Synthesis of Highly Fluorinated Chloroformates and Their Use as Derivatizing Agents for Hydrophilic Compounds and Drinking-Water-Disinfection by-Products

Article abstract of DOI:10.1002/hlca.200490034

A rapid, safe, and efficient procedure was developed to synthesize, on a small scale, fluorinated chloroformates often required to perform analytical derivatizations. This new family of agents allows straightforward derivatization of highly polar compounds (with multiple hydroxy, carboxy, and amino substituents) in the aqueous phase, compatible with GC and GC/MS analysis. A goal of this work was to develop a derivatization procedure that would enable the detection and identification of highly polar disinfection by-products in drinking water.

Full text of DOI:10.1002/hlca.200490034

370
Helvetica Chimica Acta Vol. 87 (2004)
Synthesis of Highly Fluorinated Chloroformates and Their Use as
Derivatizing Agents for Hydrophilic Compounds and Drinking-Water-
Disinfection By-Products
by Marco Vincenti*a), Nicoletta Ghiglionea), Maria Carmen Valsaniaa), Patrizia Davitb),
and Susan D. Richardsonc)
a
¡
) Dipartimento di Chimica Analitica, Universita di Torino, Via Pietro Giuria 5, I-10125 Torino
(phone: ‡390116707838; fax: ‡390116707615; e-mail: marco.vincenti@unito.it)
b
¡
) Dipartimento di Chimica IFM, Universita di Torino, Via Pietro Giuria 7, I-10125 Torino
c) National Exposure Research Laboratory, U.S. Environmental Protection Agency, Athens, GA 30605, USA
A rapid, safe, and efficient procedure was developed to synthesize, on a small scale, fluorinated
chloroformates often required to perform analytical derivatizations. This new family of agents allows
straightforward derivatization of highly polar compounds (with multiple hydroxy, carboxy, and amino
substituents) in the aqueous phase, compatible with GC and GC/MS analysis. A goal of this work was to develop
a derivatization procedure that would enable the detection and identification of highly polar disinfection
by-products in drinking water.
Introduction.
The characterization of highly polar substances dissolved in
complex aqueous matrices is frequently challenging due to a lack of direct analytical
methods and the difficulty to extract such analytes with organic solvents, especially
when these substances have to be determined at trace levels [1]. Drinking-water-
disinfection by-products (DBPs), which are formed by the reaction of a disinfectant
(such as chlorine or ozone) with natural organic matter and/or bromide, are examples
of such substances that are present at trace levels (nm À mm range). Highly polar
carbonyl DBPs have been successfully detected and identified by means of derivatiza-
tion agents such as −pentafluorobenzylhydroxylamine× [2], 1-(2,4-dinitrophenyl)hydra-
zine [3], and 4-hydrazino-6-(4-methoxynaphthalen-1-yl)-N,N-dimethyl-1,3,5-triazin-2-
amine [4]. However, experts have predicted that more-polar DBPs are likely formed,
but have not been identified due to the lack of appropriate analytical methodologies to
enable their detection and identification [1b]. Such potential DBPs are polyalcohols,
polyacids, and polyamines, which cannot be extracted and detected by current methods
[1b].
Direct-aqueous-sample derivatization represents a promising approach to make
hydrophilic functional groups more hydrophobic, but finding appropriate derivatizing
agents is difficult, as most of them typically undergo hydrolysis as soon as they come in
contact with H2O or other protic solvents. Alkyl chloroformates [5] have gained
increasing popularity in this context, particularly the most-hydrophobic ones [6]. More
recently, we and others [7] have investigated the possible use of highly fluorinated
chloroformates as aqueous-sample-derivatizing agents for highly polar analytes. The
use of fluorinated derivatizing agents makes analytes volatile and increases their

Helvetica Chimica Acta Vol. 87 (2004)
371
electron affinity, which is crucial for their gas-chromatographic (GC) separation and
detection.
Fluorinated chloroformates are very reactive [7], but commercially not available,
since they are relatively unstable and, therefore, have to be synthesized at regular time
intervals (i.e., every two months). This aspect hinders the widespread use of these
derivatization agents, as few analytical scientists are willing to carry out organic
syntheses on a regular basis unless the procedure is fast, easy, and safe. For the above
reasons, we have developed a general synthetic protocol for highly fluorinated
chloroformates, which, in one or two steps, can be quickly produced in high yields, with
minimal manipulation.
Results and Discussion.
Our original procedure [7a] for the synthesis of
2,2,3,3,4,4,5,5-octafluoropentyl chloroformate (OFPCF) involved two critical and
inherently dangerous steps: a) the use of gaseous phosgene (COCl2) and b) the
presence of traces of phosgene during product distillation. A high-boiling solvent,
dibenzyl ether, was used to make the distillation from the low-boiling OFPCF product
feasible. In the new protocol, gaseous phosgene was replaced by triphosgene (bis-
(trichloromethyl) carbonate), a stable crystalline solid that can be handled with largely
reduced risk. Abe and co-workers [8] have used triphosgene to synthesize 2,2,2-
trifluoroethyl chloroformate. Based on their experience, we also used triphosgene in
our syntheses, but substituted the classical three-neck reaction vessel with a 25-ml
septum-sealed vial. The reagents and catalysts were introduced by appropriate syringes,
so as to eliminate any risk of phosgene outgassing. Due to the minute quantity of
chloroformate used in each derivatization, the limited amount of product obtainable in
such a small reaction vessel is ideal for derivatizations of drinking water or other
aqueous samples, safer to use than the original procedure, and allows the derivatization
of hundreds of samples over the course of one month.
The second change that we introduced in the synthetic procedure was the
elimination of the distillation step. Pentane was selected as the reaction solvent for both
steps of the synthesis, namely the initial decomposition of triphosgene to phosgene and
its subsequent reaction with a highly fluorinated alkyl-or aryla-lcohol to give the
corresponding chloroformates. The use of a diluting solvent was necessary to minimize
the formation of carbonate by-products.
The progress of the reaction was followed by GC/MS. When all the alcohol was
converted to the corresponding chloroformate, the mixture was doubly extracted with
HCl and NaCl solutions to eliminate the residual excess of phosgene, HCl, and
pyridinium chloride (Scheme 1). After phase separation, the pentane extract was
stored at À208, before being used as derivatizing agent.
Scheme 1

372
Helvetica Chimica Acta Vol. 87 (2004)
Following the above procedure, four different perfluorinated chloroformates were
obtained in yields above 85%: octafluoropentyl (OFPCF), tridecafluorooctyl
(TDFOCF), pentafluorobenzyl (PFBCF), and (pentafluorophenoxy)ethyl chlorofor-
mate (PFPECF). It is noteworthy that OFPCF and PFBCF, both carrying short spacers
between the chloroformate group and the fluorinated moiety, were formed more
rapidly and in higher yields (95% or above) than TDFOCF and PFPECF. In contrast,
fluorinated alcohols without a methylene spacer, such as 2,3,4,5,6-pentafluorophenol,
failed to give any observable chloroformate.
Evaporation of the solvent (pentane) from the chloroformates was occasionally
performed either to characterize the products or to achieve more-efficient derivatiza-
tion of some particularly difficult analytes when the presence of a separated phase
disturbed the direct aqueous-sample derivatization. However, only PFBCF, TDFOCF
and PFPECF could be efficiently recovered upon solvent evaporation; the boiling point
of OFPCF is too close to that of pentane to allow its concentration. Therefore, we
looked for an alternative solvent that would form a single phase with H2O in the
subsequent derivatization step.
Acetone proved to be an excellent solvent to perform the synthesis of fluorinated
chloroformates, yielding almost complete conversion of the fluorinated alcohols. As a
consequence, the extractions with HCl and NaCl solutions could no longer be
performed, as no phase separation would result. Therefore, the subsequent derivatiza-
tions were performed with the crude chloroformate mixture, with no preliminary
purification, and little change of the derivatization conditions. Nevertheless, excellent
results were obtained for the derivatization of both highly polar and less-polar analytes.
We concluded that acetone as the solvent for the synthesis of fluorinated
chloroformates is ideal for most analytical applications of the derivatization procedure.
First of all, the small excess of phosgene, still present in the crude reaction mixture,
increases the stability of the chloroformates, allowing its use over longer time periods.
The mixture is stored in the same sealed vial used for the synthesis, can be readily
collected with a syringe and added to the sample to be derivatized in alkaline (NaOH)
H2O. This sequence of steps avoids any risk for the operator to inhale phosgene.

Helvetica Chimica Acta Vol. 87 (2004)
373
The second advantage of acetone as the reaction solvent is that the absence of any
purification step considerably decreases the time required for the preparation of the
derivatizing agent. Generally, 4 h are sufficient to prepare the chloroformates, but no
loss in yield arises by allowing the reaction to proceed overnight. Details on the
chloroformate synthesis in both pentane and acetone are given in the Exper. Part.
The derivatization of polar, highly hydrophilic compounds with chloroformates
converts carboxylic acids to the corresponding esters, alcohols and phenols to carbonates,
and amines to carbamates (Scheme 2). In primary amines, one or both NH H-atoms
may undergo substitution, depending on the chloroformate used for the derivatization
and, partly, on the analyte reactivity. For analytes carrying two or more polar functional
groups, all these substituents undergo derivatization with excellent yields. In such a
case, more than one fluorinated functional group is introduced, which results in
increased sensitivity when a detection method based on electron affinity is applied.
Scheme 2
a) aq. NaOH soln. (3m), DCC, pyridine (cat.).
The effects on the derivatization efficiency induced by varying several experimental
parameters were investigated for a large set of candidate analytes, including malic acid,
resorcinol, 2,4-dihydroxybenzoic acid, hydroxylamine, 3-aminopropanol, 3-aminophe-
nol, and valine, some of which have been suspected to be potential drinking-water
DBPs. The experimental parameters investigated included 1) the amount of derivatiz-
ing agent, 2) the amount of catalyst, 3) the sonication time, and 4) the amount of base.
Upon varying these parameters, a smooth variation in the derivatization yield was
observed, i.e., none of these parameters proved particularly critical, unless dramatically
changed. The reported experimental conditions result from this optimization and
guarantee effective derivatization of all the analytes tested, at least when OFPCF or
PFBCF are used.
The most-critical parameter for the derivatization repeatability appears to be the
efficiency of sample mixing performed by ultrasonic emission. Excellent repeatability
was achieved by introducing the reaction tube in a bath where the ultrasound-emitting
tip of the sonicator was maintained at a fixed position (1 cm) from the reaction tube.
All the chloroformates tested reacted similarly, but the derivatization yields and the
degree of substitution on the analytes with more than one active H-atom varied
considerably for the different derivatizing agents. With OFPCF, complete substitution
of all active H-atoms of 2,4-dihydroxybenzoic acid and hydroxylamine was achieved, as

374
Helvetica Chimica Acta Vol. 87 (2004)
shown in Scheme 3. Extensive investigation of the reactivity differences among the four
perfluorinated chloroformates is underway. Preliminary results observed for a limited
set of polar substances seem to indicate that OFPCF and PFBCF have a wide
applicability, whereas TDFOCF and PFPECF failed to derivatize some of the
candidate analytes. A comprehensive comparison of the various perfluorinated
chloroformates together with the corresponding analytical performances will be
reported in in a forthcoming publication.
Scheme 3
Financial support from the U.S. Environmental Protection Agency (U.S. EPA; Cooperative Agreement No.
R-82795101-1), from M.I.U.R and the Consorzio Interuniversitario Nazionale La Chimica per l×Ambiente
(I.N.C.A.) is gratefully acknowledged. This paper has been reviewed in accordance with the U.S. EPA×s peer and
administrative review policies and approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use by the U.S. EPA.
Experimental Part
2,2,3,3,4,4,5,5-Octafluoropentyl Chloroformiate (OFPCF). Bis(trichloromethyl)carbonate (1 g, ca.
3.5 mmol) was dissolved in pentane (5 ml) and cooled to À158 in a septum-sealed 25-ml vial. Pyridine
(160 ml, 2 mmol) was added with a syringe perforating the teflon septum, and the soln. was stirred for 1 h. Then,
2,2,3,3,4,4,5,5-octafluoropentan-1-ol (280 ml, 2 mmol) in pentane (8 ml) was slowly added via syringe, while
maintaining the soln. at À158 and eliminating equal volumes of gas from the vial with the same syringe before
each addition, which were passed into an Na2CO3 soln. After 6 h, no more alcohol was detected in the reaction
mixture. The resulting soln. was extracted with 3m aq. HCl soln. (5 ml) and brine (5 ml), within the reaction vial,
and dried (Na2SO4). Yield: 95%. The sole reaction byproduct was bis(octafluoropentyl)carbonate (ca. 5%).
The OFPCF pentane soln. was stored at À208. Both NMR and mass spectra of the product were identical with
those previously reported [7a]. The synthesis in acetone was performed as described above, but the extractions
with HCl and brine were omitted, and the crude reaction mixture was used in the subsequent derivatizations.
Completion of the alcohol conversion was favored by gradually raising the temp. to 08. Yield: 95%.
2,3,4,5,6-Pentafluorobenzyl Chloroformate (PFBCF). The synthesis of PFBCF was performed as described
for OFPCF, except for the following changes: 1) the temp. was maintained at 08 throughout the entire reaction;
2) four 2-ml aliquots of pentafluorobenzyl alcohol (396 mg, 2 mmol) in pentane or acetone were added at 20-
min time intervals. The yields were ca. 92%, with slightly more bis(pentafluorobenzyl) carbonate formed (ca.
8%). Characterization of the product was reported in [7c].
3,3,4,4,5,5,6,6,7,7,8,8,8-Tridecafluorooctyl Chloroformate (TDFOCF). The same procedure described for
PFBCF was used, but the four aliquots of 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctan-1-ol (440 ml, 2 mmol) were
added at 40-min time intervals, and the mixture was warmed to r.t. after the first addition to compensate for the
lower reactivity of the alcohol. Yields: 90 93%. Some unreacted alcohol (ca. 5%) remained in the reaction
mixture. 19F-NMR (376 MHz, CD3COCD3): À82.23 (m, 2 F); À114.60 (m, 2 F); À122.97 (br., 2 F); À123.96

Helvetica Chimica Acta Vol. 87 (2004)
375
(br., 2 F); À124.66 (br., 2 F); À127.32 (br., 3 F). 13C-NMR (100 MHz, pentane/CDCl3 5 :1): 150.6, 122.6 105.8
‡
(m, 6 C); 62.7 (t, OCH2, J ˆ 4.6); 30.7 (t, CH2CF2, J ˆ 22.2). CI-MS (isobutane): 427 (100, [M ‡ H] ), 429 (36).
2-(2,3,4,5,6-Pentafluorophenoxy)ethyl Chloroformate (PFPECF). As for TDFOCF, with 296 ml (2 mmol) of
2-(pentafluorophenyl)ethanol. Yield: 86%. The carbonate by-product accounted for 11%, and 3% of unreacted
alcohol remained in the reaction mixture. 19F-NMR (376 MHz, CD3COCD3): À158.64 (m, 2 F); À165.99 (m,
1 F); À166.24 (m, 2 F). 13C-NMR (100 MHz, pentane/CDCl3 5 :1): 150.7, 143.6, 141.1 (m); 139.8 (m); 137.3 (m);
‡
133.5 (m); 72.3; 69.5. CI-MS (isobutane): 291 (100, [M ‡ H] ), 293 (35), 211 (81).
Derivatization Procedure. A 2-ml aliquot of the aq. sample to be derivatized was basified with 150 ml of aq.
NaOH soln. (3m). Then, the chloroformate soln. was added (150 ml, ca. 2 mmol), while sonicating the reaction
tube at optimized power and distance from the emitting tip. Immediately after, 3 ml of a sat. soln. (400 g/l)
solution of dicyclohexylcarbodiimide (DCC) in pyridine were added, and the reaction was allowed to proceed
for 10 min under sonication. The products were extracted with 600 ml of hexane for 1 min. The org. layer was
separated and analyzed by GC/MS in the chemical ionization (CI) mode. When pentane instead of acetone was
used, only 100 ml of aq. NaOH soln. (3m) was added to the aq. sample. The remaining conditions were identical.
The hexane solns. of the derivatization products were stable for a few days, so several analytical samples could
be derivatized and stored during the day, and automatically processed overnight.
REFERENCES
[1] a) S. D. Richardson, in −The Encyclopedia of Environmental Analysis & Remediation×, Ed. R. A. Meyers,
John Wiley & Sons, New York, 1998, Vol. 3, p. 1398 1421; b) H. S. Weinberg, Anal. Chem. 1999, 71, 801A.
[2] M. J. Sclimenti, S. W. Krasner, W. H. Glaze, H. S. Weinberg, −Proceedings of the American Water Works
Association Water Quality Technology Conference×, American Water Works Association, Denver, CO,
1990.
[3] S. D. Richardson, T. V. Caughran, T. Poiger, Y. Guo, F. G. Crumley, Ozone Sci. Eng. 2000, 22, 653; C.
Zwiener, T. Glauner, F. H. Frimmel, Anal. Bioanal. Chem. 2002, 372, 615.
[4] S. D. Richardson, U. Karst, −Proceedings of the 221st American Chemical Society National Meeting×, San
Diego, CA, April 1 5, 2001.
œ
[5] P. Husek, J. Chromatogr., B 1998, 717, 57 and refs. cit. therein.
[6] C. Minero, M. Vincenti, S. Lago, E. Pelizzetti, Fresenius× J. Anal. Chem. 1994, 350, 403; M. Vincenti, C.
Minero, S. Lago, C. Rovida, J. High Resolut. Chromatogr. 1995, 18, 359; S. Angelino, V. Maurino, C.
Minero, E. Pelizzetti, M. Vincenti, J. Chromatogr., A 1998, 793, 307; B. J. Hall, A. R. Parikh, J. S. Brodbelt,
J. Forensic Sci. 1999, 44, 527; I. Abe, H. Yanagi, T. Nakahara, J. High Resolut. Chromatogr. 1997, 20, 451.
[7] a) V. Maurino, C. Minero, E. Pelizzetti, S. Angelino, M. Vincenti, J. Am. Soc. Mass Spectrom. 1999, 10,
1328; b) P. Hartvig, J. Vessman, J. Chromatogr. Sci. 1974, 12, 722; c) J. M. Lee, S. J. Norton, J. Agric. Food
Chem. 1990, 38, 273; d) J. T. Simpson, D. S. Torok, S. P. Markey, J. Am. Soc. Mass Spectrom. 1995, 6, 525;
e) J. T. Simpson, D. S. Torok, J. E. Girard, S. P. Markey, Anal. Biochem. 1996, 233, 58.
[8] I. Abe, N. Fujimoto, T. Nishiyama, K. Terada, T. Nakahara, J. Chromatogr., A 1996, 722, 221.
Received August 25, 2003