Synthesis and structure of environmentally relevant perfluorinated sulfonamides

Journal of Fluorine Chemistry 128 (2007) 595–607

www.elsevier.com/locate/ﬂuor

Synthesis and structure of environmentally relevant

perﬂuorinated sulfonamides

a

b

Hans-Joachim Lehmler ^a,, Rama Rao V.V.V.N.S. , Dhananjaya Nauduri ,

*

John D. Vargo ^c, Sean Parkin ^d

^aDepartment of Occupational and Environmental Health, The University of Iowa, Iowa City, IA 52242, USA

^bDepartment of Anesthesiology, Mitochondrial Research Interest Group, University of Rochester Medical Center, Rochester, NY 14642, USA

^cUniversity Hygienic Laboratory, The University of Iowa, Iowa City, IA 52242, USA

^dDepartment of Chemistry, University of Kentucky, Lexington, KY 40506, USA

Received 15 December 2006; received in revised form 25 January 2007; accepted 29 January 2007

Available online 6 February 2007

Abstract

Alkylated perﬂuorooctanesulfonamides are compounds of environmental concern. To make these compounds available for environmental and

toxicological studies, a series of N-alkylated perﬂuorooctanesulfonamides and structurally related compounds were synthesized by reaction of the

corresponding perﬂuoroalkanesulfonyl ﬂuoride with a suitable primary or secondary amine. Perﬂuoroalkanesulfonamidoethanols were obtained

from the N-alkyl perﬂuoroalkanesulfonamides either by direct alkylation with bromoethanol or alkylation with acetic acid 2-bromo-ethyl ester

followed by hydrolysis of the acetate. N-Alkyl perﬂuorooctanesulfonamidoacetates were synthesized in an analogous way by alkylation of N-alkyl

perﬂuoroalkanesulfonamides with a bromo acetic acid ester, followed by basic ester hydrolysis. Alternatively, N-alkyl perﬂuoroalkanesulfona-

mides can be alkylated with an appropriate alcohol using the Mitsunobu reaction. Perﬂuorooctanesulfonamide was synthesized from the

perﬂuorooctanesulfonyl ﬂuoride via the azide by reduction with Zn/HCl. All perﬂuorooctanesulfonamides contained linear as well as branched

C₈F₁₇isomers, typically in a 10:1 to 30:1 ratio. The crystal structures of N-ethyl and N,N-diethyl perﬂuorooctanesulfonamide show that the S–N

bond has considerable double bond character. This double bond character results in a signiﬁcant rotational barrier around the S–N bond

¼

(DG = 62–71 kJ mol^ꢀ1) and a preferred solid state and solution conformation in which the N-alkyl groups are oriented opposite to the

perﬂuorooctyl group to minimize steric crowding around the S–N bond.

Keywords: Environmental contaminants; Perﬂuorooctanesulfonamides; Perﬂuorobutanesulfonamides; Alkylation; Mitsunobu reaction; X-ray structure

1. Introduction

electronegativity of ﬂuorine, its large van der Waals radius

compared to hydrogen, and the strong ﬂuorine–carbon bond.

Both the strength of the ﬂuorine–carbon bond and the

‘‘shielding’’ effect of several ﬂuorine atoms also result in the

stability of perﬂuoroalkyl chains towards chemical, thermal and

biological degradation. Medium-to-long chain perﬂuorinated

surfactants, including perﬂuorooctanesulfonamides are, there-

fore, highly persistent in the environment and have been

detected worldwide in a large range of environmental matrices

and in humans, thus raising human health concerns [2].

Unfortunately, perﬂuorooctanesulfonamides are not readily

available from commercial sources, which limits the ability to

study the environmental impact and toxicity of these compounds

and creates a need for straightforward and well-documented

approaches for their synthesis. Perﬂuorooctanesulfonamides

have been synthesized industrially from perﬂuorooctanesulfonyl

Perﬂuorooctanesulfonamides, such as N-alkyl perﬂuorooc-

tanesulfonamidoethanols, N-alkyl perﬂuorooctanesulfona-

mides and perﬂuorooctanesulfonamide, have been used for

over 40 years in a range of applications including pesticides,

surfactants, surface treatments for clothes and home furnish-

ings, paper protection and other miscellaneous applications

[1,2]. This group of compounds is ideally suited for these

purposes because of unique properties such as excellent

spreading characteristics, high surface activity and water and

oil repellency. These properties are the result of the high

* Corresponding author. Tel.: +1 319 3354414; fax: +1 319 3354290.

E-mail address: hans-joachim-lehmler@uiowa.edu (H.-J. Lehmler).

doi:10.1016/j.jﬂuchem.2007.01.013

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H.-J. Lehmler et al. / Journal of Fluorine Chemistry 128 (2007) 595–607

ﬂuoride by reaction with a suitable primary or secondary amine

and further modiﬁcation of the amide, e.g. by alkylation with

chloroethanol. Laboratory syntheses of several perﬂuoroocta-

nesulfonamides, for example, perﬂuorooctanesulfonamidoetha-

nol [3,4] and N-ethyl perﬂuorooctanesulfonamide [5], have

employed the same synthetic approach; however, a comprehen-

sive description of the synthesis and characterization of these

compounds for environmental and toxicological studies has

not been reported. We herein report the synthesis and

characterization of several environmentally relevant alkylated

perﬂuorooctanesulfonamides from commercially available per-

ﬂuorooctanesulfonyl ﬂuoride for use in such studies. In addition,

we synthesized several analogous perﬂuorobutanesulfonamides

because perﬂuorobutanesulfonate based materials are emerging

as a replacement for perﬂuorooctanesulfonate based materials

[6] and as model compounds for the study of their atmospheric

chemistry [7].

conditions of Method C (Entries 1 and 2), the products

contained signiﬁcant amounts of impurities (i.e., showed

several peaks in the gas chromatogram) and were slightly

colored even after Kugelrohr distillation and/or recrystalliza-

tion. Therefore, we abandoned this approach and focused on

reaction conditions employing a solvent such as diethyl ether.

Reaction of perﬂuorooctanesulfonyl ﬂuoride with 3a and 3b at

ambient temperature yielded 43% of the desired sulfonamide

(Entries 3 and 8). To facilitate the decomposition of the

thermally unstable complex ammonium salt we also heated the

reaction mixture under reﬂux after addition of the amine 3b

(Entry 9) [9]. In the case of ethylamine (3b) this additional

heating step appears to give a slightly higher yield and,

therefore, was used in most subsequent reactions.

A major drawback of using excess 3a or 3b as a base is the

formation of a white precipitate which made it difﬁcult to

monitor the addition of the gaseous amines 3a and 3b and to

workup these reactions. Therefore, we investigated the use of

an external base, for example, triethylamine or pyridine, which

improved the yield by 13–16%, reduced the reaction time and

gave overall more reproducible yields (Entries 6, 12 and 13).

Both pyridine and triethylamine gave similar yields. Although

the reaction conditions were identical for the synthesis of 4a

and 4b, the yield of N-methyl perﬂuorooctanesulfonamide 4a

was always lower compared to its ethyl analog 4b. This

difference in yield is probably due to difﬁculties in handling the

low boiling methylamine (Entry 4).

2. Results and discussion

2.1. Synthesis of N-alkyl and N,N-dialkyl

perﬂuoroalkanesulfonamides from perﬂuoroalkanesulfonyl

ﬂuorides

Monoalkylated perﬂuorooctanesulfonamides are typically

synthesized by reaction of perﬂuorooctanesulfonyl ﬂuoride (1)

with an excess of the respective amine, e.g. 3a–c, in diethyl

ether or dioxane (for a review see [2]). This reaction initially

forms a complex ammonium salt with a proposed formula of

We also studied the inﬂuence of selected solvents (i.e., ether,

dioxane and dichloromethane) on the yield of the reaction

(Entries 5, 10 and 11). Pyridine, which has been used previously

as solvent for the synthesis of perﬂuorooctane-1-sulfonic

acid (2,2-dimethoxy-ethyl)-amide from perﬂuorooctanesulfonyl

ﬂuoride 1 [3], was not investigated because it is typically difﬁcult

to remove residual pyridine traces. We found that the solvent had

little-to-noeffectontheoverallyield. However, dichloromethane

as a solvent resulted in a signiﬁcantly colored reaction mixture

and is, therefore, a less suitable solvent for this type of reaction

(Entry 10). This is surprising because reactions of shorter chain

perﬂuoroalkylsulfonyl ﬂuorides and chlorides with alkyl amines

can be performed using a broad range of solvents (e.g.,

dichloromethane) and reaction conditions [2].

+

C₈F₁₇SO₂NR^ꢀꢁNRH₃ꢁNRH₃F. The desired alkylated perﬂuor-

ooctanesulfonamide 5a–c is subsequently isolated after thermal

decomposition of this complex salt [8–11] or by treatment of

the reaction mixture with hydrochloric or sulfuric acid [11–13].

Following these previous reports, we initially investigated the

reaction of perﬂuorooctanesulfonyl ﬂuoride (1) by using an

excess of the respective alkyl amine, e.g. methyl- (3a) or

ethylamine (3b), as a base (Scheme 1). Subsequent experiments

studied the use of an external base such as triethylamine or

pyridine. These efforts and our attempts to further optimize the

reaction conditions are summarized in Table 1.

Initial experiments employed the two gaseous amines 3a and

3b both as reactants and as base at ambient temperature, both

with (Method A) and without solvent (Method C). Although

apparently higher yields were obtained under the solvent free

To facilitate the conversion of the complex ammonium salt

to the desired perﬂuorooctanesulfonamide, we investigated

different aqueous workup conditions such as acidic and basic

Scheme 1. Synthesis of mono- and dialkylated perﬂuorooctanesulfonamides.

H.-J. Lehmler et al. / Journal of Fluorine Chemistry 128 (2007) 595–607

597

Table 1

Synthesis of mono- and dialkylated perﬂuorooctanesulfonamides from perﬂuorooctanesulfonyl ﬂuoride

Entry

Amine

Base

Solvent

Reaction conditions

Method

Percentage linear:isopropyl

branched isomer^a

Yield (%)

1

2

3a

3b

3a

3b

6d

6e

6f

3a

3b

3a

NEt₃

3b

None

Ether

DCM

Ether

DCM

Ether

Dioxane

Ether

None

Ether

AT

C

A

B

A

B

A

B

E

n.d.

70^b,c

43

AT

n.d.

3

AT

98:2

92:8

98:2

96:4

98:2

95:5

97:3

96:4

98:2

99:1

94:6

95:5

4

Reﬂux

AT

24–28^d

46^e

5

6

46

43^f

7

8

43

9

3b

Reﬂux

AT

48–50

57

10

11

12

13

14

15

16

17

18

NEt₃

Pyridine

NEt₃

6g

AT

Reﬂux^h

46^g

42–58

51ⁱ

AT

Reﬂux^g

Reﬂux

56^f

55

69^b,c

E

B

D

53

6g

76

a

The percentage of the linear and isopropyl branched isomer was determined based on the integral of the respective CF₃signals.

Slightly yellow, waxy solid with several peaks in the gas chromatogram.

Recrystallized from reagent alcohol/dichloromethane.

b

c

d

e

f

The low yield is probably due to the ten times smaller scale of these reaction compared to most reactions reported in this table.

Worked-up with diluted hydrochloric acid to remove traces of pyridine.

Non-aqueous work-up was adopted.

g

h

i

Reaction mixture was hydrolyzed with saturated NaHCO₃solution.

20 h of reaction time.

Dark brown crude product.

AT = ambient temperature.

DCM = dichloromethane.n.d. = not determined.

aqueous workup (Entries 5 and 11, respectively). Overall, no

improvement in the yield of the reaction was observed

suggesting that the complex ammonium salt readily decom-

poses under the reaction conditions employed. In subsequent

experiments we avoided an aqueous workup altogether and

directly puriﬁed the product by column chromatography as

outlined in Method B (Entries 7 and 11). The reaction

conditions of Method B, with slight modiﬁcations (i.e.,

acetonitrile as solvent), were also employed to synthesize

the corresponding perﬂuorobutane-1-sulfonamides 5a and 5b

from perﬂuorobutanesulfonyl ﬂuoride 2 in good yields.

The dialkyl perﬂuoroalkanesulfonamides 7d–g and 8g,

compounds of interest as analytical standards, were prepared

from ﬂuoride 1 or 2 and the respective dialkyl amines 6d–g

using the same strategies employed for the monoalkyl

derivatives 4a and 4b (Methods D and E, Entries 15–18).

The best results with regard to purity were obtained using an

excess of the amine as a base (Method D, entries 15 and 17).

C₈F₁₇SO₂Farealsopresent.Theseinclude(F₃C)₂CF(CF₂)₅SO₂F

(isopropyl), F₃C(CF₂)_xCF(CF₃)(CF₂)_5ꢀxSO₂F (internally bran-

ched) and (F₃C)₃C(CF₂)₄SO₂F (t-butyl). We investigated

recrystallization and column chromatography techniques to

purify the crude product and, if possible, to remove branched

impurities. Among these two puriﬁcation methods, only column

chromatography on silica gel was able to remove a signiﬁcant

percentage of the branched perﬂuorooctanesulfonamides and

other ﬂuorinated impurities. Initial fractions were eluted with

ethyl acetate–hexane as eluent and, based on ¹H and ¹⁹F NMR

spectroscopy, contained a mixture of branched impurities

(major), some linear isomer (minor) and other, uncharacterized

impurities. The straight chain isomer and some branched

impurities were eluted by further increasing the polarity of the

mobile phase (up to 7% of ethyl acetate). In these later fractions,

the ratios of linear to branched perﬂuorooctanesulfonamide

were determined using ¹⁹F NMR spectroscopy. The ratios of

linear to isopropyl perﬂuorooctanesulfonamide (F₃C)₂CF(CF₂)₅

SO₂NRR⁰typically ranged from 10:1 to 30:1 in all perﬂuor-

ooctanesulfonamides synthesized (e.g., Table 1). All samples

also contained small quantities of the t-butyl and other branched

perﬂuorooctanesulfonamides. Recrystallization did not remove

all branched impurities, but worked well to remove the dark

brown color from the crude product.

2.2. Isomer composition of perﬂuorooctanesulfonyl amides

Commercially available perﬂuorooctanesulfonyl ﬂuoride 1 is

manufactured by electrochemical ﬂuorination, a process that

results in a signiﬁcant number of organic and inorganic

byproducts.Onlyapproximately70%ofperﬂuorooctanesulfonyl

ﬂuoride1arethedesiredlinearisomer[2]. Signiﬁcantamountsof

various branched C₈F₁₇isomers with the general structure

The perﬂuorobutanesulfonyl ﬂuoride 2 used in this study

was most likely synthesized by electrochemical ﬂuorination of

the corresponding butanesulfonyl ﬂuoride [2]. In contrast to

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H.-J. Lehmler et al. / Journal of Fluorine Chemistry 128 (2007) 595–607

its long chain homologue 1, the ¹⁹F NMR spectrum of

perﬂuorobutanesulfonyl ﬂuoride 2 showed only the four signals

of the perﬂuorobutyl chain. No impurities could be detected in

the ¹⁹F NMR spectrum even with neat 2. The high purity of

ﬂuoride 2 is not unexpected because the electrochemical

ﬂuorination of shorter-chain alkanesulfonyl chlorides and

ﬂuorides is known to give the respective ﬂuorides in good

purities and excellent yields [1]. As a result, the perﬂuor-

obutanesulfonamides 5a–c derived from ﬂuoride 2 are also free

of branched impurities.

9b in 65% and 93% yield, respectively. Because of the overall

lower yields, this approach is less suitable for the synthesis of

the dialkylated sulfonamides.

We also employed a similar alkylation reaction for the

synthesis of N-ethyl perﬂuorooctanesulfonamideacetate 12. As

shown in Scheme 3, alkylation of an N-ethyl perﬂuoroocta-

nesulfonamide with a bromoacetic acid methyl ester yields the

desired ester 11 in good yields. We initially investigated the

base catalyzed hydrolysis (2–10% aqueous as well as ethanolic

KOH solutions) of ester 11 to obtain the desired acid. These

severe reaction conditions gave a complex mixture of

uncharacterized decomposition products. However, controlled

basic hydrolysis [17] yielded the desired acid 12 in moderate

yield and acceptable purity.

2.3. Synthesis of N,N-dialkyl perﬂuoroalkanesulfonyl

amides

N-methyl-N-(2-hydroxyethyl)-perﬂuorooctane-1-sulfona-

mide 9a and N-ethyl-N-(2-hydroxyethyl)-perﬂuorooctane-1-

sulfonamide 9b were important industrial products and are

known environmental contaminants [2]. Both amides have been

industrially synthesized by alkylation of the respective amides,

for example, 4a or 4b, with chloroethanol [14], oxirane [15] or

1,3-dioxolan-2-one (ethylene carbonate) [4]. Following these

earlier (patent) reports we initially investigated the synthesis of

perﬂuorooctanesulfonamide 7f by alkylation of N-methyl

perﬂuorooctanesulfonamide 4a with iodoethane. The desired

perﬂuorooctanesulfonamide 7f was obtained in 78% yield

when sodium methoxide was employed as a base [16], but the

reaction was more straightforward and the yields signiﬁcantly

improved when potassium carbonate was used as a base.

We subsequently investigated the alkylation of the N-alkyl

perﬂuorooctanesulfonyl amides 4a and 4b with bromoethanol

using potassium carbonate as base and catalytic amount of

sodium iodide in acetone (Scheme 2). Initial experiments gave

low yields of the desired sulfonamides 9a and 9b due to

impurities present in commercially available bromoethanol;

however, good yields ranging from 62 to 99% were obtained by

alkylation of 4a and 4b with freshly distilled bromoethanol. In a

second approach (Scheme 2), the N-alkyl amide 4a or 4b was

alkylated with 2-bromoethyl acetate in the presence of the

potassium carbonate base and catalytic amount of sodium

iodide. The acetates 10a or 10b were deacetylated with aqueous

potassium hydroxide to yield the desired sulfonamides 9a and

2.4. Synthesis of N,N-dialkyl perﬂuoroalkanesulfonamides

using the Mitsunobu reaction

The Mitsunobu reaction has been successfully employed for

the N-alkylation of derivatives of triﬂamide (CF₃SO₂NH₂) with

various alcohols [18–20]. We investigated this approach as an

alternative route to N,N-dialkyl perﬂuorooctanesulfonamides.

As shown in Scheme 4, the Mitsunobu reaction of 4b with

methyl glycolate gave ester 11 in good yield. The Mitsunobu

reaction of 4b with ethylene glycol did not yield the desired

product 9b; however, the Mitsunobu reaction of 4b with

TBDMS (t-butyldmethylsilyl) protected ethylene glycol 13

gave the desired product 14 in 98% yield. Hydrolysis of 14

using hydrochloric acid at 25 8C yielded 9b in 96% yield.

Overall, the Mitsunobu reaction gives the target molecules in

good to excellent yields, and thus, is an alternative approach for

the alkylation of perﬂuoroalkanesulfonamides.

2.5. Synthesis of perﬂuorooctanesulfonamide 17 from

perﬂuoroalkanesulfonyl ﬂuoride

Perﬂuorooctanesulfonamide 17 can be prepared by reaction

of ammonia with perﬂuorooctanesulfonyl ﬂuoride 1 [8–11]. We

explored a different approach that avoids the use of ammonia

and, as shown in Scheme 5, prepared the amide 17 in a two-step

synthesis via the azide. In the ﬁrst step, perﬂuorooctanesulfonyl

Scheme 2. Synthesis of mono- or N-alkylated perﬂuorooctanesulfonamidoethanol 9a and 9b.

H.-J. Lehmler et al. / Journal of Fluorine Chemistry 128 (2007) 595–607

599

Scheme 3. Synthesis of 2-(N-ethyl perﬂurooctanesulfonamido)acetic acid 12.

Scheme 4. Synthesis of N,N-dialkylated perﬂuorooctanesulfonamides 11 and 14 from N-alkylated perﬂuorooctanesulfonamides using the Mitsunobu reaction.

ﬂuoride was reacted with an aqueous solution of sodium azide

at room temperature to yield the perﬂuorooctanesulfonyl azide

15. This azide 15 was subsequently converted into the

perﬂuorooctanesulfonamide 16 by treatment with zinc and

aqueous hydrochloric acid [21].

sulfonamide (4b), N,N-diethyl-perﬂuorooctane-1-sulfonamide

(7e) and 2-(N-ethyl-perﬂuorooctanesulfonamido) acetic acid

(12).

The crystal structure of 4b is shown in Fig. 1. Crystals of

¯

amide 4b are triclinic (space group P1) with a = 6.3411(1),

˚

b = 9.5670(3), c = 28.2303(9) A, and a = 88.579(2)8, b =

85.758(2)8, g = 87.348(2)8. The asymmetric unit contains

two independent molecules that are rotational isomers and

are enantiomeric to each other (Fig. 1). The crystal structure

of 7e is shown in Fig. 2. Amide 7e is monoclinic (space group

2.6. Structure of N-alkyl and N,N-dialkyl

perﬂuoroalkanesulfonyl amides

To fully understand the biological effects of perﬂuoroocta-

nesulfonamides it is important to know their three-dimensional

structures. Although (partially) ﬂuorinated compounds are

often very difﬁcult to crystallize [22], typically forming

exceedingly thin, poorly stacked platelets, we were able to

determine the crystal structure of N-ethyl-perﬂuorooctane-1-

˚

P2₁/c) with a = 7.3103(7), b = 6.4514(6), c = 39.904(4) A,

and a = 908, b = 95.089(5)8, g = 908. An interesting feature

of this crystal structure is that the perﬂuorooctyl chains of the

disorder components are enantiomeric—they spiral around

both ways, thus resulting in a disordered crystal. This is not

surprising because perﬂuoroalkane chains typically adopt a

helical conformation resulting from the larger van der Waals

radius of ﬂuorine relative to hydrogen (see Fig. 2B) [23]. The

crystal structure of 12 is shown in Fig. 3. Amide 12 is also

monoclinic (space group Pc; an alternative model in P2/c

was less satisfactory) with a = 33.150(3), b = 5.8124(7),

Scheme 5. Synthesis of perﬂuorooctanesulfonamide 16.

600

H.-J. Lehmler et al. / Journal of Fluorine Chemistry 128 (2007) 595–607

Fig. 1. Structure of N-ethyl-perﬂuorooctane-1-sulfonamide (4b). Displacement ellipsoids are drawn at the 50% probability level.

Fig. 2. View of N,N-diethyl-perﬂuorooctane-1-sulfonamide (7e). (A) Structure of 7e showing the atom-labelling scheme. (B) View of 7e along the carbon backbone

to illustrate the helical conformation of the perﬂuorooctyl chain of the major component in the crystal. Displacement ellipsoids are drawn at the 50% probability level.

˚

c = 10.0365(15) A, and a = 908, b = 91.220(6)8, g = 908.

Since crystallographic study of compounds containing

perﬂuorinated chains is generally very difﬁcult owing to

poor quality crystals, the quality of resulting structures is

often somewhat lower than for typical small-molecule

structure determinations (vide infra). Although this is

particularly true of amide 12, it is nevertheless possible to

extract chemically meaningful results from the structure

models.

Fig. 3. View of 2-(N-ethyl-perﬂuorooctanesulfonamido) acetic acid (12) showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50%

probability level.

H.-J. Lehmler et al. / Journal of Fluorine Chemistry 128 (2007) 595–607

601

Fig. 4. Packing diagram of N-ethyl-perﬂuorooctane-1-sulfonamide (4b), viewed down the b axis, illustrating the bilayers of 4b oriented parallel to the a–b plane. H

atoms have been omitted for clarity.

As illustrated in Figs. 4–6, the packing diagrams of all three

crystal structures show segregation of the electronically

different parts of the perﬂuorooctanesulfonamide molecules

to form bilayers with a perﬂuoroalkyl core which are separated

by the sulfonamide groups. Speciﬁcally, both 4b and 7e form

bilayers parallel to the a–b plane (Figs. 4 and 5), whereas, 12

forms bilayers parallel to the b–c plane (Fig. 6). The respective

perﬂuorooctanesulfonamides molecules are tilted within the

bilayer by approximately 608 (4b), 358 (7e) and 808 (12),

respectively. The formation of bilayers by all three perﬂuor-

ooctanesulfonamides is not a surprising observation because

Aꢁ ꢁ ꢁB interactions (e.g., interactions between different parts of

a molecule) are usually less favorable than the mean of Aꢁ ꢁ ꢁA

and Bꢁ ꢁ ꢁB interactions (i.e., interactions between similar parts

of a molecule) [22]. This is particularly true for the

hydrophobic and lipophobic perﬂuoroalkyl chains and, in the

Fig. 5. Packing diagram of N,N-diethyl-perﬂuorooctane-1-sulfonamide (7e), viewed down the b axis, illustrating the bilayers of 7e oriented paralel to the a–b plane.

H atoms have been omitted for clarity.

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H.-J. Lehmler et al. / Journal of Fluorine Chemistry 128 (2007) 595–607

Table 2

Geminal-coupling-constant values, coalescence temperature, chemical shift

difference at the coalescence temperature Dn and barriers of rotation about

¼

the S–N bond DG for several sulfonamides in d₆-acetone

Sulfonamide Geminal

coupling

Coalescence

Dn

temperature (K) (Hz) activation DG

Free energy of

¼

constant^a(Hz)

(kJ mol^ꢀ1

)

7e

7f

9a^b

9b^b

14.4

309

312

319

315

36

99

64

62

63

64

14.3

n.d.

129

52

14.6

10a^b,c

15.1^b

12.1^c

319

307

136

104

63

10b^b

12

15.5

n.d.

307

312

47

3

63

71

n.d. = not determined.

a

Determined at temperatures below 273 K, i.e. well below the coalescence

temperatures of the respective sulfonamide.

b

–NCH₂CH₂OR.

c

–NCH₂CH₂OR.

and in solution [16]. The S–N bonds of 4b (1.574(5) and

˚

1.576(5) A), 7e (1.581(5) A) and 12 (1.590(9) A) are short due

to hyperconjugation with the perﬂuorooctyl chain [16]. For

comparison, the unweighted sample mean for C–SO₂–N(H)C

and C–SO₂–N(C)C bonds is 1.633 ꢂ 0.019 and 1.642 ꢂ 0.024,

respectively [24]. The short S–N bond length suggests an

appreciable double-bond character, and thus a hindered rotation

around the S–N bond.

1

We used H NMR spectroscopy to further investigate the

hindered rotation around the S–N bond of all dialkylated

perﬂuorooctanesulfonamides. At ambient temperature several

of the –N–CH₂– systems show magnetically nonequivalent

protons and at temperatures below 0 8C typical geminal

coupling constant of approximately 14.3–18.5 Hz were

¼

observed (Table 2). The free energy of activation DG for

several –N–CH₂– systems was estimated using variable

temperature NMR spectroscopy to be approximately 62–

71 kJ mol^ꢀ1[16,25]. These values are in good agreement with

literature values [16].

Fig. 6. Packing diagram of 2-(N-ethyl-perﬂuorooctanesulfonamido) acetic acid

(12), viewed down the b axis, illustrating the bilayers of 12 oriented paralel to

the b–c plane. H atoms have been omitted for clarity.

3. Conclusions

In summary, the synthesis and characterization of several

environmentally relevant perﬂuorooctanesulfonamides and

related perﬂuorobutanesulfonamides from ﬂuoride 1 or 2 is

described. These sulfonamides are needed for environmental

and toxicological studies but are also useful as analytical

standards. The puriﬁcation of the perﬂuorooctanesulfonamides

represented a challenge because of the impurities present in

commercial perﬂuorooctanesulfonyl ﬂuoride (1). Although

ﬂuorinated impurities can largely be removed by column

chromatography, some branched C₈F₁₇isomers are still present

in the ﬁnal product. The ratio of these branched isomers to the

linear sulfonamides can be easily determined using ¹⁹F NMR

spectroscopy.

case of 12, the –COOH groups which from dimers linked by

hydrogen bonds in the crystal structures.

The crystal structures of 4b, 7e and 12 have several

structural similarities that are the result of both steric and

electronic effects. The –CH₂N(R)–S( O)₂–CF₂– (R H or

CH₂) fragment in all three structures adopts a staggered

conformation with a trigonal planar nitrogen atom. The ethyl

groups in both structures are on the site opposite to the

perﬂuorooctyl group to minimize steric crowding around the S–

N bond. A similar conformation has been reported for N,N-

dibenzyl-perﬂuorobutane-1-sulfonamide in both the solid state

H.-J. Lehmler et al. / Journal of Fluorine Chemistry 128 (2007) 595–607

603

4. Experimental

ꢃ Method B: Perﬂuoroalkanesulfonyl ﬂuoride 1 or 2 (25 g,

50 mmol) and triethylamine (10.1 g, 100 mmol) were

placed under a nitrogen atmosphere in a three necked

round bottom ﬂask containing dry ether or acetonitrile

(100 mL) and equipped with a reﬂux condenser. The

respective alkyl amine 3a or 3b (60 mmol) was passed

slowly through the reaction mixture over a period of 3 h at

0–5 8C, the reaction mixture was allowed to stir for 14 h at

ambient temperature and reﬂuxed for 3 h. The reaction

mixture was cooled to room temperature and the solvent

was removed from the reaction mixture by rotary

evaporation under reduced pressure. The resultant crude

product was dissolved in acetone (20 mL), absorbed on

silica gel (25–40 mm mesh) and puriﬁed by column

chromatography as described under Method A.

4.1. General experimental procedures

¹H, ¹³C and ¹⁹F NMR spectra were recorded on a Bruker

Avance-300 spectrometer. All NMR chemical shifts (d) are

reported in parts per million (ppm) and were determined

relative to TMS for ¹H and ¹³C NMR spectra and CFCl₃for ¹⁹

F

NMR spectra. Signals of the linear perﬂuoroalkyl chains were

assigned and labeled as described previously [26]. A GC 6890

series (Agilent Technologies, Palo Alto, CA, USA) gas

chromatograph equipped with a J&W Scientiﬁc HP-1 capillary

column (Agilent Technologies, Wilmington, USA) and a ﬂame

ionization detector was used to monitor the reactions and to

determine the purity of all compounds. The following program

was employed: initial temperature: 50 8C, initial time: 1 min,

rate: 10 8C/min, ﬁnal temperature: 250 8C, ﬁnal time: 2 min.

Combustion analyses were obtained from Atlantic Microlab

Inc. (Norcross, GA, USA).

ꢃ Method C: An excess of the alkyl amine 3a or 3b was slowly

passed through perﬂuorooctanesulfonyl ﬂuoride 1 (3.65 g,

7.3 mmol). The mixture was stirred at ambient temperature for

5 h and the resulting dark brown, waxy solid was treated with

Zn(2 g)andHCl(5 mL) todecolorizetheproduct. Theproduct

was puriﬁed by Kugelrohr distillation to yield the product as a

slightly brown, waxy solid. Crystals of 4b suitable for crystal

structure analysis were obtained by recrystallization from

reagent alcohol/dichloromethane at 4 8C.

Volatile amides without acidic protons were analyzed in the

University of Iowa High Resolution Mass Spectrometry

Facility using a ThermoFinnigan Voyager GC–MS system

(ThermoFinnigan, San Jose, CA, USA) equipped with a ZB-1

column (Phenomenex, Torrance, CA, USA). Additional

structural conﬁrmation for amide with acidic protons was

provided by LC/MS/MS. In short, solutions of the puriﬁed

derivatives were dissolved in methanol at a concentration of

5 mg/mL and subsequently infused into a Micromass Quattro

LC/MS/MS system equipped with an electrospray (ESI)

interface and operated in the negative ion monitoring mode.

Conﬁrmation was obtained by observation of the correspond-

ing deprotonated molecular ions ([M–H]^ꢀ) coupled with MS/

MS product ion scans of the deprotonated molecular ions

showing unique and predictable fragmentation of the precursor

ions. The observed fragmentation patterns of several per-

ﬂuorooctanesulfonamides were consistent with spectra

obtained from samples that had been provided by the 3M

Company [27,28].

4.2.1. N-methyl-perﬂuorooctane-1-sulfonamide (4a)

mp 104 8C (Lit. 101–103 8C [4]); IR (KBr); n 3335 (–NH–),

1439, 1362, 1241, 1206, 1182, 1152, and 1126 cm^ꢀ1; ¹H NMR

(300 MHz, d₆-DMSO): d 1.9(3H, s, –CH₃), 8.4 (1H, br s, –HN–);

¹³C NMR (75 MHz, d₆-DMSO): d 29.0 (–CH₃); ¹⁹F NMR

(288.8 MHz, d₆-DMSO): d ꢀ80.6 (CF₃), ꢀ112.1 (a-CF₂),

ꢀ119.8 (b-CF₂), ꢀ121.2 (3 ꢄ CF₂), ꢀ122.2 (z-CF₂), ꢀ125.7

(u–CF₂); MS, m/z (rel. int.): 512 [M ꢀ H]⁺(100%). Anal. Calcd

for C₉H₄F₁₇NO₂S: C, 21.07; H, 0.79; S, 6.25; N, 2.73. Found: C,

21.23; H, 0.72; S, 6.45; N, 2.97.

4.2.2. N-Ethyl-perﬂuorooctane-1-sulfonamide (4b)

mp 87 8C (Lit. 87–88.5 8C [29] and 120 8C [5]); IR (KBr); n

3318 (–NH–), 1454, 1363, 1238, 1206, 1152, 1126, and

;

1072 cm^ꢀ^{1 1}H NMR (300 MHz, d₆-DMSO): d 1.2 (3H, t,

J = 7.2 Hz, –CH₃), 3.2 (2H, ‘‘q’’, J = 7.2 Hz, –CH₂–), 9.3 (1H,

br s, –HN–); ¹³C NMR (75 MHz, d₆-DMSO): d 15.1 (–CH₃),

38.7 (–CH₂–); ¹⁹F NMR (288.8 MHz, d₆-DMSO): d ꢀ80.6

(CF₃), ꢀ112.1 (a-CF₂), ꢀ119.8 (b-CF₂), ꢀ121.1 (3 ꢄ CF₂),

ꢀ122.2 (z-CF₂), ꢀ125.7 (u–CF₂); MS, m/z (rel. int.): 526

[M ꢀ H]⁺(1 0 0). Anal. Calcd for C₁₀H₆F₁₇NO₂S: C, 22.78; H,

1.15; S, 6.08; N, 2.66. Found: C, 23.03; H, 1.28; S, 6.15; N,

2.85.

4.2. General procedures for the synthesis of N-alkyl

perﬂuorooctanesulfonamide derivatives

ꢃ Method A: Perﬂuorooctanesulfonyl ﬂuoride

1 (5.0 g,

10 mmol) was placed under a nitrogen atmosphere in a

three necked round bottom ﬂask containing dry ether (75 mL)

and equipped with a reﬂux condenser. A two-fold excess of

the respective alkyl amine 3a or 3b (30 mmol) was passed

slowly through the reaction mixture at 0–5 8C over a period of

1 h, the reaction mixture was allowed to stir for 24 h at

ambient temperature and heated under reﬂux for 1 h. The

reaction mixture was cooled to room temperature and a white

precipitate was ﬁltered off. The precipitate was washed with

ether (30 mL). The solvent was removed by rotary

evaporation under reduced pressure. The crude product

was further puriﬁed by column chromatography using silica

gel (25–40 mm mesh) with hexane and ethyl acetate as eluent

(gradient from 100% to approximately 93% hexane).

4.2.3. N-Methyl-perﬂuorobutane-1-sulfonamide (5a)

Eighty percent; mp 36–37 8C; IR (KBr): n 3338 (–NH–),

1429, 1364, 1235, 1206, 1186, and 1142 cm^ꢀ^{1 1}H NMR

;

(300 MHz, CDCl₃): d 3.03 (3H, s, –CH₃), 5.13 (1H, br s, –HN–).

¹³C NMR (75 MHz, CDCl₃): d 30.7 (–CH₃); ¹⁹F NMR

(288.8 MHz, CDCl₃): d ꢀ81.28 (CF₃), ꢀ112.72 (a-CF₂),

ꢀ121.94 (b-CF₂), ꢀ126.51 (g-CF₂); GC–MS 40 eV, m/z (rel.

int.): 312(100), 219(22), 112(10). Anal. Calcd for C₅H₄F₉NO₂S:

604

H.-J. Lehmler et al. / Journal of Fluorine Chemistry 128 (2007) 595–607

C, 19.18; H, 1.29; S, 10.24; N, 4.47. Found: C, 19.11; H, 1.15; S,

10.06; N, 4.38.

1.15; S, 6.08; N, 2.68. Found: C, 22.82; H, 1.04; S, 6.16; N,

2.68.

4.2.4. N-Ethyl-perﬂuorobutane-1-sulfonamide (5b)

Sixty-one percent; mp 35–36 8C (Lit. 40 8C [9]); IR (KBr): n

4.3.2. N,N-Diethyl-perﬂuorooctane-1-sulfonamide (7e)

mp 48–50 8C; IR (KBr); n 2992, 1468, 1385, 1244, 1217,

1155, 1055, and 1024 cm^ꢀ1; ¹H NMR (300 MHz, CDCl₃): d 1.3

(6H, t, J = 7.1 Hz, –CH₃), 3.4–3.7 (4H, m, –NCH₂–); ¹³C NMR

(75 MHz, CDCl₃): d 14.0 (–CH₃), 42.9 (–NCH₂–); ¹⁹F NMR

(288.8 MHz, CDCl₃): d ꢀ81.3 (CF₃), ꢀ113.1 (a-CF₂), ꢀ120.7

(b-CF₂), ꢀ122.2 (3 ꢄ CF₂), ꢀ123.2 (z-CF₂), ꢀ126.6 (u-CF₂);

GC–MS 40 eV, m/z (rel. int.): 540 [M ꢀ CH₃]⁺(11), 448

[C₈F₁₆SO]⁺(8). Anal. Calcd for C₁₂H₁₀F₁₇NO₂S: C, 25.96; H,

1.82; S, 5.77; N, 2.52. Found: C, 25.95; H, 1.86; S, 5.76; N,

2.64.

3321 (–NH–), 1437, 1373, 1238, 1206, 1190, and 1141 cm^ꢀ1

;

¹H NMR (300 MHz, CDCl₃): d 1.28 (3H, t, J = 7.2 Hz, –CH₃),

3.41 (2H, q, J = 7.2 Hz, –CH₂–), 5.06 (1H, br s, –HN–); ¹³C

NMR (75 MHz, CDCl₃): d 16.0 (–CH₃), 40.3 (–CH₂–); ¹⁹F

NMR (288.8 MHz, CDCl₃): d –81.30 (CF₃), ꢀ113.20 (a-CF₂),

ꢀ121.83 (b-CF₂), ꢀ126.53 (g-CF₂); GC–MS 40 eV, m/z (rel.

int.): 326(100), 219(25), 126(10). Anal. Calcd for

C₆H₆F₉NO₂S: C, 22.03; H, 1.85; S, 9.80; N, 4.28. Found: C,

22.31; H, 1.89; S, 9.78; N, 4.31.

4.2.5. N-(2-Methoxy-ethyl)-perﬂuorobutane-1-sulfonamide

(5c)

4.3.3. N-Ethyl-N-methyl-perﬂuorooctane-1-sulfonamide

(7f)

Forty-seven percent; Colorless liquid; IR (Neat): n 3310–

3146 (–NH), 1434, 1376, 1237, 1188, 1140, 1082, and 1036

mp 44–46 8C; IR (KBr); n 1375, 1240, and 1150 cm^ꢀ1; ¹H

NMR (300 MHz, d₆-acetone): d 1.3 (3H, t, J = 7.2 Hz, –CH₃),

3.2 (3H, s, –NCH₃), 3.3–3.8 (2H, m, –NCH₂–); ¹³C NMR

(300 MHz, d₆-acetone): d 13.9 (–CH₃), 35.4 (–NCH₃), 47.2 (–

NCH₂–); ¹⁹F NMR (288.8 MHz, d₆-acetone): d ꢀ80.5 (CF₃),

ꢀ112.1 (a-CF₂), ꢀ119.9 (b-CF₂), ꢀ121.2 (3 ꢄ CF₂), ꢀ122.1

(z-CF₂), ꢀ125.6 (u-CF₂); GC–MS 40 eV, m/z (rel. int.): 526

[M ꢀ CH₃]⁺(2), 462 [C₈F₁₆SON]⁺(4). Anal. Calcd for

C₁₁H₈F₁₇NO₂S: C, 24.41; H, 1.49; S, 5.92; N, 2.59. Found:

C, 24.68; H, 1.41; S, 5.98; N, 2.49.

1

cm^ꢀ1; H NMR (300 MHz, CDCl₃): d 3.40 (3H, s, –OCH₃),

3.48–3.56 (4H, m, –NCH₂CH₂O–), 6.11 (1H, br s, –NH–); ¹³

C

NMR (75 MHz, CDCl₃): d 44.4 (–NCH₂–), 59.0 (–OCH₃), 71.4

(–CH₂O–); ¹⁹F NMR (288.8 MHz, CDCl₃): d –81.29 (CF₃),

ꢀ113.25 (a-CF₂), ꢀ121.80 (b-CF₂), ꢀ126.00 (g-CF₂); GC–MS

40 eV, m/z (rel. int.): 358 [M + H]⁺(1), 326 [M–OCH₃]⁺(5), 312

[M–CH₂OCH₃]⁺(18), 248(18), 219(30), 131(30), 69(100). Anal.

Calcd for C₇H₈F₉NO₃S: C, 23.54; H, 2.26; S, 8.98; N, 3.92.

Found: C, 23.55; H, 2.26; S, 8.88; N, 3.87.

4.3.4. 4-(Heptadecaﬂuorooctane-1-sulfonyl)-morpholine

(7g)

4.3. General procedures for the synthesis of N,N-dialkyl

perﬂuorooctanesulfonamides (7d–g and 8g)

mp 118 8C (Lit. 127–129 8C [30]); IR (KBr): n 1390, 1268,

1184, 1148, 1134, 1113, 1080, and 969 cm^ꢀ^{1 1}H NMR

;

ꢃ Method D: Perﬂuorooctanesulfonyl ﬂuoride

1

(25 g,

(300 MHz, d₆-acetone): d 3.4–4.1 (8H, m); ¹³C NMR (75 MHz,

d₆-acetone): d 48.0 (–NCH₂–), 67.2 (–CH₂O–); ¹⁹F NMR

(288.8 MHz, d₆-acetone): d ꢀ80.51 (CF₃), ꢀ112.03 (a-CF₂),

ꢀ119.83 (b-CF₂), ꢀ121.15 (3 ꢄ –CF₂–), ꢀ122.11 (z-CF₂),

ꢀ125.63 (u-CF₂); GC–MS 40 eV, m/z (rel. int.): 569 [M]⁺(23),

526(14), 486(4), 442(5), 150(100), 134(34), 56(82); Anal.

Calcd for C₁₂H₈F₁₇NO₃S: C, 25.32; H, 1.42; S, 5.63; N, 2.46.

Found: C, 25.45; H, 1.56; S, 5.56; N, 2.65.

50 mmol) was dissolved in anhydrous ether (100 mL) under

a nitrogen atmosphere. The dialkyl amine 6d–g (100 mmol)

was added slowly to the reaction mixture over a period of

30 min, allowed to stir for 16 h at room temperature and

heated under reﬂux for 3 h. The reaction mixture was cooled

to room temperature and the solvent was removed by rotary

evaporation under reduced pressure. The crude product was

puriﬁed by column chromatography as described above under

Method A.

4.3.5. 4-(Nonaﬂuorobutane-1-sulfonyl)-morpholine (8g)

Sixty-one percent; mp 81 8C; IR (KBr): n 1390, 1265, 1236,

1187, and 1138 cm^ꢀ1; ¹H NMR (300 MHz, d₆-acetone): d 3.3–

4.1 (8H, m); ¹³C NMR (75 MHz, d₆-acetone): d 48.0 (–N–CH₂–

), 67.2 (–CH₂–O–); ¹⁹F NMR (288.8 MHz, d₆-acetone): d

ꢀ80.62 (CF₃), ꢀ112.28 (a-CF₂), 120.92 (b-CF₂), ꢀ125.62 (g-

CF₂); GC–MS 40 eV, m/z (rel. int.): 369 [M]⁺(7), 326(6),

242(7), 150(98), 134(24), 86(100). Anal. Calcd for

C₈H₈F₉NO₃S: C, 26.03; H, 2.18; S, 8.68; N, 3.79. Found: C,

26.23; H, 2.22; S, 3.75; N, 8.67.

ꢃ Method E: Perﬂuorooctanesulfonyl ﬂuoride 1 (3.65 g,

7.3 mmol) and N,N-diethylamine (3.8 mL, 37 mmol) were

stirred at ambient temperature for 4 h. Excess N,N-

diethylamine was removed under reduced pressure and the

product was recrystallized at 4 8C from reagent alcohol/

dichloromethane to give 7e as a slightly yellow, waxy solid.

4.3.1. N,N-dimethyl-perﬂuorooctane-1-sulfonamide (7d)

mp 80–81 8C; IR (KBr); n 2966, 1483, 1369, 1238, 1212,

1

1149, and 1061 cm^ꢀ1; H NMR (300 MHz, d₆-acetone): d 3.2

(6H, s, –CH₃); ¹³C NMR (75 MHz, d₆-acetone): d 39.6 (–CH₃);

¹⁹F NMR (288.8 MHz, d₆-acetone): d ꢀ81.3 (CF₃), ꢀ112.0 (a-

CF₂), ꢀ121.0 (b-CF₂), 122.1 (3 ꢄ CF₂), ꢀ123.2 (z-CF₂),

ꢀ125. 6 (u-CF₂); GC–MS 40 eV, m/z (rel. int.): 526 [M ꢀ H]⁺

(1), 108(100). Anal. Calcd for C₁₀H₆F₁₇NO₂S: C, 22.78; H,

4.4. General procedure for the N-alkylation of N-alkyl

perﬂuoroalkanesulfonamide derivatives 4 and 5

The respective N-alkyl perﬂuorooctanesulfonamide 4 or 5

(5.0 mmol), dry potassium carbonate (1.4 g, 10 mmol) and

H.-J. Lehmler et al. / Journal of Fluorine Chemistry 128 (2007) 595–607

605

corresponding bromo- or iodo-alkyl derivative (5.5 mmol) were

dissolved in acetone (25 mL) and the resultant mixture was

heated under reﬂux until complete conversion. The reaction

mixture was allowed to cool to room temperature and ﬁltered.

The precipitate was washed with acetone (2 ꢄ 10 mL) and the

solvent was removed by rotary evaporation under reduced

pressure. The crude product was puriﬁed by column

chromatography using silica gel with hexane and ethyl acetate

(96:4) as eluent.

(300 MHz, CDCl₃): d 1.3 (3H, t, J = 7.1 Hz, –CH₃), 2.1 (3H, s,

–OCOCH₃), 3.4–3.9 (4H, m, –NCH₂–), 4.3 (2H, t, J = 5.6 Hz, –

CH₂OCOCH₃); ¹³C NMR (75 MHz, CDCl₃): d 13.8 (–CH₃),

20.6 (–OCOCH₃), 44.4 (–CH₂CH₃), 46.4 (–NCH₂–), 61.2 (–

CH₂OCOCH₃), 170.6 (–OCOCH₃); ¹⁹F NMR (288.8 MHz, d₆-

acetone): d ꢀ80.5 (CF₃), ꢀ112.0 (a-CF₂), ꢀ119.8 (b-CF₂),

ꢀ121.1 (3 ꢄ –CF₂–), ꢀ122.1 (z-CF₂), ꢀ125.6 (u-CF₂); GC–

MS 40 eV, m/z (rel. int.): 553 [M ꢀ CH₃COOH]⁺(5), 540

[M ꢀ C₃H₅O₂]⁺(42), 448 [C₈F₁₆SO]⁺(27). Anal. Calcd for

C₁₄H₁₂F₁₇NO₄S: C, 27.42; H, 1.97; S, 5.23; N, 2.28. Found: C,

27.37; H, 1.79; S, 5.26; N, 2.35.

4.4.1. N-(2-Hydroxyethyl)-N-methyl-perﬂuorooctane-1-

sulfonamide (9a)

Ninety-six percent; mp 83 8C; IR (KBr); n 3420 (–OH), 1384,

4.4.5. Methyl 2-(N-ethyl-perﬂuorooctanesulfonamido)

acetate (11)

1

1219, and 1151 cm^ꢀ1; H NMR (300 MHz, d₆-acetone): d 3.2

(3H, s, –CH₃), 3.4 (1H, m, –NCH₂–), 3.7 (3H, m, –CH₂CH₂OH),

4.1 (1H, t, J = 5.5 Hz, –CH₂OH); ¹³C NMR (75 MHz, CD₃OD):

d 37.2 (–CH₃), 54.3 (–NCH₂–), 60.6 (–CH₂OH); ¹⁹F NMR

(288.8 MHz, CD₃OD): d –80.5 (CF₃), ꢀ112.6 (a-CF₂), ꢀ119.8

(b-CF₂), ꢀ121.2 (3 ꢄ CF₂), ꢀ122.1 (z-CF₂), ꢀ125.6 (u-CF₂);

MS, m/z (rel. int.): 616(50), 141(100), 119(55), 223(15). Anal.

Calcd for C₁₁H₈F₁₇NO₃S: C, 23.71; H, 1.45; S, 5.75; N, 2.51.

Found: C, 23.82; H, 1.33; S, 5.82; N, 2.53.

Ninety percent; mp 55–56 8C; IR (KBr); n 1756, 1379, 1202,

1

1180, 1167, and 1124 cm^ꢀ1; H NMR (300 MHz, CD₃OD): d

1.24 (3H, t, J = 7.1 Hz, –CH₃), 3.5–3.7 (2H, m, –CH₂CH₃),

3.78 (2H, s, –CH₂CO₂–), 4.27 (2H, s, –CO₂CH₃); ¹³C NMR

(75 MHz, CD₃OD): d 13.9 (–CH₃), 46.9 (–CH₂CH₃), 49.2 (–

CH₂CO₂–), 53.1 (–CO₂CH₃), 170.1 (–CO₂CH₃); ¹⁹F NMR

(288.8 MHz, CD₃OD): d ꢀ80.48 (CF₃), ꢀ112.41 (a-CF₂),

ꢀ119.69 (b-CF₂), ꢀ121.15 (3 ꢄ CF₂), ꢀ122.13 (z-CF₂),

ꢀ125.59 (u-CF₂); GC–MS 40 eV, m/z (rel. int.): 600 [M + H]

(68), 540(50), 448(40), 56(100); Anal. Calcd for

C₁₃H₁₀F₁₇NO₄S: C, 26.06; H, 1.68; S, 5.35; N, 2.34. Found:

C, 26.22; H, 1.73; S, 5.32; N, 2.41.

4.4.2. N-Ethyl-N-(2-hydroxyethyl)-perﬂuorooctane-1-

sulfonamide (9b)

Ninety-nine percent; mp 70 8C (Lit. 65–71 8C [4]); IR

1

(KBr); n 3412 (–OH), 1384, 1212, and 1150 cm^ꢀ1; H NMR

(300 MHz, CDCl₃): d 1.3 (3H, t, J = 7.1 Hz, –CH₂CH₃), 2.2

(1H, br s, –CH₂OH), 3.3–3.8 (4H, m, –CH₂–), 3.8 (2H, ‘‘t’’,

J = 5.3 Hz, –CH₂OH); ¹³C NMR (75 MHz, CDCl₃): d 13.9 (–

CH₂CH₃), 45.0 (–NCH₂CH₃), 49.9 (–NCH₂CH₂OH), 60.8 (–

CH₂OH); ¹⁹F NMR (288.8 MHz, CDCl₃): d ꢀ81.3 (CF₃),

ꢀ112.6 (a-CF₂), ꢀ120.7 (b-CF₂), ꢀ122.2 (3 ꢄ –CF₂–),

ꢀ123.2 (z-CF₂), ꢀ126.6 (u-CF₂); MS, m/z (rel. int.):

630(60), 141(100), 119(75), 223(15). Anal. Calcd for

C₁₂H₁₀F₁₇NO₃S: C, 25.23; H, 1.76; S, 5.61; N, 2.45. Found:

C, 25.27; H, 1.83; S, 5.71; N, 2.59.

4.5. Synthesis of 2-(N-ethyl-

perﬂuorooctanesulfonamido)acetic acid 12

Methyl 2-(N-ethyl-perﬂuorooctanesulfonamido) acetate 11

was dissolved in 1N NaOH (1.5 equiv., 1.4 mL) and 1,4-

dioxane (3 mL), stirred for 2 h at 65 8C, diluted with water

(20 mL) and ﬁltered. The ﬁltrate was acidiﬁed with 1N HCl

(10 mL) and extracted with ethyl acetate (ꢅ20 mL). The

organic layer was washed with water (2 ꢄ 20 mL) and dried

over sodium sulfate. The solution was treated with charcoal,

ﬁltered and concentrated under reduced pressure to give 12 as a

white solid in 40% yield.

4.4.3. 2-(N-Methyl-perﬂuorooctylsulfonamido) ethyl

acetate (10a)

mp 156–157 8C (Lit. 162 8C [31]); IR (KBr); n 1728, 1379,

Eighty-six percent; mp 82–83 8C; IR (KBr); n 1732 (–C O),

1201, 1168, 1149, and 1124 cm^ꢀ^{1 1}H NMR (400 MHz,

;

1

1380, 1373, 1236, 1204, and 1151 cm^ꢀ1; H NMR (300 MHz,

d₆-acetone): d 2.9 (3H, s, –OCOCH₃), 3.2 (3H, s, –NCH₃), 3.5–

CD₃OD): d 1.25 (3H, t, J = 7.1 Hz, –CH₃), 3.63 (2H, q,

J = 7.1 Hz, –CH₂CH₃), 4.24–4.56 (2H, m, –CH₂CO₂–); ¹³C

NMR (75 MHz, CD₃OD): d 13.9 (–CH₃), 46.8 (–CH₂CH₃),

49.1 (–CH₂CO₂–), 170.1 (–CO₂H); ¹⁹F NMR (288.8 MHz,

CD₃OD): d ꢀ80.64 (CF₃), ꢀ112.38 (a-CF₂), ꢀ119.0 (b-CF₂),

ꢀ121.13 (3 ꢄ CF₂), ꢀ122.04 (z-CF₂), ꢀ125.59 (u-CF₂); MS,

m/z (rel. int.): 584(95), 141(35), 369(20), 499(20), 223(10),

217(10). Anal. Calcd for C₁₂H₈F₁₇NO₄S: C, 24.63; H, 1.38; S,

5.48; N, 2.39. Found: C, 24.37; H, 1.59; S, 5.71; N, 2.29.

4.1 (2H, m, (–NCH₂–), 4.2–4.5 (2H, br m, –CH₂OCOCH₃); ¹³

C

NMR (75 MHz, d₆-acetone): d 21.7 (–OCOCH₃), 37.6 (–CH₃),

51.8 (–NCH₂–), 62.2 (–CH₂OCOCH₃), 171.9 (–OCOCH₃); ¹⁹

F

NMR (288.8 MHz, d₆-acetone): d ꢀ80.5 (CF₃), ꢀ111.7 (a-CF₂),

ꢀ119.9 (b-CF₂), ꢀ121.2 (3 ꢄ –CF₂–), ꢀ122.2 (z-CF₂), ꢀ125.6

(u-CF₂); GC–MS 40 eV, m/z (rel. int.): 539 [M ꢀ CH₃COOH]⁺

(12), 526 [M ꢀ C₃H₆O₂]⁺(28), 462 [C₈F₁₆SON]⁺(40). Anal.

Calcd for C₁₃H₁₀F₁₇NO₄S: C, 26.06; H, 1.68; S, 5.35; N, 2.34.

Found: C, 26.11; H, 1.59; S, 5.57; N, 2.46.

4.6. Synthesis of N,N-dialkyl perﬂuorooctanesulfonamides

using the Mitsunobu reaction

4.4.4. 2-(N-Ethyl-perﬂuorooctylsulfonamido) ethyl acetate

(10b)

4.6.1. General procedure for the Mitsunobu reaction [18]

A solution of DIAD (diisopropyl azodicarboxylate, 0.3 g,

15 mmol) in ether (2 mL) was added slowly to a sonicated

Ninety-two percent; mp 104 8C; IR (KBr); n 2966, 2934,

1

1732 (C O), 1379, 1240, 1214, and 1151 cm^ꢀ1; H NMR

606

H.-J. Lehmler et al. / Journal of Fluorine Chemistry 128 (2007) 595–607

mixture of alcohol 13 [32] or methyl glycolate (10 mmol), N-

ethyl-perﬂuorooctanesulfonamide 4b (10 mmol) and triphe-

nylphosphine (0.4 g, 15 mmol) in anhydrous ether (3 mL) at

0 8C. After completion of the addition, the reaction mixture was

sonicated at 25 8C until the starting material had disappeared.

The solventwas removed under reduced pressureand the product

was puriﬁed by column chromatography using silica gel using

ethyl acetate (0–5%) and hexane (100–98%) as eluent.

ꢀ125.7 (u-CF₂); GC–MS m/z, (rel. int.): 499.9 [M]⁺(30). Anal.

Calcd for C₈H₂F₁₇NO₂S: C, 19.25; H, 0.40; S, 6.42; N, 2.81.

Found: C, 19.49; H, 0.41; S, 6.35; N, 2.90.

4.9. X-ray crystallography [33]

Flaky platelet crystals of 4b (synthesized using Method C),

7e (synthesized using Method E) and 12 were obtained by

recrystallization from reagent alcohol/dichloromethane at 4 8C.

These crystals proved far too small for analysis on conventional

small-molecule diffraction equipment but gave recordable,

albeit weak, diffraction using Cu Ka X-rays on a specially

conﬁgured hybrid small/macromolecule diffraction system

based on the Bruker-Nonius X8 Proteum (Nonius FR-591

rotating anode X-ray generator, Bruker Helios graded multi-

layer optics, Nonius Kappa goniometer, Bruker SMART 6000

CCD detector, CryoCool LN2 low temperature device from

CryoIndustries of America).

4.6.2. 1,1,2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-Heptadecaﬂuoro-

octane-1-sulfonic acid [2-(tert-butyl-dimethyl-silanyloxy)-

ethyl]-ethyl-amide (14)

Ninety-eight percent; mp 29 8C; IR (KBr); n 2932, 1391,

1

1243, 1215, and 1150 cm^ꢀ1; H NMR (300 MHz, CDCl₃): d

0.08 (6H, s, 2 ꢄ –SiCH₃), 0.90 (9H, s, –C(CH₃)₃), 1.28 (3H, t,

J = 7.2 Hz, –CH₂CH₃), 3.35–3.75 (4H, m, –N(CH₂CH₃)CH₂

CH₂–), 3.81 (2H, t, J = 5.5 Hz, –CH₂O–); ¹³C NMR (75 MHz,

CDCl₃): d ꢀ5.6 (2 ꢄ –SiCH₃), 13.9, 18.1, 25.7 (–C(CH₃)₃),

45.1, 49.7, 62.2; ¹⁹F NMR (288.8 MHz, CDCl₃): d ꢀ81.26

(CF₃), ꢀ112.95 (a-CF₂), ꢀ120.78 (b-CF₂), ꢀ122.18, ꢀ122.22

(3 ꢄ CF₂), 123.20 (z-CF₂), ꢀ126.63 (u-CF₂); Anal. Calcd for

C₁₈H₂₄F₁₇NO₃SSi: C, 31.54; H, 3.53; S, 4.68; N, 2.04. Found:

C, 31.64; H, 3.48; S, 4.57; N, 2.07.

For each crystal, initial unit cell parameters were obtained

using APEX2 software [34] from v-scans at six different f and x

angles. Final cell parameters were obtained (program SaintPlus

in APEX2 [34]) using spot positions from all data collection

frames. Crystal decay (negligible) was checked in each case by

re-measurement of a portion of the ﬁrst data collection scan. A

total of 17,923, 19,116 and 3455 reﬂections were collected for

4b, 7e and 12, respectively. Merging of symmetry equivalents

resulted in 6071 (4288 with I > 2s(I)), 3491 (2988 with

I > 2s(I)) and 1951 (1594 with I > 2s(I)) reﬂections for 4b, 7e

and 12, respectively. Correction of Lorentz and polarization

effects, data reduction, merging and an empirical absorption

correction for each dataset were performed within the APEX2

package (programs SaintPlus and Sadabs [34]). The structures

weresolvedbydirectmethodsusingSHELXS97[35]andreﬁned

by full-matrix least-squares against F²using SHELXL97 [35].

All non-hydrogen atoms in both structures were reﬁned with

anisotropic displacement parameters (ADPs).

4.7. Procedure for the hydrolysis of TBDMS protected

ether 14

The TBDMS protected ether 14 (0.15 mmol) was dissolved

in 1N HCl and methanol (5 mL, 1:1, v/v) and stirred for 2 days

at ambient temperature. The solvent was removed under

reduced pressure. The product was extracted with ethyl acetate

(5 mL), the combined organic extracts were washed with water

(2 ꢄ 5 mL) and dried over sodium sulfate. The solvent was

removed under reduced pressure to give 9b in 96% yield.

4.8. Synthesis of perﬂuorooctane-1-sulfonamide (16)

The structure of 7e was extensively disordered and

reﬁnement required strong restraints. Similar bond lengths

and angles within and between each disordered pair

(major:minor component ratio 62:38) were restrained to similar

values (commands ‘SADI’ and ‘SAME’ in SHELXL) and

anisotopic displacement parameters (ADPs) were subject to

rigid-body (‘DELU’ in SHELXL97) and approximate isotropic

(‘ISOR’ in SHELXL97) restraints. Further, the ADPs of

disordered pairs of atoms in close proximity (C3, C3⁰; C6, C6⁰;

C8, C8⁰) were constrained to be the same.

Perﬂuorooctanesulfonyl ﬂuoride 1 (2.0 g, 3.9 mmol) was

dissolved in ether (5 mL) and an aqueous solution of sodium

azide (1.2 g, 19 mmol, in 1 mL of water) was added. The

reaction mixture was allowed to stir at room temperature for

12 h. Extraction with ether (15 mL) and evaporation of the

solvent gave crude perﬂuorooctane-1-sulfonyl azide 15 as a

colorless liquid. The crude azide 15 was directly converted into

the amide 16 without further puriﬁcation. The azide 16 was

added to a suspension of Zn dust (1.3 g, 20 mmol) in ether

(5 mL). Hydrochloric acid solution (5N, 3 mL) was added

slowly to this suspension until the Zn dust was completely

dissolved. The mixture was stirred for 24 h at room temperature

and extracted with ether (3 ꢄ 10 mL). Evaporation of the

solvent under reduced pressure gave a waxy, brown solid. This

solid was dissolved in reagent alcohol and the sulfonamide 16

was precipitated as a white waxy solid with dichloromethane.

IR (KBr); n 3344, 3176, 3058, 1378, 1229, 1203, and

1147 cm^ꢀ1; ¹H NMR (300 MHz, CDCl₃): d 8.2 (2H, br s, NH₂);

¹⁹F NMR (288.8 MHz, CDCl₃): d ꢀ80.7 (CF₃), ꢀ112.8 (a-

CF₂), –119.8 (b-CF₂), ꢀ121.1 z-CF₂), ꢀ122.2 (3 ꢄ –CF₂–),

All hydrogens atoms in both 4b, 7e and 12 were found in

difference Fourier maps and were subsequently placed at calcu-

lated positions using appropriate riding models with distances of

˚

0.98 A (C–H₃), 0.99 A (C–H₂) and 0.88 A (N–H in 4b). Isotropic

displacementparameterswereﬁxedateither 1.2times(C–H2, N-

H), or 1.5 times (C–H3) the U_eqof the carrier atom.

Acknowledgment

The authors would like to thank Air Products and Chemicals

Inc. (Allentown, PA, USA) for a donation of free lecture bottles

H.-J. Lehmler et al. / Journal of Fluorine Chemistry 128 (2007) 595–607

607

¨

[16] I.M. Lyapkalo, H.-U. Reissig, A. Schafer, A. Wagner, Helv. Chim. Acta 85

of methyl and ethyl amine. This work was supported by grants

from the National Institute of Environmental Health Sciences

(ES12475 (HJL)) and the National Science Foundation (NIRT

0210517 (HJL) and NSF MRI grant #0319176 (SP)). Its

contents are solely the responsibility of the authors and do not

necessarily represent the ofﬁcial views of the funding agencies.

(2002) 4206–4215.

[17] M. Kawase, N. Motohashi, M. Niwa, M. Nozaki, Heterocycles 45 (1997)

1121–1129.

¨ ¨

[18] A.-M. Balint, A. Bodor, A. Gomory, K. Vekey, D. Szabo, J. Rabai, J.

Fluorine Chem. 126 (2005) 1524–1530.

[19] K.E. Bell, D.W. Knight, M.B. Gravestock, Tetrahedron Lett. 36 (1995)

8681–8684.

[20] M.L. Edwards, D.M. Stemerick, J.R. McCarthy, Tetrahedron 50 (1994)

5579–5590.

References

[21] S.-Z. Zhu, Y. Xu, Y.-L. Wang, W.-M. Peng, Chin. J. Chem. 19 (2001)

1259–1262.

[1] E. Kissa, Fluorinated Surfactants and Repellents Surfactant Science

Series, vol. 97, Marcel Dekker, New York, 2001.

[22] H.-J. Lehmler, S. Parkin, C.P. Brock, Acta Cryst. B 60 (2004) 325–332.

[23] C.W. Bunn, E.R. Howells, Nature 174 (1954) 549–551.

[24] E. Prince, International Tables for Crystallography, Volume C: Mathe-

matical, Physical and Chemical Tables, 3rd ed., 2004.

[25] A. Ahmed, R.A. Bragg, J. Clayden, L.W. Lai, C. McCarthy, J.H. Pink, N.

Westlund, S.A. Yasin, Tetrahedron 54 (1998) 13277–13294.

[26] D.P. Bossev, M. Matsumoto, T. Sato, H. Watanabe, M. Nakahara, J. Phys.

Chem. B 103 (1999) 8259–8266.

[2] H.-J. Lehmler, Chemosphere 58 (2005) 1471–1496.

[3] L. Xu, D.M. Krenitsky, A.M. Seacat, J.L. Butenhoff, M.W. Anders, Chem.

Res. Toxicol. 17 (2004) 767–775.

[4] H. Niederpruem, P. Voss, M. Wechsberg, Liebigs Ann. Chem. (1973) 11–19.

[5] S. Beneﬁce-Malouet, H. Blancou, R. Teissedre, A. Commeyras, J. Fluor-

ine Chem. 31 (1986) 319–332.

[6] Organization for Economic Co-operation and Development (OECD),

Environment Directorate, Results of survey on production and use of

PFOS, PFAS and PFOA, related substances and products/mixtures con-

taining these substances, Report ENV/JM/MONO(2005)1, 2005.

[7] J.W. Martin, D.A. Ellis, S.A. Mabury, M.D. Hurley, T.J. Wallington,

Environ. Sci. Technol. 40 (2006) 864–872.

[27] B. Boulanger, J. Vargo, J.L. Schnoor, K.C. Hornbuckle, Environ. Sci.

Technol. 38 (2004) 4064–4070.

[28] B. Boulanger, J.D. Vargo, J.L. Schnoor, K.C. Hornbuckle, Environ. Sci.

Technol. 39 (2005) 5524–5530.

[29] E.K. Kleiner, German patent 2,015,332 (1970).

[8] R. Bussas, G. Kresze, Liebigs Ann. Chem. (1982) 545–563.

[9] A.V. Podol’skii, M.I. Kachalkova, R.E. Ilatovskii, M.I. Kodess, I.P.

Kolenko, Russ. J. Org. Chem. (1990) 1242–1244.

[30] T.J. Brice, P.W. Trott, US patent 2,732,398 (1956).

[31] H.A. Brown, US patent 2,809,990 (1957).

[32] I. Azumaya, D. Uchida, T. Kato, A. Yokoyama, A. Tanatani, H. Takaya-

nagi, T. Yokozawa, Angew. Chem. Int. Ed. 43 (2004) 1360–1363.

[33] Crystallographic data (excluding structure factors) for the structures in this

paper have been deposited with the Cambridge Crystallographic Data

Centre as supplementary publication nos. CCDC 635104, 635105 and

635106. Copies of the data can be obtained, free of charge, on application

to CCDC, Cambridge CB2 1EZ, UK.

[10] H.W. Roesky, G. Holtschneider, H.H. Giere, Z. Naturforsch. 25b (1970)

252–254.

[11] J.N. Meussdoerffer, H. Niederpruem, Chemiker-Zeitung 96 (1972) 582–

583.

[12] S.-Z. Zhu, J. Zhang, B. Xu, A. Li, Phosphorus Sulfur Silicon Relat. Elem.

89 (1994) 77–82.

[13] P.J. DeChristopher, J.P. Adamek, G.D. Lyon, S.A. Klein, R.J. Baumgarten,

J. Org. Chem. 39 (1974) 3525–3532.

[34] Bruker-Nonius, APEX2: software suite for data collection and processing

of single crystal X-ray diffraction data, 2004.

[14] A.H. Ahlbrecht, H.A. Brown, US 2,803,656 (1957).

[15] K.H. Mitschke, K. Geisler, H. Niederpruem, DE 2832346 (1980).

[35] G.M. Sheldrick, SHELX-97: Programs for the solution (SHELXS97) and

reﬁnement (SHELXL97) of crystal structures from diffraction data, 1997.

Article Doi

Synthesis and structure of environmentally relevant perfluorinated sulfonamides

DOI: 10.1016/j.jfluchem.2007.01.013

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