Practical use of NH4X salts for difunctional oxyethylene-based intermediates

Article abstract of DOI:10.1016/j.tetlet.2007.05.081

A series of tosyl functionalized oxyethylene-based organic compounds were selected to analyze the scope and efficiency of a general substitution method for conversion to difunctional, soluble oxyethylene based intermediates using readily available ammonium salts, glycols and commercially modified ethoxy-ethanols. Straightforward preparation, product purification and low cost reagents are particularly advantageous for compounds incorporating halides, thiocyanates and methoxy groups.

Full text of DOI:10.1016/j.tetlet.2007.05.081

Tetrahedron Letters 48 (2007) 4813–4815
Practical use of NH4X salts for difunctional
oxyethylene-based intermediates
Brian T. Holmes and Arthur W. Snow*
Department of Chemistry, Naval Research Laboratory, Washington, DC 20375, USA
Received 24 August 2006; revised 11 May 2007; accepted 14 May 2007
Available online 18 May 2007
Abstract—A series of tosyl functionalized oxyethylene-based organic compounds were selected to analyze the scope and efficiency of
a general substitution method for conversion to difunctional, soluble oxyethylene based intermediates using readily available ammo-
nium salts, glycols and commercially modified ethoxy-ethanols. Straightforward preparation, product purification and low cost
reagents are particularly advantageous for compounds incorporating halides, thiocyanates and methoxy groups.
Published by Elsevier Ltd.
Numerous short-chain oxyethylene compounds with a
variety of halogen and pseudohalogen terminal func-
tional groups have been synthesized from corresponding
precursor alcohols, olefins and halides by various meth-
ods and functionalizing reagents that include SOCl2,1
PBr3,2 ClBr,3 NaI4 and KSCN.5 A majority of the
research is driven by the utility of these compounds as
reagents in classical crown ether chemistry.6 These com-
pounds are also useful reagents for the preparation of
bioadhesion resistant surface treatments,7 for the pen-
dant functionalization of rigid rod macromolecules into
processible molecular composites,8 and for transforming
large dye chromophores into intrinsic liquids.9 Remark-
ably, to our knowledge there has not been a general
substitution study for conversion to difunctional
intermediates utilizing a single, efficient method for a
set of ethylene oxide oligomers.
using tetrabutylammonium fluoride,13 this expanded
method provided a reliable synthetic pathway for
numerous difunctional synthetic pieces.
Originally, tetrabutylammonium fluoride was employed
for the nucleophilic displacement of tosylate (p-toluene-
sulfonate) functional groups as a procedure for the con-
venient access of 18F-labeled octanoic acid derivatives. It
was discovered in our hands that an analogous reaction
utilizing tetrabutylammonium bromide in refluxing
tetrahydrofuran converted a di-tosylated oxyethylene
tri-oligomer in high yield. Unfortunately, alkylammonium
salts are limited commercially, relatively expensive and
remained present as byproducts following workup of
the reaction mixture.
Comparatively, simple ammonium salts of the general
type NH4X are commercially abundant, relatively inex-
pensive and are easily removed following aqueous work-
up of the reaction mixture. Although the ammonium
salts available were not soluble in tetrahydrofuran com-
pared to their alkylammonium analogues, they were sol-
uble in polar organic solvents such as dimethyl sulfoxide
and N,N-dimethyl formamide and subsequent experi-
ments were performed accordingly. These solvents were
particularly useful since they did not require the rigor-
ous drying and purification procedures typical for tetra-
hydrofuran and for their generally broad solubility.
Limited kinetic studies were formerly reported using
dipolar aprotic solvent hexamethylphosphoric triamide,
for nucleophilic substitution between ethyl tosylate and
chloride and bromide ions.14
Recent interest in both water-soluble gold nanoclusters
stabilized by ligands containing short ethylene oxide
oligomers10 and difunctional solubilizing tether agents
for monomer/polymer synthesis via Williamson cou-
pling11 required analysis of convenient routes towards
several related compounds. Coupled with our current
research involving tetrabutylammonium cyanide as a
catalyst for thioacetate deprotection,12 the availability of
common ammonium salts, and a modification of the
conversion of tosylate groups by fluoride substitution
*
Corresponding author. Tel.: +1 202 767 5341; fax: +1 202 767
0594; e-mail: arthur.snow@nrl.navy.mil
0040-4039/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.05.081

4814
B. T. Holmes, A. W. Snow / Tetrahedron Letters 48 (2007) 4813–4815
Initially, a commercial glycol and two modified ethoxy-
ethanols, tri(ethylene glycol), 2-(2-methoxyethoxy)etha-
nol and 2-[2-(2-chloroethoxy)-ethoxy]ethanol, were cho-
sen for further experimentation.15 The alcohols were
converted to their respective tosylates by reaction with
tosyl chloride in a pyridine-dichloromethane mixture
in moderate yield.16
of the ammonium salt in acetone were attributing
factors.
Attempts to employ ammonium fluoride as a reagent for
reaction with the three tosylated compounds in dimethyl
sulfoxide, N,N-dimethyl formamide and methanol were
unsuccessful. Despite varying conditions and workup,
neither product nor starting material was ever recov-
ered. Substitution of fluoride for a tosyl group at the
end of an alkane chain has been reported using tetra-
butylammonium fluoride in tetrahydrofuran at room
temperature.13 These conditions have also been successful
on a tosylate terminated oxyethylene chain.19
Ammonium chloride, bromide, iodide and thiocyanate
salts were originally selected as nucleophilic reagents
for reaction with three model tosylates (see Table 1). It
was determined by solubility tests that ammonium
iodide was more suitable in N,N-dimethyl formamide,
whereas chloride, bromide and thiocyanate dissolved
readily in dimethyl sulfoxide. It was also noted that
reaction temperatures greater than 65 ꢀC were required
for complete conversion of the tosylate to the halide
or thiocyanate for samples stirring for a minimum of
4 h. Selective conversion reactions were typically heated
to 70 ꢀC overnight, whereas non-competitive reactions
were performed at slightly elevated temperatures of
80–85 ꢀC for 4–5 h.17,18
Yields were generally equivalent or superior to alternate
published procedures. For instance, experiment
8
reveals more than double the yield found from the
conversion of 1,8-dichloro-3,6-dioxaoctane and sodium
iodide in refluxing acetone and an identical yield for
experiment 7 under similar conditions.4a The liquids
possessed similar physical properties identical with those
reported.18
Yields greater than 50% were obtained under these
conditions for experiments 1–12 (Table 1). Selective
conversion for samples 5, 8 and 11 were achieved using
1.2 M equiv of ammonium salt at 70–75 ꢀC for 16 h. It
was discovered that a slight ammonium reagent excess
did not produce a mixture of products by competitive
reaction with the chlorine, although higher molar equiv-
alencies (>1.3) revealed mono- and disubstituted prod-
ucts. These results are particularly advantageous for
further chemoselective reactions. For non-competitive
experiments 1–4, 6, 7, 9, 10 and 12, an excess of ammo-
nium reagent was utilized for efficient conversion and
shorter reaction times. For 10a and 10b, appropriate
choice of solvent improved yields from 52% with DMSO
to 76% with DMF.
Tetra(ethylene glycol)di(p-toluenesulfonate)20 under-
went nucleophilic substitution with ammonium iodide
in N,N-dimethyl formamide at 80 ꢀC for 5 h to form
1,11-diiodo-3,6,9-trioxaundecane (Fig. 1). Compared
to the previously reported 4 day conversion required
from 1,11-dichloro-3,6,9-trioxaundecane with sodium
iodide/acetone in 67% yield,21 results were encouraging.
Our method required a short reaction time for complete
conversion and resulted in a higher yield. The diiodide
product represented in Figure 1 is one oxyethylene unit
longer than the product in Table 1, entry 7. Our isolated
yield decreased from 85% to 75% as a result of this one
unit extension in chain length. It is our opinion that this
lower yield is a consequence of purification difficulty due
to increasing chain length rather than terminal group
reactivity differences.22
Attempts to employ more common solvents in place of
the aprotic solvents were not successful. Methanol and
acetone were investigated, but starting material was
recovered for each attempt. Generally, poor solubility
of the tosylated reactant in methanol and poor solubility
We see two key advantages in the preparation of the tos-
ylate intermediate: (1) this route appears to avoid side
reactions that generate inseparable byproducts at short
oxyethylene chain lengths previously observed in earlier
Table 1. Nucleophilic substitution of tosylated model compounds
NH4X
O
R
O
R1
TosO
O
X
O
R
X
R1
Conditions
Yield (%)
1
C2H4–OTos
C2H4–Cl
CH3
C2H4–OTos
C2H4–Cl
CH3
C2H4–OTos
C2H4–Cl
CH3
C2H4–OTos
C2H4–OTos
C2H4–Cl
CH3
Cl
Cl
Cl
SCN
SCN
SCN
I
I
I
Br
Br
C2H4–Cl
C2H4–Cl
CH3
C2H4–SCN
C2H4–Cl
CH3
C2H4–I
C2H4–Cl
CH3
C2H4–Br
C2H4–Br
C2H4–Cl
CH3
4 equiv, DMSO 85 ꢀC, 5 h
1.2 equiv, DMSO 70 ꢀC, 16 h
2 equiv, DMSO 80 ꢀC, 5 h
4 equiv, DMSO 80 ꢀC, 5 h
1.2 equiv, DMSO 75 ꢀC, 16 h
2 equiv, DMSO 80 ꢀC, 5 h
4 equiv, DMF 80 ꢀC, 5 h
1.2 equiv, DMF 70 ꢀC, 16 h
2 equiv, DMF 80 ꢀC, 4 h
4 equiv, DMSO 85 ꢀC, 5 h
4 equiv, DMF 85 ꢀC, 5 h
1.2 equiv, DMSO 70 ꢀC, 16 h
2 equiv, DMSO 85 ꢀC, 4 h
71
64
51
86
71
83
85
70
76
52
76
53
63
2
3
4
5
6
7
8
9
10a
10b
11
12
Br
Br

B. T. Holmes, A. W. Snow / Tetrahedron Letters 48 (2007) 4813–4815
6. Pederson, C. J. J. Am. Chem. Soc. 1967, 89, 7017.
4815
O
O
Tos
O
O
Tos
7. Kingshott, P.; Griesser, H. J. Curr. Opin. Solid State
Mater. Sci. 1999, 4, 403.
3
8. Lauter, U.; Meyer, W. H.; Wegner, G. Macromolecules
1997, 30, 2092.
9. Snow, A. W.; Shirk, J. S.; Pong, R. G. S. J. Porphyrins
Phthalocyanines 2000, 4, 518.
DMF, NH4I
80oC, 5 hr
10. (a) Foos, E. E.; Snow, A. W.; Twigg, M. E.; Ancona, M.
G. Chem. Mater. 2002, 14, 2401; (b) Clark, T. D.; Dugan,
E. C. Synthesis 2006, 7, 1083; (c) Foos, E. E.; Congdon, J.;
Snow, A. W.; Ancona, M. G. Langmuir 2004, 20, 10657.
11. (a) Allan, C. B.; Spreer, L. O. J. Org. Chem. 1994, 59,
7695; (b) Holmes, B. T.; Mastrangelo, J.; Snow, A. W.
unpublished results..
I
I
3
Figure 1. Tetra(ethylene glycol) di(p-toluenesulfonate) reacts with
ammonium iodide in 75% yield.
12. Holmes, B. T.; Snow, A. W. Tetrahedron 2005, 61, 12339.
13. Nagatsugi, F.; Sasaki, S.; Maeda, M. J. Fluorine Chem.
1992, 56, 373.
research2 and (2) as a result of solubility differences,
mono-tosylated intermediates are separable from oligo
ethylene glycol reactant and disubstituted tosylated
byproduct. This distinction is particularly important
for the preparation of unsymmetrically terminated oxy-
ethylene chain molecules.
14. Muller, P.; Siegfried, B. Helv. Chim. Acta 1972, 55, 2965.
¨
15. Tri(ethylene glycol), 2-(2-methoxyethoxy)ethanol, 2-[2-(2-
chloroethoxy)-ethoxy]ethanol, p-toluenesulfonyl chloride,
ammonium bromide, iodide, thiocyanate and fluoride,
diethyl ether and dimethyl sulfoxide were commercially
available from Aldrich and used as received. Acetone,
N,N-dimethyl formamide, pyridine, dichloromethane and
methanol were commercially available from Fisher and
used as received. Ammonium chloride was commercially
available from Malinckrodt and used as received.
Tetra(ethylene glycol) was commercially available from
Fluka and used as received.
In conclusion, the chloride, bromide, iodide or thiocya-
nate ion in a series of ammonium salts nucleophilically
displace the tosylate group at the end of an oxyethylene
chain in dimethyl sulfoxide or N,N-dimethyl formamide
solvents. High yields were obtained with three tosylate
terminated oxyethylene substrates. This general substi-
tution study has implications towards chemoselective
intermediates of varying halogenated ends and lengths.
16. (a) Selve, C.; Ravey, J.-C.; Stebe, M.-J.; El Moudjahid, C.;
Moumni, E. M.; Delpuech, J.-J. Tetrahedron 1991, 47,
411; (b) Christensen, C. A.; Bryce, M. R.; Becher, J.
Synthesis 2000, 12, 1695.
17. All synthetic procedures were performed under an inert
nitrogen atmosphere with oven-dried glassware. 1H and
13C NMR were recorded on a Bruker Avance-300
instrument. Chemical shifts were referenced to the residual
chloroform peak at 7.26 and 77.0 ppm, respectively.
Proton and carbon NMR spectra of reacted species were
compared to published material and analyzed for side
products, conversion and yields.
Acknowledgements
We thank Dr. Andrew Purdy, Dr. Michael Pepitone and
Dr. Alan Berry for supplying ammonium fluoride, bro-
mide and iodide, ASEE Postdoctoral Fellowship and the
Office of Naval Research for financial support of this
work.
18. Representative experimental procedure for the synthesis of
1,8-diiodo-3,6-dioxaoctane 7: Under an atmosphere
of nitrogen, N,N-dimethyl formamide (5 mL) was added
to tri(ethylene glycol)di(p-toluenesulfonate) (0.20 g,
0.44 mmol) and ammonium iodide (0.65 g, 1.7 mmol).
After stirring for 5 h at 80 ꢀC, the reaction mixture was
poured directly into a separatory funnel containing
distilled water (20 mL) and diethyl ether (20 mL). The
aqueous phase was extracted with diethyl ether
(2 · 20 mL) and the organic layers were combined, washed
with distilled water (2 · 20 mL), dried with MgSO4,
filtered, passed through an activated plug of alumina
(Bodman Neutral-Super I) and concentrated in vacuo to
reveal an analytically pure product.
19. Foos, E. E.; Snow, A. W., in preparation.
20. Karakaplan, M.; Aral, T. Tetrahedron: Asymmetry 2005,
16, 2119.
21. Jousselme, J.; Blanchard, P.; Levillain, E.; Delauney, J.;
Allain, M.; Richomme, P.; Rondeau, D.; Gallego-Planas,
N.; Roncali, J. J. Am. Chem. Soc. 2003, 125, 136.
22. The reviewer is appreciatively acknowledged for raising
this issue.
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