 36 h, then allowed to cool to rt. The reaction mixture
was concentrated and the residue was purified by flash chromato-
graphy by using as eluant a gradient of 10% to 15% methanol
in dichloromethane to give the title salt as an off-white solid:
yield 0.7 g (68%); mp 212-215 °C; Rf 0.4 on basic alumina (8%
methanol in dichloromethane); 1H NMR (DMSO-d6) δ 0.88
(t, 6H, J = 6.5 Hz, CH3), 1.25-1.37 (m, 20 H, 10 ꢀ CH2), 1.49
(p, 4H, J = 6.5 Hz, OCH2CH2), 1.96 (4H, AA 0 part of AA0BB0
pattern, NCH2CH2), 3.11 (s, 18H, N(CH3)3), 3.31 (s, 4H,
octylOCH2C), 3.33 (t, 4H, J = 6.5 Hz, OCH2), 3.36 (s, 4H,
CH2OCH2C), 3.38 (4H, BB0 part of AA0BB0 pattern, NCH2),
3.42 (t, 4H, J = 6.0 Hz, OCH2); 13C NMR (CDCl3) δ 70.7 (octyl
CH2O), 69.4 (OCH2CH2CH2N), 68.8 (OCH2C), 67.7 (OCH2C),
63.3 (NCH2), 52.3 (N(CH3)3), 45.0 (qC), 31.1 (OCH2CH2),
28.74, 28.65, 25.63 (decyl CH2), 23.0 (NCH2CH2), 22.0
(CH3CH2), 13.9 (CH3); HR ESI MS m/z calcd for C33H72IN2O4
(M - I), 687.4531; found, 687.4522.
Diethyl 3,13-Diazonia-3,3,13,13-tetramethyl-8,8-bis(octyloxy-
methyl)-6,10-dioxapentadecanedioate Dibromide (6.1). When
a solution of compound 4.1 (0.61 g, 1.21 mmol) and ethyl
bromoacetate (0.31 mL, 2.79 mmol, 2.3 equiv) in diethyl ether
(20 mL) was stirred for 26 h, a colorless solid formed that was
isolated by filtration, then washed with ether. The solid was
crystallized from ethyl acetate and methanol to give the title
compound as a colorless crystalline solid: yield 0.88 g, 84%; mp
110-111 °C; Rf on basic alumina 0.59 (butanol:water:methanol
20:5:2); 1H NMR δ 0.88 (t, 6H, J = 6.9 Hz, 2 ꢀ Me), 1.27 (br s,
20H, 10 ꢀ CH2), 1.32 (t, 6H, J = 7.2 Hz, 2 ꢀ Me), 1.50 (pentet,
4H, J = 6.0 Hz, 2 OCH2CH2), 3.28 (s, 4H, octyl OCH2C), 3.33
(t, 4H, J = 6.6 Hz, octyl OCH2C), 3.50 (s, 4H, CCH2O(CH2)2N),
3.71 (s, 12H, 2N(CH3)2), 3.96 (br AA0 part of AA0BB0 pattern,
4H, 2 OCH2CH2N), 4.27 (q, 4H, J = 7.2 Hz, OCH2CH3), 4.32
(br BB0 part of AA0BB0 pattern, 4H, 2 NCH2CH2O), 4.96 (s, 4H,
CH2COOR); 13C NMR δ 164.9 (CH2COOR), 71.8 (CH2CH2-
OC), 71.1 (CCH2O(CH2)2N), 69.4 (CCH2O octyl), 65.4 (OCH2-
CH2N), 64.1 (NCH2CH2O), 62.7 (CH2COOCH2CH3), 62.3
(CH2COOCH2CH3), 52.4 (N (CH3)2), 45.1(qC), 32.0 (CH2-
CH2CH3), 29.6, 29.5, 29.3 (octyl CH2), 26.2 (CH2CH2CH2O),
22.7 (CH2CH3), 14.12 (Me), 14.06 (CH3CH2); HR ESI MS
m/z calcd for C37H76N2O8/2 ((M - 2Br)/2) 338.2795, found
338.2811.
N,N0-Dibutyl-5,5-bis(dodecyloxymethyl)-N,N,N0,N0-dimethyl-
3,7-dioxa-1,9-nonanediammonium Dibromide (4.27). 1-Bromo-
butane (4.70 mL, 44.0 mmol, 10 equiv) then sodium bicarbonate
(1.84 g, 22.0 mmol, 5.0 equiv) were added to a stirred solution of
compound 4.3 (3.03 g, 4.4 mmol) in THF (40 mL) and the
resulting mixture was refluxed for 33 h, cooled to rt, and fil-
tered, then the filtrate was concentrated to give the title com-
pound as a colorless solid. Crystallization from ethyl acetate
and methanol gave colorless crystals: yield 3.46 g, 88.7%;
mp 110 °C; Rf on basic alumina 0.53 (butanol:water:metha-
nol 20:5:2); 1H NMR δ 0.88 ppm (t, 6H, J = 6.9 Hz, 2 ꢀ Me),
1.01 (t, J = 7.3 Hz, 6H, 2 ꢀ N (CH2)3CH3), 1.26-1.31 (br s,
36H, 18 ꢀ CH2), 1.48 (sextet, 4H, J = 7.4 Hz, 2 ꢀ NCH2CH2-
CH2CH3), 1.51 (pentet, 4H, J = 6.2 Hz, 2 OCH2CH2), 1.78
(AA0 part of AA0XX0 pattern, 4H, 2 ꢀ NCH2CH2CH2-
CH3), 3.28 (s, 4H, dodecylOCH2C), 3.32 (t, J = 6.6 Hz, 4H,
dodecyl OCH2), 3.35 (s, 4H, N(CH2)2OCH2C), 3.44 (s, 12H, 2 ꢀ
N(CH3)2), 3.48 (s, 4H, CCH2O(CH2)2N), 3.65 (XX0 part of
AA0XX0 pattern, 4H, 2 ꢀ NCH2CH2CH2CH3), 3.94 (AA0 part
of AA0BB0 pattern, 4H, 2 OCH2CH2N), 3.99 (BB0 part of
AA0BB0 pattern, 4H, 2 NCH2CH2O); 13C NMR δ 71.9 (CH2-
CH2OC), 71.0 (CCH2O(CH2)2N), 69.5 (CCH2Ododecyl), 65.6
(NCH2CH2CH2CH3), 65.4 (OCH2CH2N), 63.7 (NCH2CH2O),
51.8 (N(CH3)2), 45.2 (q C), 32.0 (CH2CH2CH3), 29.8, 29.7, 29.6,
29.4 (dodecyl CH2), 26.3 (CH2CH2CH2O), 24.9 (NCH2CH2-
CH2CH3), 22.7 (CH2CH3), 14.2 (Me), 13.9 (N (CH2)3CH3); HR
ESI MS m/z calcd for C45H96BrN2O4 (M - Br) 807.6553, found
807.6548.
N,N,N0,N0-Tetramethyl-6,6-bis(octyloxymethyl)-4,8-dioxa-1,
11-undecanediamine (5.1). Sodium hydride (1.33 g, 55.4 mmol)
was added slowly to a stirred solution of 2,2-dioctyloxymethyl-
1,3-propanediol (9) (2.0 g, 5.5 mmol) in DMF (100 mL) under an
N2 atmosphere at 50 °C. The mixture was then stirred at 80 °C
for 1 h. After the reaction mixture had been allowed to cool to rt,
3-chloro-N,N-dimethyl-1-propanamine hydrochloride (1.93 g,
12.2 mmol) was added in portions and the reaction mixture was
stirred at 80 °C under nitrogen for another 24 h, then quenched
with methanol and filtered. The filtrate was concentrated, and
the residue was taken up in ethyl acetate (50 mL). This solution
was washed with water (2 ꢀ 20 mL) and brine (20 mL), then
dried (Na2SO4) and concentrated to a residue that was purified
by flash column chromatography. Elution with a gradient of
10% to 15% methanol in dichloromethane gave compound 5.1
as a light brown liquid: yield 1.6 g (54%); Rf on basic alumina 0.6
(dichloromethane:methanol 93:7); 1H NMR (CDCl3) δ 0.88 (t,
6H, J = 6.5 Hz, 2 CH3), 1.26-1.35 (m, 20 H, 10 ꢀ CH2), 1.52 (p,
4H, J = 7.0 Hz, 2 OCH2CH2), 1.71 (p, 4H, J = 6.5 Hz, 2 NCH2-
CH2), 2.22 (s, 12H, 2 N(CH3)2), 2.32 (t, 4H, J = 7.5 Hz, 2 NC-
H2), 3.34 (t, 4H, J = 6.5 Hz, 2 CH2CH2O), 3.35 (s, 4H, 2 OCH2),
3.37 (s, 4H, 2 OCH2), 3.41 (t, 4H, J = 6.5 Hz, OCH2); 13C NMR
(CDCl3) δ 71.7 (octyl CH2O), 70.0 (OCH2CH2CH2N), 69.85
(OCH2C), 69.78 (OCH2C), 57.0 (NCH2), 45.64 (N(CH3)2),
45.59 (qC), 32.0 (CH3CH2CH2), 29.82, 29.63, 29.49 (3 octyl
CH2), 28.2 (NCH2CH2), 26.4 (OCH2CH2CH2), 22.9 (CH3CH2),
14.2 (CH3); HR ESI MS m/z calcd for C31H67N2O4 (M þ H)
531.5095, found 531.5087.
3,13-Diazonia-3,3,13,13-tetramethyl-8,8-bis(octyloxymethyl)-6,10-
dioxapentadecanedioate (6.5). Compound 6.1 (0.44g, 0.51 mmol)
and IRA-400 anion-exchange resin (OH-) (11.0 g) in ethanol
(30 mL) were stirred at rt for 24 h. The reaction mixture was
filtered and the filtrate was concentrated to a semisolid residue
that precipitated from ethyl acetate and methanol to give the
title compound as a colorless waxy mass: yield 0.28 g, 90%; mp
183 °C; Rf on basic alumina 0.37 (butanol:water:methanol
1
20:5:2); H NMR δ 0.88 (t, 6H, J = 6.7 Hz, 2 ꢀ Me), 1.28-
1.32 (br s, 20H, 10 ꢀ CH2), 1.51 (pentet, 4H, J = 6.2 Hz,
2 OCH2CH2), 3.29 (s, 4H, octyl OCH2C), 3.33 (t, 4H, J = 6.4
Hz, octyl OCH2), 3.39 (s, 4H, CCH2O(CH2)2N), 3.39 (s, 12H,
2N(CH3)2), 3.82 (br AA0 part of AA0BB0 pattern, 4H,
2 NCH2CH2O), 3.99 (BB0 part of AA0BB0 pattern, 4H,
2 OCH2CH2N), 3.99 (s, 4H, CH2COO-); 13C NMR δ 166.2
(CH2COO-), 71.4 (CH2CH2OC), 70.6 (CCH2O(CH2)2N), 69.2
(CCH2O octyl), 65.46 (NCH2CH2O), 65.3 (OCH2CH2N), 62.4
(CH2COO-), 52.0 (N (CH3)2), 44.7 (q C), 31.6 (CH2CH2C H3),
29.3, 29.2, 29.1 (octyl CH2), 25.9 (CH2CH2CH2O), 22.4
(CH2CH3), 13.8 (Me); HR ESI MS m/z calcd for C33H67N2O8
(M þ H) 619.4892, found 619.4859.
N,N,N,N0,N0,N0-Hexamethyl-6,6-bis(octyloxymethyl)-4,8-
dioxa-1,11-undecanediammonium Diiodide (5.5). Methyl iodide
Acknowledgment. We thank the Atlantic Innovation
Fund and the Natural Sciences and Engineering Research
7772 J. Org. Chem. Vol. 74, No. 20, 2009

Jahan et al.
JOCArticle
Council (NSERC) of Canada for support. Christian Petro-
polis is grateful for an NSERC USRA award. NMR spectra
were recorded at the Atlantic Region Magnetic Resonance
Centre. We thank Eric Bond, Malcolm Huestis, Douglas
Staple, and Tyler Mercer for preparation of starting
materials and Dr. Eugen A. Karpichev and Tyler Mercer
for measurement of surface tensions. We are also grateful to
Dr. Hussein Al-Mughaid for performing some preliminary
experiments.
Supporting Information Available: Experimental proce-
dures, characterization data, and 1H NMR and 13C NMR
spectra of all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 20, 2009 7773