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Journal of Environmental Science and Health, Part A
Publication details, including instructions for authors and subscription information:
http://www.informaworld.com/smpp/title~content=t713597268

A new class of perfluorinated acid contaminants: Primary and secondary
substituted perfluoroalkyl sulfonamides are acidic at environmentally and
toxicologically relevant pH values
Sierra Rayne ab; Kaya Forest c
a
Department of Chemistry, University of Winnipeg, Winnipeg, Manitoba, Canada b Ecologica Research,
Penticton, British Columbia, Canada c Department of Chemistry, Okanagan College, Penticton, British
Columbia, Canada
Online Publication Date: 01 November 2009

To cite this Article Rayne, Sierra and Forest, Kaya(2009)'A new class of perfluorinated acid contaminants: Primary and secondary

substituted perfluoroalkyl sulfonamides are acidic at environmentally and toxicologically relevant pH values',Journal of Environmental
Science and Health, Part A,44:13,1388 — 1399
To link to this Article: DOI: 10.1080/10934520903217278
URL: http://dx.doi.org/10.1080/10934520903217278

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Journal of Environmental Science and Health Part A (2009) 44, 1388–1399
C Taylor & Francis Group, LLC
Copyright
ISSN: 1093-4529 (Print); 1532-4117 (Online)
DOI: 10.1080/10934520903217278

A new class of perfluorinated acid contaminants: Primary
and secondary substituted perfluoroalkyl sulfonamides
are acidic at environmentally and toxicologically relevant
pH values
SIERRA RAYNE1,2 and KAYA FOREST3
1

Department of Chemistry, University of Winnipeg, Winnipeg, Manitoba, Canada
Ecologica Research, Penticton, British Columbia, Canada
3
Department of Chemistry, Okanagan College, Penticton, British Columbia, Canada

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2

The SPARC software program was validated for nitrogen-hydrogen acidity constant estimation of primary and secondary sulfonamides
against a broad suite of substituted derivatives with experimental datasets in water and dimethylsulfoxide solvent systems and across
a wide pKa range. Following validation, amidic proton pKa values were estimated for all C1 through C8 congeners of five major
perfluoroalkyl sulfonamide classes: unsubstituted sulfonamides, N-methyl and N-ethyl sulfonamides, sulfonamidoethanols, and
sulfonamidoacetates. Branching of the perfluoroalkyl chain is expected to have substantial impacts on amide moiety acidity in
these contaminant groups, with intrahomologue variability of up to four pKa units and increasing pKa values with both increasing
chain branching and greater proximity of the chain branching to the sulfonamide head group. Perfluoroalkyl chain length is not
predicted to have a substantial influence on sulfonamide acidity. The predicted pKa values and variability are anticipated to have
substantial impacts on the environmental partitioning and degradation of these compounds, as well as the modes and magnitudes of
toxicological effects. Substantial pH dependent isomeric fractionation of perfluoroalkyl sulfonamides is expected both in situ and in
vivo, necessitating the incorporation of amide group acidities in multimedia environmental models and pharmacokinetic studies.
Keywords: Perfluoroalkyl sulfonamides, amide acidity, pKa values, environmental fate, toxicology.

Introduction
Perfluorinated alkyl sulfonamides (Fig. 1) are a subclass of
perfluorinated compounds (PFCs) that have been used in a
variety of industrial and consumer products over the past
several decades. In particular, sulfonamides have found a
wide range of uses such as surface active materials in protecting paper, fabrics, leather, carpet, and upholstery, as fire
fighting foams and mining surfactants, as well as cleaners,
polishes and pesticides.[1] The broad diversity of applications throughout society results in a large and complex
number of routes by which these compounds may migrate
into the environment. To date, the major focus has been on
a related group of PFCs, namely the two primary members
of the perfluorinated acids (PFAs) subclass: perfluoroalkyl
sulfonic acids (PFSAs) and carboxylic acids (PFCAs).

Address correspondence to Sierra Rayne, Ecologica Research,
Penicton, BC, Canada. E-mail: rayne.sierra@gmail.com
Received April 8, 2009.

Over the last several years, an increasing number of publications have examined the presence of sulfonamides in
environmental matrices such as the atmosphere,[2−10] marine and fresh waters,[11] wildlife,[12,13] humans,[14] as well
as their potential fate in natural and engineered systems
such as soils, sediments, and water and wastewater treatment plants.[15−17] Furthermore, while the sulfonamides are
a class of contaminants in their own right, they are also
known precursors of PFSAs and PFCAs due to the actions
of abiotic[18,19] and biotic degradation processes.[20] As with
the PFSAs and PFCAs, sulfonamides have also been historically produced by the electrochemical fluorination method
that leads to a potentially large, and presently undefined,
suite of linear and branched congeners that could be present
in the environment.[1,21]
However, with the exception of a single study that
calculated the pKa of one sulfonamide congener (nperfluorooctane sulfonamide; n-FOSA) as part of a
broader work primarily focused on PFA removal via
nanofiltration,[22] no previous works—including those
concerned solely with the partitioning behavior of

Perfluoroalkyl sulfonamides

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Fig. 1. General structures of the perfluoroalkyl sulfonamide
classes under consideration.

PFCs[23,24] —have considered the potential acidity of the
amide group when investigating their environmental and
toxicological fate. As a result, the current study sought to
address this knowledge gap on this important emerging
contaminant class by validating and applying a method
for estimating the congener specific pKa values of all
C1 through C8 isomers in five major primary and secondary substituted sulfonamide classes including unsubstituted sulfonamides (SAs), N-methyl (NMeSA) and Nethyl (NEtSA) sulfonamides, sulfonamidoethanols (SEs),
and sulfonamidoacetates (SAAs). In addition, we seek to
demonstrate to the PFC research community the importance of both generating an experimental pKa data set
(which is currently nonexistent) using members of the sulfonamide classes having currently available authentic standards, as well as including amidic proton ionization in all
future environmental fate and toxicological studies on this
PFC subclass.

Methods and materials
The numbering system for sulfonamide congeners follows
the approach outlined previously.[25] SMILES molecular
formats[26,27] of the unionized acid form of each congener were used as computational inputs. pKa values were
estimated using SPARC (http://ibmlc2.chem.uga.edu/
sparc/; August 2007 release w4.0.1219-s4.0.1219) with the
acidity constant options for full speciation and nitrogen
atoms capable of acting as both acids and bases.[28] For
some members of the validation set, SPARC pKa calculations were conducted using the non-aqueous pKa algorithm and the default dimethylsulfoxide settings as solvent.
Macroscopic pKa values reported herein were generated by
SPARC that incorporate the composite suite of potential
ionization combinations for molecules with multiple acid
and base sites.
To validate the SPARC pKa estimation approach
for sulfonamides, computationally derived acidity constants were compared to experimental values obtained in
dimethylsulfoxide (n = 7; from the online Bordwell pKa
table [http://www.chem.wisc.edu/areas/reich/pkatable/]
and ref.[29,31] ) and water (n = 86; ref.[32−39] ) on a representative suite of compounds. Air-water partitioning constants
in SPARC were estimated using the following options: total solids concentration, 0 mg L−1 ; metals concentration,
0 mol L−1 ; no carbon acidity. Octanol-water distribution

1389
constants (log D) in SPARC were estimated using the default parameters.
PM6 semiempirical calculations[40] were conducted
using MOPAC2009 (http://openmopac.net/home.html).
SMILES formats were converted to three dimensional
structures using the FRee Online druG conformation
generation (Frog v1.01; http://bioserv.rpbs.jussieu.fr/cgibin/Frog), conformationally minimized to a single conformer out of 50 starting conformers with an energetic
threshold of 100 and 1000 Monte Carlo search steps, and
output as mol2 format.[41] The resulting mol2 format was
converted to MOPAC internal format using OpenBabel
v.2.2.0 (http://openbabel.sourceforge.net/).[42] PM6 calculations were performed using the following keywords in the
header row: PM6 BONDS CHARGE = 0 (for molecular forms) or −1 (for ionized forms) LET DDMIN = 0.0
GNORM = 0.0 GRAPHF CYCLES = 100000.

Results and discussion
Validation of sulfonamide pKa prediction method
The SPARC program was first validated for sulfonamide
nitrogen atom acidity by estimating the amidic proton
pKa values of a representative suite of compounds with
varying aromatic and alkyl substituents in both dimethylsulfoxide (DMSO) and water solutions followed by comparison to the corresponding literature experimental values. SPARC generally underestimates DMSO pKa values,
with increasing deviation from experimental values with
decreasing experimental acidity (regression of the form
pKa,SPARC,DMSO = 0.80 × pKa,expt,DMSO +1.86; r = 0.984,
P < 0.0001), an average signed error of −1.07 units, an average unsigned error of 1.10 units, and minimum and maximum errors of 0.11 and −2.54 units, respectively (Fig. 2).
However, one member of the training set was the C1 SA (i.e.,
trifluoromethylsulfonamide), for which SPARC accurately
predicted the pKa value (pKa,exp = 7.90, pKa,est = 8.01).
Across a broad range of substituted sulfonamides in water,
SPARC displayed an amide ionization prediction accuracy
dependent on the source experimental data set (Fig. 3). For
all 86 compounds, the average signed, average unsigned,
minimum, and maximum pKa errors were 0.52, 0.79, 0.03,
and 3.55 units, respectively. However, significantly better
pKa prediction was observed for the datasets of Balaban (avg. signed/unsigned error = 0.22/0.52; min/max =
0.03/1.81; n = 43),[37] Lin et al. (avg. signed/unsigned error = 0.05/0.67; min/max = 0.06/3.55; n = 12),[33−35] and
Remko and Lieth (avg. signed/unsigned error = 0.33/0.45;
min/max = 0.13/1.13; n = 5)[36] than for the datasets
of Geiser et al. (avg. signed/unsigned error = 0.69/1.05;
min/max = 0.03/2.50; n = 5)[32] and Tharkur et al. (avg.
signed = unsigned error = 1.41; min/max = 0.81/2.33; n =
21).[38,39]

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1390

Fig. 2. Comparison between experimental and SPARC
estimated pKa values in dimethylsulfoxide (DMSO) for
the sulfonamide calibration set. Compound identities are
as follows: 1, trifluoromethylsulfonamide (C1 SA); 2, Nphenylmethylsulfonamide; 3, N-hydroxybenzenesulfonamide; 4,
N-dimethylaminobenzenesulfonamide; 5, benzenesulfonamide;
6, N-aminobenzenesulfonamide; and 7, methylsulfonamide.
A regression line (solid) of the equation pKa,SPARC,DMSO =
0.80(±0.07; ±SE) × pKa,expt,DMSO +1.86 ± 0.98 and a 1:1 line
(dashed) are shown for comparison.

No relationship between sulfonamide substitution patterns or identities was linked to varying differences between experimental and estimated pKa values. It is also
important to note that there is significant uncertainty and
differences in the literature regarding reported pKa values
of sulfonamides, particularly where different instrumen-

Fig. 3. Comparison between experimental and SPARC estimated
pKa values in water for the sulfonamide calibration set. Values
taken from Geiser et al.[32] (circles), Lin et al.[33−35] (squares),
Remko and Lieth[36] (up triangles), Balaban et al.[37] (down triangles), and Tharkur[38] /Tharkur et al.[39] (diamonds). A 1:1 line
(dashed) is shown for comparison.

Rayne and Forest
tal techniques are employed (e.g., capillary electrophoresis, potentiometric titration, nuclear magnetic resonance
[NMR] titration, spectrophotometric methods, liquid
chromatography[43] ). As such, calibration of computationally based pKa prediction methods remains a challenge
for these (and other) nitrogen acids relative to the higher
accuracy typically observed with the carbon oxyacids.[44]
We also investigated using the semiempirical PM6[40] pKa
estimation module (http://openmopac.net/home.html)
and the ADME/Tox WEB pKa estimation program
(http://www.pharma-algorithms.com/webboxes/) within
the Virtual Computational Chemistry Laboratory suite
(http://www.vcclab.org/).[45,46] We have previously shown
the ADME/Tox WEB program to adequately model the
pKa values of PFCAs,[47] while the PM6 method is not
suitable for PFCAs[48] or PFSAs[49] as well as most noncarbon oxyacids.[44] Unfortunately, neither the PM6 nor
ADME/Tox WEB programs are capable of pKa estimation on nitrogen acids, precluding a comparison of these
approaches with the SPARC and experimental results.
pKa estimates for perfluoroalkyl sulfonamides
Following validation, amidic proton pKa values were estimated for all C1 through C8 congeners of the unsubstituted sulfonamides (SAs), N-methyl (NEtSA) and Nethyl (NEtSA) sulfonamides, sulfonamidoethanols (SEs),
and sulfonamidoacetates (SAAs). Within each sulfonamide
class, estimated pKa values do not vary with increasing perfluoroalkyl chain length (P > 0.05; Tukey-Kramer
parametric pairwise comparisons), but significant intrahomologue variation by up to four pKa units is expected
depending on the degree of chain branching (Fig. 4). Increasing chain branching is expected to increase the pKa
values, resulting in the estimated intrahomologue and intraclass ranges of predicted acidity constants given in Table 1.
For all sulfonamide classes, the closer the perfluoroalkyl
chain branching is to the sulfonamide head group, the
higher the estimated pKa since the steric and electronic
chain branching effects can be more readily transmitted to
the amidic moiety with more favorable geometric proximity. For example, the C8 SA 83 (1-monomethyl branched)
has a predicted pKa of 8.93, whereas the C8 SA 84 (2monomethyl branched) has a predicted pKa of 6.64. No
chain length or branching effect was observed for the estimated pKa values on the SAA carboxylate groups, which
range from 3.86 to 4.04. Thus, the SAAs will be at least
singly ionized under most environmentally and toxicologically relevant conditions due to ionization of the carboxylate group. At near neutral pH values, many of the more
linear SAA congeners will be doubly ionized due to the
acidity of the amide group.
Semiempirical PM6 calculations were conducted on the
molecular and ionized forms of the C8 SA 83 and C8 SA
89 congeners with the hopes of rationalizing the SPARC
estimated perfluoroalkyl chain branching effects. The large

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Perfluoroalkyl sulfonamides

1391

Fig. 4. Congener specific SPARC pKa estimates for the C1 through C8 perfluorinated sulfonamide classes under consideration. For
the SAAs, closed circles represent pKa values for the amido moiety and open circles indicate pKa values for carboxyl function.

perfluoroalkyl chain branching effects SPARC reports for
sulfonamides are much different in both magnitude and
direction from the perfluoroalkyl chain branching effects
this same program predicts for the PFCAs.[47] For example,
SPARC predicts the pKa of the straight chain C8 PFCA
89 (i.e., n-perfluorononanoic acid [n-PFNA]) at −0.17 to
be slightly higher than for the 1-monomethyl branched C8

PFCA 83 (pKa = −0.42). Similarly, SPARC estimates the
pKa values of the corresponding sulfonic acids as essentially equal at 0.14 (C8 PFSA 89) and 0.13 (C8 PFSA 83),
respectively.
In comparison, the PM6 method predicts that branched
PFCA[48] and PFSA[49] congeners will have much lower
pKa values than their more linear counterparts, often by

Table 1. Estimated intrahomologue pKa ranges for the sulfonamide classes under consideration. Cx refers to the length of the
perfluoroalkyl chain.

C1
C2
C3
C4
C5
C6
C7
C8

(n = 1)
(n = 1)
(n = 2)
(n = 4)
(n = 8)
(n = 17)
(n = 39)
(n = 89)

SAs

NMeSAs

NEtSAs

SEs

SAAs

5.86
6.27
6.28–8.91
6.27–9.72
6.26–9.40
6.25–9.39
6.24–9.64
6.24–9.51

8.25
8.73
8.77–11.44
8.78–12.29
8.78–11.97
8.77–11.96
8.76–12.21
8.75–12.07

8.42
8.96
9.03–11.72
9.05–12.60
9.05–12.28
9.04–12.26
9.03–12.51
9.03–12.38

7.72
8.28
8.36–11.06
8.39–11.95
8.39–11.63
8.38–11.62
8.38–11.87
8.37–11.73

6.82
7.34
7.41–10.10
7.43–10.97
7.43–10.65
7.42–10.64
7.42–10.89
7.41–10.75

Number of congeners in each homologue is given in parentheses following the Cx designation.

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1392
up to several units. The ADME/Tox WEB method does
not predict any perfluoroalkyl branching effects for either
PFCAs and PFSAs. Our PM6 calculations on the two SA
congeners did not support the SPARC results, but rather
supported our previous PFCA and PFSA findings of increasing perfluoroalkyl chain branching decreasing the pKa
value, rather than increasing it as SPARC predicts. In other
words, the PM6 method predicts higher N-H bond orders
(0.890 and 0.891) and a more negative unionized nitrogen
atom partial charge (qN = −0.935) for the linear C8 SA
89 compared to the 1-monomethyl branched isomer (NH bond orders of 0.887 and 0.888, qN = −0.932). These
PM6 results would suggest increasing perfluoroalkyl chain
linearity should decrease acidity (increase pKa values), in
contrast to what SPARC predicts.
In addition, we note that the pKa values of a simple
suite of hydrocarbon carboxylic acid analogs shows little
chain branching effect, with reported pKa values of 4.83 (at
20◦ C), 4.80 (at 25◦ C), 4.77 (at 25◦ C), and 5.03 (at 20◦ C) for
pentanoic acid, 2-methylbutanoic acid, 3-methylbutanoic
acid, and 2,2 -dimethylpropanoic acid, respectively.[50] By
comparison, 1-, 2-, and t-butanol have pKa values of 16.1,
17.6, and 19.2, respectively (United States Department of
Health and Human Services National Toxicology Program
database; http://ntp.niehs.nih.gov/index.cfm), showing a
substantial chain branching effect on alcohol ionization.
In sum, despite SPARC’s predictions of substantial lower
sulfonamidic acidities due to perfluoroalkyl chain branching, these results should be considered preliminary in light
of the conflicting trends reported for other analog compounds using various methods and experimental data sets.
Once a sufficient pure authentic standard of one branched
sulfonamide congener is available, the pKa value should
be reported to allow development and calibration of reliable computational methods for the remaining sulfonamide
congeners. The importance of reliable pKa measurements
and estimates for the sulfonamides cannot be underestimated, given the primary role this physicochemical process
plays in their fate and toxicology.
Environmental and toxicological implications
The environmental fate and toxicological implications of
sulfonamides ionizing at in situ and in vivo pH values, as
well as having pKa values that vary due to perfluoroalkyl
chain branching, are potentially significant. For example,
the speciation diagrams of the straight chain C8 SA 89
(n-FOSA), the highly branched C8 SA 23, C8 NMeSA 89
(n-N-MeFOSA), C8 NEtSA 89 (n-N-EtFOSA), C8 SAA
89 (n-FOSAA), and C8 NEtSAA 89 (n-N-EtFOSAA) are
shown in Figure 5, along with representative pH values of
the stomach (1.7), unpolluted rain water (5.6), blood (7.4),
and the ocean (8.1). In the high acidity of the stomach,
the ionization of all sulfonamides (branched and linear; including the carboxyl group of SAAs) should be suppressed,
and the partitioning and/or transformation pathways of

Rayne and Forest

Fig. 5. pH dependent speciation diagrams for the (a) (i) straight
chain C8 SA 89 (perfluoro-n-octanesulfonamide; n-FOSA) and
its (ii) 1,1 ,2,2 -tetramethylbutyl branched C8 SA 23 counterpart
(b) (i) C8 NMeSA 89 (N-methylperfluoro-n-octanesulfonamide;
n-N-MeFOSA) and (ii) C8 NEtSA 89 (N-ethylperfluoro-noctanesulfonamide; n-N-EtFOSA), and (c) (i) C8 SAA 89
(perfluoro-n-octanesulfonamidoacetate; n-FOSAA) and (ii) C8
NEtSAA 89 (N-ethylperfluoro-n-octanesulfonamidoacetate; nN-EtFOSAA): molecular species (solid lines); single ionized
species (dashed lines); and double ionized species (dash-dot-dot
lines). For all compounds except n-FOSAA, the first ionization
yields an amide anion. For n-FOSAA, the first ionization gives
the carboxylate anion, followed by amide ionization at higher
pH values. Vertical lines indicate representative pH values of the
stomach (1.7; solid), rain water (5.6; dashed), blood (7.4; dashdot-dot), and the ocean (8.1; dotted).

these compounds in this region of the body should be governed by the reactivity of the molecular species with no
pH-dependent isomeric fractionation occurring.
For sulfonamides in the blood, the speciation analysis is
more complex and the relative proportions of the molecular and ionized species depend on both the sulfonamide
substitution and perfluoroalkyl chain branching patterns.
Consequently, for the range of in vivo environments having pH values between that of the acidic gastrointestinal
regions and neutral blood, a substantial and complex suite
of pH-dependent isomeric fractionations is expected to occur. This congener partitioning will influence the observed
isomeric signatures in various regions of the body, as well
as alter the in vivo sulfonamide profiles compared to external ambient and food sources. The amidic moiety will
require superacids to protonate (i.e., pKa 0 for R1 -NH+
R2 →R1 -NH+
2 -R2 or R-NH2 →R-NH3 ). Thus, only the
neutral and anionic forms of the perfluoroalkyl sulfonamides are relevant under ambient environmental and biological conditions.
Substantial pH-dependent atmospheric and aquatic fractionation of linear versus branched sulfonamides is expected to occur depending on the acidity of the particular
environment and the sulfonamide subclass. With carboxyl

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Perfluoroalkyl sulfonamides
group pKa values of about 4, the SAAs are not expected
to behave solely as entirely molecular species in natural
atmospheric and aquatic systems. The lack of any perfluoroalkyl branching effect on the ionization constants
for the SAA carboxyl groups indicates that no significant
pH-dependent fractionation will occur for alkylated SAAs
(which do not have an amidic proton to ionize). For the
nonalkylated SAs and SAAs, pH values between about 5
and 8 will result in differential speciation profiles between
linear and branched congeners. By comparison, little fractionation at ambient pH values will occur for the NMeSAs,
NEtSAs, and SEs. As a result, in aquatic and atmospheric
systems, the same source branched/linear chain profiles of
SAs, NMeSAs, NEtSAs, SEs, and SAAs will fractionate to
different extents, greatly complicating intra- and inter-class
source apportionment studies that fail to incorporate any
pH-dependent degradation and partitioning processes.
In the higher pH values of marine systems, where a significant proportion of these compounds’ global mass resides,
linear nonalkylated SAs are expected to be present predominantly in the ionized form, whereas the more branched isomers are estimated to be almost entirely in the molecular
form. By comparison, addition of an alkyl group (methyl
or ethyl) increases the pKa value such that both linear and
branched NMeSAs and NEtSAs should be present primarily as the molecular form not only in marine systems, but
also in almost all in vivo and environmental matrices. However, only the highly branched NMeSAs and NEtSAs (with
pKa values up to 12.5) can have the contributions of the
anionic forms entirely neglected. For more linear NMeSAs
and NEtSAs (with pKa values as low as 8.25), there may
be sufficient contributions of the ionized species (up to 10
to 20% of total concentrations) in marine systems to play
a major role in partitioning and degradation processes.
This will be particularly important where such processes are highly selective for either the molecular or ionized forms, such as air-water partitioning at the marineatmosphere interface. For example, SPARC estimates pure
component (molecular form) air-water partitioning cono
stants (Kaw ) for the linear C8 SA 89 (n-FOSA) and the
1,1 ,2,2 -tetramethylbutyl branched C8 SA 23 at 8.86 ×
10−3 and 3.87 × 10−3 atm L mol−1 , respectively, indicating a 2.3-fold higher fractionation into the gas phase from
an aqueous system for the linear congener relative to its
o
branched counterpart. However, the Kaw values only directly apply at pH values much less the pKa of each compound where ionization is suppressed. Thus, using the reo
lationship Kaw,eff = Kaw /(1+10pH-pKa ), where Kaw,eff is the
effective air-water partitioning coefficient and pKa is the
acidity constant,[51] Kaw,eff values of 1.51 × 10−4 and 3.75
× 10−3 atm L mol−1 , respectively, are calculated at pH 8 for
C8 SA 89 (pKa = 6.24) and C8 SA 23 (pKa = 9.51). The
direction of fractionation at pH 8 is now reversed relative
to the pure component forms due to the differential ionization constants for the two isomers. In marine systems, the
air-water fractionation process is expected to preferentially

1393
concentrate the branched isomer in the gas phase (by a factor of nearly 25; or a 56-fold reversal compared to the pure
component values), leaving behind an aqueous phase that
is enriched in the linear congener.
In addition, there is much interest in the role that sulfonamides play as degradation precursors (either in the atmospheric or post-transport in situ decomposition) towards
PFCA and PFSA loadings in remote regions.[18,19,52−55]
Unfortunately, previous studies have not considered amide
acidity when estimating the atmospheric lifetimes of primary and secondary substituted sulfonamides,[18,19,52] leading to potential overestimates in their resistance to wet and
dry depositional modes and the corresponding capacity
for long range atmospheric transport. Indeed, literature
references to acidic sulfonamides such as n-FOSA have
referred to them as “neutral PFOS precursors”.[12] In addition to there being potential n-FOSA precursors that
can skew interpretations of field acquired biomagnification
factors (BMFs), the acidity of the amide group in n-FOSA
(pKa = 6.24 and therefore substantially ionized in vivo,
particularly in blood [>93%]) may allow this compound to
bind with proteins much more readily than n-N-EtFOSA
(pKa = 9.03 and not dominantly ionized in vivo [ca. 2% in
blood]), thereby potentially helping to explain the two- to
four-fold lower BMFs reported[12] for n-N-EtFOSA in an
arctic marine food web. Similarly, the ionization of some
sulfonamides at environmentally relevant pH values may
make them less susceptible to organic carbon based sorptive scavenging from the water column in aquatic systems.
In addition, where both gas and particle phase ionizable sulfonamide concentrations have been reported in atmospheric samples,[8] wide variability in the gas-particle
distribution of total sulfonamide levels is evident and no
information on the surface charge and/or aerosol pH of
the atmospheric particulate is discussed. This complicates
the application and assessment of equilibrium partitioning
models, as it is difficult to determine whether the atmospheric partitioning of these compounds can be adequately
described by an equilibrium approach, or whether the inclusion of ionization effects in the modeling effort is required
in order to achieve good agreement between expected and
observed values.
For the long-range atmospheric transport pathways to
be active, the sulfonamides must have sufficiently long
residence times to allow their movement from industrial
sources to more pristine areas before removal via wet and
dry scavenging. To estimate wet deposition lifetimes (τWD )
and dry deposition lifetimes (τDD ) on the two representative
C8 congeners (branched 23 and linear 89), we followed the
method of Brimblecombe and Dawson[56] and Shepson[57]
for the rate of wet deposition (kWD ) and that of Pul et
al. for the rate of dry deposition (kDD )[58] as applied by
Ellis et al.[59] and Martin et al.[18] Under this approach,
kWD = (Rr × E× e(−z/Zx) )/(Zx × (Kaw,eff + φ)) and kDD =
vDD /Zx = 1/[(ra +rb +rs )× Zx ], where Rr is the annual rainfall rate (3.2 × 10−8 m s−1 ), E is the enhancement factor

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1394

Fig. 6. pH dependence on the atmospheric lifetimes towards wet
(kWD ) and dry (kDD ) deposition for C8 SA 89 and 23: C8 SA 89
kWD (solid line); C8 SA 23 kWD (dash-dot-dot line); C8 SA 89
kDD (dashed line); and C8 SA 23 kDD (dotted line).

due to evaporation of falling rain droplets (1.33), z is the
characteristic height of stratus clouds (3500 m), Zx is the
scale height (2300 m), ϕ is the fraction of air volume occupied by liquid water (1 × 10−6 ), ra (192 s m−1 ) and rb (67
s m−1 ) are aerodynamic and transport resistance terms, respectively, and rs is the water surface resistance term (rs =
Kaw,eff × rw , where rw is assumed to be 105 for most organic
compounds).
The pH dependence on τWD and τDD for C8 SA 23 and 89
is shown in Figure 6, illustrating that at pH values between
5 and 9, the efficiency of wet deposition scavenging for C8
SA 89 is highly pH dependent. By comparison, τWD for the
branched C8 23 congener is not affected by pH until values >8. For these compounds, dry deposition scavenging
is not significantly influenced by the Henry’s law constant,
and hence, both compounds show little pH dependence on
τDD . Although in this example, dry deposition is the dominant removal process at relevant atmospheric precipitation
pH values (<6), the 57% reduction in τWD that occurs at
pH 6 for C8 89 by accounting for the amide ionization reo
duction in the Kaw,eff (versus the use of Kaw to estimate
τWD ) clearly shows that, for sulfonamides where kDD is
a more important contributor to the overall atmospheric
scavenging process, amide acidity will need to be explicitly
considered in atmospheric models.
The results also highlight the need to experimentally
determine sulfonamide air-water partitioning constants at
pH values where ionization is assuredly suppressed in oro
der to acquire accurate Kaw values that can subsequently
be translated into reliable Kaw,eff values for environmental
and toxicological modeling. However, to the best of our
knowledge, no peer-reviewed studies have yet reported any
ionization dependent partitioning constants for these compounds. Our current physicochemical property database
appears limited to vapor pressure and octanol-air partitioning (Koa ) estimates for n-N-EtFOSA, n-N-MeFOSE, and
n-N-EtFOSE (of which, only n-N-EtFOSA has an acidic

Rayne and Forest
amide).[60] Organic carbon normalized sediment/soil-water
partitioning constants (Koc ) have been reported for two
SAA congeners (n-N-MeFOSAA and n-N-EtFOSAA)[61]
at pH values above the SPARC calculated pKa values
(about 3.9) for the carboxyl moieties. It would be of interest to see the pH influence on the Koc values for these
compounds (and other sulfonamides) near and below the
pKa points, in particular because the findings would be directly applicable to future modeling efforts of sulfonamide
sorption on acidic organic atmospheric aerosols and with
dissolved and particulate organic matter in acidic lakes.
The reported biological activity of perfluoroalkyl sulfonamides is consistent with these contaminants containing the sulfonamide head group, which has well defined
pharmacological utility in the large class of “sulfa drugs”
that display antibiotic, diuretic, ophthalmologic, anticonvulsant, dermatological, and other activities.[62] Yet, despite
the intense historical knowledge regarding the general biological activity of the sulfonamide group, relatively little
effort has been invested in how the perfluoroalkyl derivatives behave in vivo. Most work to date has focused on
the PFCAs and PFSAs, which are classified as peroxisome
proliferators and are thought to structurally mimic fatty
acids and competitively inhibit mitochondrial β-oxidation,
as well as uncouple mitochondrial respiration.[63−73] Studies on the sulfonamides, entirely by the groups of Wallace and O’Brien, have focused on the peroxisome proliferation and mitochondrial bioenergetic behavior and are
limited to the straight chain n-FOSA, n-N-EtFOSA, nN-EtFOSE, n-FOSAA, and n-N-EtFOSAA isomers.[74−77]
Collectively, these investigations have shown that the SAAs
exert their mitochondrial disruption via a bimodal mechanism. The first component is the initial, partial, and adenine
nucleotide translator-mediated depolarization of the mitochondrial membrane potential, which arises from charge
translocation across the inner mitochondrial membrane,
resulting in mitochondrial permeability transition induction. The second component involves a direct interaction
between the SAA molecule and the adenine nucleotide
translator. The induction of mitochondrial permeability
transition involves the SAA carboxylate group. Esterification of this functionality results in a lack of mitochondrial
effects, and non-carboxylate containing sulfonamides (e.g.,
SAs and SEs) do not induce mitochondrial permeability
transition.
Studies have also suggested that the ionization of an
amidic proton reduces this type of biological potency. nN-EtFOSAA, which lacks an amidic proton, was found to
be five times more potent than n-FOSAA, whose amidic
proton we estimate to have a pKa of 7.41 and is likely
substantially or dominantly ionized in vitro. O’Brien et al.
put forward a hypothesis, which our data supports, that
amidic ionization on n-FOSAA would render this compound much less soluble in the mitochondrial membrane,
thereby inhibiting the proposed mechanism of action.[76]
This mechanism, if correct, would result in substantially

Downloaded By: [Canadian Research Knowledge Network] At: 17:55 5 October 2009

Perfluoroalkyl sulfonamides
different mitochondrial bioenergetic activity due to perfluoroalkyl chain branching. Our estimates suggest that
branched SAAs could have amidic proton pKa values of
up to 11, and thus, branched SAAs could exhibit potential
mitochondrial disruption (much as with N-EtSAA) due to
suppression of amide ionization at biologically relevant pH
values, whereas the more linear congeners would display the
much reduced bioactivity as found for the straight chain
C8 SAA 89 (n-FOSAA). We note that perfluoroalkyl chain
branching and amide alkylation are not anticipated to significantly alter the acidity constant of the SAA carboxylate moiety, and as a result, a possible major toxicological
control on mitochondrial disruption by SAAs involves the
perfluoroalkyl chain branching influence on amide acidity.
Additional work by Starkov and Wallace suggested that
n-FOSA (pKa = 6.24), n-N-EtFOSA (pKa = 9.03), and
n-FOSAA (pKa = 3.92 [carboxylate] and 7.41 [amide])
elicited a strong uncoupling of mitochondrial oxidative
phosphorylation at low µM concentrations.[78] It was suggested by Starkov and Wallace that an ionizable amide
with a favorable pKa value (5 to 7) shuttles protons into
the mitochondrial matrix and dissipates the force generated by the electron transport chain. The absence of similar activity by n-N-EtFOSE (pKa = 14.4 for the alcohol)
and n-N-EtFOSAA (pKa = 3.9 for the carboxylate), whose
acidity constants lie outside this ideal pKa range, support
this proposed mechanism. Our pKa estimate of 9.0 for
n-N-EtFOSA may require an expansion of the optimum
pKa range, perhaps from 5 to 9, for mitochondrial oxidative phosphorylation uncoupling by sulfonamides. Again,
if this mechanism of sulfonamide bioactivity is correct, we
then anticipate large variations in mitochondrial oxidative
phosphorylation uncoupling ability dependent on perfluoroalkyl chain branching, with more linear SA, NMeSA,
NEtSA, SE, and SAA congeners having pKa values <9
and displaying correspondingly high activity, whereas the
branched counterparts may be inert towards mitochondrial
oxidative phosphorylation.
As well, the protein binding ability of perfluorinated
chemical is well established, although most work has focused on the PFCAs and PFSAs.[79−81] In a study of nPFOS, n-PFOA, n-N-EtFOSA, and n-N-EtFOSE interactions with rat liver fatty acid binding protein (L-FABP),
Luebker et al. thought that the relative potencies of LFABP binding could not be explained by differences in
head group polarity and hydrogen bonding ability of these
compounds, since n-N-EtFOSA was found to have a IC50
(9.7 µM) similar to that of n-PFOS (4.9 µM) but lower
than that of n-PFOA (>10 µM) and n-N-EtFOSE (>10
µM).[79] Potential ionization of the amidic proton in nN-EtFOSA was not considered as a potential explanation
for the purportedly unusually high protein binding behavior of this compound. In light of our findings that n-NEtFOSA likely has a pKa of about 9.0, this may confer
sufficient polarity to the head group for it to form hydrogen bonds with the various amino acid residues known to

1395
occur at both the primary and secondary L-FABP binding
sites.[82,83] However, this rationalization does not help explain the lower binding affinity for n-PFOA (pKa between
about 3 and 4[47,48,84] ) compared to the higher affinity of
both n-PFOS (pKa of about −5.5[49] ) and n-N-EtFOSA
(pKa = 9.0). Yet, the potential requirement of high head
group polarity and hydrogen bonding capacity for binding
with L-FABP suggest a possible pKa -dependent control on
binding affinity driven by changes in perfluoroalkyl chain
branching. If these structural features govern head group
electrostatic properties and subsequent binding to proteins,
they may also control (along with hydrophobicity of the
perfluoroalkyl chain) the pH dependent bioconcentration
and bioaccumulation behavior of sulfonamides.
A number of other studies on the environmental behavior of perfluoroalkyl sulfonamides have ignored the amide
acidity for primary and secondary substituted members of
this class, warranting cautionary notes about any corresponding interpretations made in these investigations. For
example, Murakami et al. examined the movement of nFOSA through soils in groundwater.[85,86] The groundwater pH in the samples from these studies ranged from 6.1
to 9.3; thus, n-FOSA (pKa = 6.24) would be expected to
be present in varying degrees of ionization across these
samples, greatly complicating any data interpretations.
Ahrens et al.[87,88] also erroneously assumed that all perfluoroalkyl sulfonamides were neutral substrates in their
studies of these compounds in seawater, waste water treatment plants, and river water, whereas the n-FOSA and
n-N-methylperfluorobutane sulfonamide (n-MeFBSA) analytes in their samples would in fact have been almost
entirely (for n-FOSA) and significantly (for n-MeFBSA)
ionized. In their study of the hydroxyl radical initiated oxidation of perfluoroalkyl sulfonamides, Plumlee et al.[89]
similarly failed to consider amidic group acidities of their
starting materials, intermediates, and products, leading to
incomplete and incorrect mechanistic interpretations. Because of the acidity of primary and secondary substituted
perfluoroalkyl sulfonamides, all such mechanisms for hydroxyl radical attack (and other degradation methods) will
be pH dependent, with unique mechanistic pathways and
rate constants as a function of pH. The lack of information regarding the pH used for their studies, and lack of
consideration for pH dependent changes in the absorption
spectra of all possible compounds present during their indirect photolysis experiments, strongly suggests that the
results of this study will be limited in applicability pending
follow-up work that explicitly considers the pH dependence
of the degradation mechanisms.
During their recent studies of various perfluoroalkyl
compounds in Canadian arctic marine food webs, both
Kelly et al.[90] and Tomy et al.[91] incorrectly assumed nFOSA was a neutral compound. Kelly et al.[90] also inappropriately quoted a pH-independent octanol-water partitioning constant (log Kow ) value of 6.3 for n-FOSA, and
then applied a log Kow /octanol-air partitioning constant


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