Radical addition of RFI to alkenylsuccinic anhydrides and gem-substituted alkenyl triesters. Zinc and radical induced, or spontaneous radical cyclization, of the δ-iodoalkanoic esters to γ-lactones

Article abstract of DOI:10.1016/S0022-1139(03)00160-X

Radical addition of R_FI to alkenylsuccinic anhydrides affords ω-(perfluoroalkyl)-δ-iodoalkyl-2-butane-1,4-dioc acid anhydrides, and these adducts are reductively dehalogenated and esterified by zinc and acid in ethanol without lactonization. However, the R_FI adducts react with KOH in ethanol to give the alkenyl half esters (but no γ-lactone), which convert to the γ-lactones by acid catalysis. When treated with water, ethanol, Zn and 48% HBr, the R_FI adduct from but-3-en-2-yl-succinic anhydride converts to the iodo half ester, R_FCH₂CHICH(CH₃)CH (CO₂H)CH₂CO₂Et, which undergoes Zn induced (S_Hi) conversion to γ-lactone. R_FI (AIBN) and the triester CH₂=CHCH₂C (CO₂Et)₂CH₂CO₂Et yield R_FCH₂CHICH₂C(CO₂Et) ₂CH₂CO₂Et (95%). When heated to 140 °C, the adduct loses iodoethane.and cyclizes to diester γ-lactones (94%). With benzoyl peroxide, R_FI and the triester at 99 °C, spontaneous radical cyclization of the adduct to lactone occurs. Evidently, the gem-disubstituted triester readily forms a five-membered lactone as a consequence of steric compression in the open chain form.

Full text of DOI:10.1016/S0022-1139(03)00160-X

Journal of Fluorine Chemistry 123 (2003) 237–248
Radical addition of RFI to alkenylsuccinic anhydrides and
gem-substituted alkenyl triesters
Zinc and radical induced, or spontaneous radical cyclization,
of the d-iodoalkanoic esters to g-lactones$
Neal O. Brace*
Wheaton College, Wheaton, IL 60187, USA
Received 24 March 2003; received in revised form 25 May 2003; accepted 26 May 2003
Abstract
Radical addition of RFI to alkenylsuccinic anhydrides affords o-(perfluoroalkyl)-d-iodoalkyl-2-butane-1,4-dioc acid anhydrides, and these
adducts are reductively dehalogenated and esterified by zinc and acid in ethanol without lactonization. However, the RFI adducts react with KOH
in ethanol to give the alkenyl half esters (but no g-lactone), which convert to the g-lactones by acid catalysis. When treated with water, ethanol, Zn
and 48% HBr, the RFI adduct from but-3-en-2-yl-succinic anhydride converts to the iodo half ester, RFCH2CHICH(CH3)CH(CO2H)CH2CO2Et,
which undergoes Zn induced (SHi) conversion to g-lactone. RFI (AIBN) and the triester CH2¼CHCH2C(CO2Et)2CH2CO2Et yield
RFCH2CHICH2C(CO2Et)2CH2CO2Et (95%). When heated to 140 8C, the adduct loses iodoethane.and cyclizes to diester g-lactones (94%).
With benzoyl peroxide, RFI and the triester at 99 8C, spontaneous radical cyclization of the adduct to lactone occurs. Evidently, the
gem-disubstituted triester readily forms a five-membered lactone as a consequence of steric compression in the open chain form.
# 2003 Elsevier B.V. All rights reserved.
Keywords: RFI free radical addition reactions; RF-substituted anhydrides; Perfluoroalkyl lactones; Acid catalyzed lactonization; Homolytic (SHi)
lactonization; gem-Dialkyl induced lactonization; Peroxide induced lactonization
1. Introduction
way in the liver [4]. Known as ‘‘Liptor1’’, it ‘‘has become
the world’s fastest growing and top-selling pharmaceutical
since its launch in 1997’’.2 Ismail, in his review, cites the
effects caused by fluorine on the properties of drugs; ‘‘the
incorporation of fluorine in a drug allows simultaneous
modulation of electronic, lipophilic and steric parameters,
all of which can critically influence both the pharmacody-
namic and pharmacokinetic properties of drugs [2,3]’’.
Ismail also reports that fluorine substitution in the A ring
(a phenyl ring) of homocamptothecin greatly enhances its
biological activity [2]. The parent compound contains a 7-
membered lactone ring. Fluorine occupies a van der Waals
The synthesis of fluorinated g-lactones is of continuing
interest, and Qing and Jiang review the extensive literature
on this subject in connection with the synthesis of 3-tri-
fluoromethyl-2-(5H)-furanones (g-lactones) [1]. Though
lactones as a class are widely distributed in nature, fluor-
ine-containing lactones are seldom encountered [2,3].1 A
g-lactone, ‘‘atorvastatin,’’ contains a p-fluorophenyl group
and is highly effective in cholesterol-lowering therapy. The
drug was first conceptualized as a pharmacore, and was
synthesized by Roth as an inhibitor for (HMG CoA) reduc-
tase, a crucial enzyme in the cholesterol biosynthetic path-
˚
˚
radius (1.47 A) positioned between oxygen (1.52 A) and
˚
hydrogen (1.30 A), allowing it to mimic a hydroxyl group,
and to participate in hydrogen bonding interactions [2].3
$ This work is done at Wheaton College during 1976–1984. A portion
of the synthetic work is reported in a review [6]. The lactonization of iodo
esters, and mechanistic implications, are presented at the International
Symposium on Organic Free Radicals [10].
2 Roth invented the substance, [R-(R*,R*)]-2-(4-fluorophenyl)-b,d-dihy-
droxy-5-(1-methylethyl-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-
1-heptanoic acid, lactone. The substance is named atorvastatin, and sold as
‘‘Liptor1’’ by Pfizer [4].
3 The small elemental radius of fluorine is cited as an important
requirement when these compounds bind within topoisomerase I, the
intended drug target: [38] in this paper [2].
* Present address: 1901 W. Warren Street, Marion, IL 62959,
USA. Tel.: þ1-618-993-1996.
E-mail address: nobrace@juno.com (N.O. Brace).
1 O’Hagan reports that only about a dozen natural products containing
fluorine have been isolated [3].
0022-1139/$ – see front matter # 2003 Elsevier B.V. All rights reserved.
doi:10.1016/S0022-1139(03)00160-X

238
N.O. Brace / Journal of Fluorine Chemistry 123 (2003) 237–248
Table 1
Radical addition of perfluoroalkyl iodides (1) to prop-2-en-1-yl- and but-3-en-2-yl-succinic anhydrides (2 and 3); 3-(perfluoroalkyl)-2-iodoalkyl-2-butane-
1,4-dioic acid anhydrides (4a,b and 5a,b)a
Reactants
Entry
Products
Code
RFI
RF
Anhydride
Code
Initiatora
Code
Time (h)
Temperature (8C)
Conversion (%)
Yield (%)
mmol
mmol
mmol
1b
2
n-C6F13
n-C8F17
n-C8F17
RFI
123
2
2
2
2
2
3
101
A
A
B
D
D
A
2.60
1.00
1.65
4.10
2.00
2.22
7.0
2.0
4.5
1.75
1.5
6.0
70–92
77–101
100–103
133–147
131–150
72–84
4a,b
4a,b
4a,b
4a,b
4a,b
5a,b
99.6
99.6
96.7
97.3
95.5
94.4
99.6
99.6
96.7
97.3
95.5
99.7
60.0
57.7
117.8
60.0
72.2
50.0
58.0
100
3
4c
5
n-C8F17
n-C6F13
50.9
50.0
6
a The initiators used are A, AIBN; B, benzoyl peroxide; and D, bis-tert-butyl peroxide.
b For a typical procedure of an AIBN induced reaction, see Section 3.2.1.
c The RFI (1) is a mixture of RFI homologues (C6, C8 and C10), and the 4a,b is a clear liquid. In another run, the initiator is AIBN (2 mol% on 2) and the
mol amounts of 1 and 2 are the same as in entry 2. The conversion to 4a,b, C6, C8, and C10 homologues is 90% (IR, 1H NMR), and the yield is 100%.
Similar results are obtained with the use of BPO as initiator as in entry 3.
RF-long chain, substituted lactones were encountered
during the free radical addition of perfluoroalkyl iodide
(1; RFI) to certain unsaturated acids and esters [5,6]. The
process has the characteristics of a radical reaction, and it is
accelerated by heat or peroxide initiators [7–10]. The pur-
pose of this paper is to explore further the effects of structure
and reaction conditions on the lactonization of certain
perfluoroalkyl substituted, iodoalkanoic esters and acids.
Mechanistic implications for these reactions are discussed,
and new perfluoroalkyl substituted g-lactones are described
in detail.
diastereomeric 4a,b in 99% yield and conversion; and,
similarly, but-3-en-2-yl-succinic anhydride (3) converts to
diastereomers 5a,b in 99% yield. Either azonitrile or per-
oxide initiators may be used at 70–140 8C without evidence
of lactonization (Table 1, entries 1–6). Controlled addition
and useful procedures are described in Section 3 [11].
Chemical reactions of adducts 4a,b, and 5a,b are described
below.
2.1.1. The reductive dehalogenation and esterification of
d-iodoalkylanhydrides (4a,b) by zinc and acid in
ethanol occurs without lactonization (Scheme 2)
Zinc and acid reduction of 4a,b to iodine free, half ester 7
occurs rapidly [10]. As in previous work with RF-substi-
tuted iodoalkanoic esters, lactonization does not occur
[12].4 Reaction of the iodoalkanoic ester 6 in Path A (step
1b) with Zn0 (‘‘activated’’ by reaction with Hþ) produces
the 2-propyl radical (7ꢀ), which abstracts hydrogen and
converts to half ester 7 [12,13].5 In Path B, similar reduc-
tion of 4a,b to radical (9ꢀ) is followed by Hꢀ abstraction
to give 3-(perfluoroalkyl)propylsuccinic anhydride (9)
(Scheme 2). Esterification of 9 gives half ester 7 and diester
8. Reaction conditions may determine which path takes
precedence.
2. Results and discussion
2.1. Radical addition of RFI to alkenylsuccinic anhydrides
affords o-(perfluoroalkyl)-d-iodoalkyl-2-butane-1,4-dioc
acid anhydrides and derivatives (Scheme 1)
The radical addition of RFI (1, RF ¼ n-C6F13 to n-C10F17)
to 2-propenylsuccinic anhydride (2) (Scheme 1) affords
4 RF-terminated a-aminoalkanoic acids, etc. [12]. Zinc and acid, in
ethanol, reacting with 3-(perfluoropropyl)-2-iodo-butanoic acid gives ethyl
4-(perfluoropropyl)butanoate (67%); and, ethyl 3-(perfluoropropyl)-2-iodo-
propylmalonate gives ethyl 3-(perfluoropropyl)propylmalonate (74%) [12].
5 The radical (7ꢀ), in Scheme 4, step 1c, abstracts hydrogen (possibly,
from hydrogen molecules adsorbed on the Zn(s) surface), and converts
to half ester 7. Cyclization during the zinc reduction of iodoalkenes is
observed, suggesting free radical intermediates [13].
Scheme 1. Addition of RFI to prop-2-en-yl-2-butane-1,4-dioic acid
anhydride (2) and to but-2-en-1-yl-2-butane-1,4-dioic acid anhydride (3).

N.O. Brace / Journal of Fluorine Chemistry 123 (2003) 237–248
239
Scheme 2. Esterification of anhydride 4 to iodo ester 6, and reduction to
esters 7 and 8. Reductive dehalogenation of 4 to anhydride 9 and
esterification to esters 7 and 8.
Scheme 3. Base induced deiodination of 2-acetamido-3-(perfluropro-
pyl)-2-iodoalkylmalonic esters to 3iii, or 4iii; acid induced lactonization
of the unsaturated acid (3iv) to w-lactone (3v). Hydrogenation of 4iv to 2-
acetamido-2-[5-(perfluoropropyl)-pentyl]-1,3-propanedioc acid, 4vi; and
decarboxylation of 4vi to 2-acetamido-7-(perfluoropropyl)-heptanoic
acid, 4vii.
2.1.2. Dehydroiodination of d-iodoalkylanhydrides (4a,b) to
half ester 10 and conversion to g-lactones (11a,b) by acid
catalyzed lactonization. The effect of a b-perfluoroalkyl (RF)
group on the rate and products of reaction
In previous work, which serves as a model for the present
study, homologues of ethyl RF-iodoalkyl-acetamidomalo-
nates (3ii or 4ii) react with strong base to eliminate HI and
give RF-alkenyl-acetamidomalonic acids, disodium salts
(3iii or 4iii), respectively, Scheme 3 [12]. Heat and acid
cyclizes the free malonic acid (3iv), which decarboxylates to
the g-lactone (3v). By contrast, the homologue, 4iii ðn ¼ 3Þ
converts to free acid 4iv (which can not lactonize), and
hydrogen over Pt reduces 4iv to the saturated dicarboxylic
acid (4vi). When heated, 4vi decarboxylates (as a malonic
acid) to the 2-acetamido-6-(RF)-hexanoic acid (95%) [12].
Strong base does not lactonize the 4-iodo ester (3ii) by an
SNi process, as previously observed with 4-haloalkanoic
acids or esters [14,15].6 However, 3ii and 4ii are b-RF-
substituted iodoalkanes, for which the rate of E-2 reaction is
three orders of magnitude greater than that of the hydro-
carbon analogue, 2-iodooctane [16].7
6 4-Haloalkanoic acids and esters convert to g-lactones by heating in
boiling alcohol with sodium ethoxide, or by heating the dry sodium salt of
the acid [14,15].
7 Reaction of RFCH2CHI(CH2)nCH2 (n ¼ 3, 4, or 5) with NaOH at
30.0 8C, in 92.6% aqueous ethanol gives k2 ¼ 3:3–4:1 ꢁ 10ꢂ2 l/mol s
(second order), and the sole product is RFCH¼CH(CH2)nCH2 (n ¼ 3, 4, or
5; E=Z ¼ ca: 3). Similar reaction of 2-iodooctane with NaOH gives
k2 ¼ 7:9 ꢁ 10ꢂ5 l/mol s (second order), and the products are 1-octene, 9.1%;
2-octanol, 3.9%; E-2-octene, 61%; and 25.9% recovery of 2-iodooctane [16].
Scheme 4. Dehydroiodination of 4a,b to 3-(perfluorohexyl)-E-2-prope-
nylsuccinic acid salt 10. Conversion of salt to free acid half ester 10. Acid
catalyzed lactonization of 10 to w-lactone 11 (isomers).

240
N.O. Brace / Journal of Fluorine Chemistry 123 (2003) 237–248
Scheme 5. Reductive deiodination of anhydride 5a,b to half ester 14a,b in
ethanol, with HBr and Zn.
By chemistry similar to that of Scheme 3, anhydrides 4a,b
are converted to g-lactones (11a,b), Scheme 4. In step (a),
4a,b reacts with KOH to give the 3-(perfluorohexyl)-E-2-
propenylsuccinate half ester (10, K salt), but no g-lactone
(IR and NMR) [16]. Treated with 50% H2SO4 in steps (c)
and (d), 10 converts to the g-lactones (11a,b) [17].8 When
chromatographed on alumina, pure cis-11 (37.6%) is iso-
lated from the mixture (IR and 1H NMR) [18,19]. The
stereochemistry of these g-lactones is elaborated further
below [19].
2.1.3. Reductive dehalogenation of anhydrides 5a,b
with HBr and Zn in ethanol, and esterification to
half ester 14
In Scheme 5, the diastereomeric 5a,b undergo zinc reduc-
tion in ethanol, water, and 48% HBr, to provide the half
esters 14a,b (94%). There is no g-lactone (IR, NMR)
[18,19]. The reaction mixture is less polar than that in
Section 2.1.4, and this apparently increases the rate of
reduction, relative to the rate of lactonization.
Scheme 6. Reactions of anhydride 5: catalytic reduction to 12; salt
formation with K2CO3; esterification of 5, 12 and 13 to half esters 14 and
15; Zn induced lactonization of 15 to lactones 16a,b.
2.1.4. Part I. Catalytic reduction of anhydrides 5a,b to
anhydride 12, and partial conversion to the K salt of
diacid 13. Part II. Simultaneous esterification and
zinc-induced lactonization reactions (Scheme 6)
converted to the g-lactones (16a,b) by a free radical process
[10,13]. In the work up, the reaction mixture of 14, 15 and
16a,b is made basic with NaHCO3/Na2CO3 to remove the
half ester 14. The neutral layer of 16a,b (83.6%) is frac-
tionally distilled, and cis-isomer 16a (IR and 1H NMR)
crystallizes from the pot residue [18,19].
A straightforward catalytic reduction of the iodoalkyl
anhydride 5a,b, with hydrogen over Pd/C in anhydrous ethyl
acetate solution (K2CO3 acid acceptor) in a Parr hydrogena-
tion apparatus, gives the iodine free anhydride 12 in only ca.
35% conversion. The absorption of hydrogen ceases because
of the unexpected foaming of the slurry into the H2 line. At
the same time, 5a,b converts in part to the insoluble iodo
succinic acid, K salt (13).
In Part II of Scheme 6, the mixture of 5a,b and its products
is treated with granular zinc, HBr in water and ethanol, in
order to complete the reduction as in Section 2.1.3. Vigorous
gas evolution and exothermic reaction ensues, and surpris-
ingly, a substantial conversion to lactones 16a,b occurs. It is
speculated that esterification of 5a,b and 13 to half ester 15
occurs first. Then, 15 undergoes SHi concerted displacement
of iodine by its carbonyl oxygen, simultaneously with the
abstraction of the iodine atom by zinc. Thus, iodo ester 15 is
2.2. RFI, in a radical reactions, adds to propenyl triester,
CH2¼CHCH2C(CO2Et)2CH2CO2Et (17)
2.2.1. Heating the adduct,
RFCH2CHICH2C(CO2Et)2CH2CO2Et (18) gives g-lactones
(19a,b) and iodoethane
Triester 17 is readily prepared in two steps from diethyl
malonate [20–22].9 Free radical addition of 1 (n-C8F17I) to
17 (AIBN) at 70 8C, yields 18 (95%), Scheme 7, Part I
9 Ethyl 3,3-(bis-ethoxycarbonyl)-hex-5-enoate (17) is prepared from
ethyl 2-propenylmalonate and ClCH2CO2H5 [20]. Ethyl ethoxycarbo-
nyl-butane-1,4-dioate (22) is prepared from ethyl malonate and ethyl
chloroacetate [21]; and, 17 is prepared in 95% yield and conversion
from alkylation of 22 with allyl bromide [10,22].
8 2-, 3- or 4-Pentenoic acids, when boiled with 50% H2SO4, give g-
lactones (97–100%) and little or no d-lactone, with a total conversion
(yield) of 17–40% lactone [17].

N.O. Brace / Journal of Fluorine Chemistry 123 (2003) 237–248
241
which decarboxylate when heated (i.e. as a malonic acid).
1
The H NMR assignment of cis-20a is based on the field
effects in the NMR (Section 3).
2.2.3. Literature precedents for homolytic cyclization of
d-iodoalkanoate esters to g-lactones (Scheme 8)
(1) In the reaction of 1 (C6) with 2,2-dimethyl-4-pentenoic
acid (24) at 75 8C, as AIBN is added, an exotherm to
85 8C occurs, the color of HI/I2 appears, and further
reaction is inhibited [5,6,10]. All of 24 is gone.10 By
contrast, 1 reacts with ethyl 2,2-dimethyl-4-pentenoate
(27) at 67 8C for 10 h (AIBN), to give ca. 80% conver-
sion to lactone 26 (66%) and adduct 28 (34%; ethyl
ester). In this respect, esters 18 and 27 are similar. The
proposed two-step mechanism (Scheme 8) envisions the
shifting of an unpaired electron from the ether oxygen to
the carbonyl oxygen of 17 (or 27), and an unpaired
electron from the carbonyl oxygen of 18 (or 28) to the
anti-bonding orbital of the C–I bond, with the expulsion
of Iꢂ. The coplanarity of the necessary bonds is readily
assumed, as discerned from models, and the radical
nature of lactone formation is proved for some similar
reactions by Nikishin et al. [8,9].
(2) A study of iodonorbornane esters (29 and 30) sheds
new light on this situation, Scheme 8, Part II
[6,7,10,31]. Heat causes homolytic cyclization of the
exo-6-iodo ester (29), with inversion of the carbon atom
no. 6. Iodomethane is displaced while the g-lactone
(31) (100%) is being formed [7,31]. There is strong
stereospecificity in the transition state for lactonization.
In a mixture of exo-29 and endo-6-iodo ester (30), only
the exo isomer reacts and 30 is recovered unchanged.
The attack of an unpaired electron of the C¼O in 29 on
the antibonding orbital of HC-I causes inversion of C6,
and this SHi reaction is thus similar to the SN2 reaction.
For steric reasons, the antibonding orbital of CH-I in
6-endo-30 is not accessible to the unpaired electron.
Further, the process does not involve the formation of a
free carbon radical. If it did, both the exo- and the endo-
6-iodo isomers should react.
(3) This remarkable stereospecificity for lactone formation
is seen in the base induced conversion of the exo-iodo-29
to the three-membered ring nortricyclene (32), Scheme 8,
Part II [7,10,31]. Under mild conditions, a base (–OH, –
OMe, or even an amine) gives SNi displacement of
iodine in exo-iodo-29. The base abstracts an exo-
hydrogen atom of CH(2), and the carbanion thus formed
displaces an iodine ion from HC(6)-I, with inversion,
leading to 32 [7,31]. In aqueous base, of course, the
diester 32a, first formed, hydrolyzes to the diacid 32b.
Scheme 7. Lactone formation during free radical addition of RFI to 2-
alkenyl-2-carboethoxysuccinate esters. Part II: Hydrolysis of 19a,b to
dicarboxylic acid mixture 20a,b; isolation of cis isomer 20a. Decarbox-
ylation of 20a to 21a.
(Eq. (1)) [6,10]. Heating the highly substituted iodoalkyl
triester 18 to 140 8C at 0.05 mm (Eq. (2)), causes the
evolution of iodoethane and cyclization to isomeric g-lac-
tones (19a,b). Analogous reaction of 1 (n-C8F17I) and 17 is
induced by benzoyl peroxide (2 mol%) at 99 8C. The reac-
tion mixture turns dark with iodine and HI, iodoethane
refluxes, and impure g-lactones (19a,b) are obtained (ca.
95% conversion; 1:1). The 1H NMR cleanly differentiates the
cis- and trans-isomers. This aggressive behavior of peroxide
is a significant feature of reactions involving RFI and alkenes
[6,10,23–26]. Benzoyl peroxide induces side reactions with
ꢀ
1; specifically, (RF ) abstracts allylic hydrogen atoms from
17, and a side product probably H(CF2)7CF3 is isolated
[6,23–26]. Evidently, thegem-disubstituted triester 18 readily
cyclizes into a five-membered lactone ring as a consequence
of steric compression in the open chain form (‘‘gem-dialkyl’’
effect; Thorpe–Ingold effect) [5,6,10,12,27–30].
2.2.2. g-Lactone diacids (20a,b), and isolation of
pure cis-20a, with the larger groups cis to each other
(Scheme 7, Part II)
10 Acid catalyzed lactonization of 24, induced by the strong acid HI
(formed during the reaction) reduces the concentration of 24; further,
HI and I2 are both strong inhibitors of free radical chain reactions [23].
The conversion to g-lactone CH3[CHCH2C(CH3)2C¼O(O)] increases
from 21 to 70% during 3–10 h reaction time.
Basic hydrolysis (NaOH, or KOH) of lactone diesters
19a,b provides isomeric cis- and trans-diacids 20a,b (97%),

242
N.O. Brace / Journal of Fluorine Chemistry 123 (2003) 237–248
Scheme 8. Part I. Homolytic lactonization of iodoalkanoic acids and esters: self lactone of 24 (70%); total conversion of 80% to 26 and 28 (distilled). Part II.
Lactone 31 from exo-5-RF exo-6-iodo-2,3-norbornane diester 29. Nortricyclene 32 from diester 29; neither product from endo-6-iodo diester 30.
This is important, because the carbanion at C(2)
dominates the reaction, and the carboxylate ion attached
to C(2) does not bring about SNi displacement of iodine
in exo-iodo-diacid (29b).11
from Ciba-Geigy Corp., Ardsley, NY. The alkenylsuccinic
anhydrides 2 and 3 are a gift from the Humphrey Chemical
Co., New Haven, CT, and are distilled before use. The
elemental analysis and 1H NMR are satisfactory. Ethyl
3,3-(bis-ethoxycarbonyl)-hex-5-enoate (17) is prepared by
alkylation of ethyl (2-ethoxycarbonyl)-1,3-propanedioate
(22) with allyl bromide, in 95% yield and conversion
(Section 3.5.2) [20–22]. Alkylation of ethyl 2-propenyl-
1,3-propanedioate (23) with ethyl chloroacetate by a litera-
ture method gives 17 in 60.8% conversion [10,20]. The 22 is
prepared from ethyl propane-1,3-dioate (2 eq.) and ethyl
chloroaetate in 82% conversion, in a modified literature
method [10,21,22].
3. Experimental
3.1. General experimental procedures
3.1.1. A typical procedure for the addition of
perfluoroalkyl iodides to an alkenylsuccinic anhydride,
or an alkenyltriester compound
See Section 3.2.1 for the preparation of 3-(perfluoro-
hexyl)-2-iodopropyl-2-butane-1,4-dioic anhydride (4a,b).
3.1.3. Physical methods
Samples for1H NMRare dissolved in DCCl3, and are run at
100 MHz unless otherwise indicated. 13C NMR (at 80 MHz)
and elemental analyses are done through the courtesy of the
Analytical Research Division of Ciba-Geigy Corp., Ardsley,
NY. The purities and structures of all the compounds prepared
3.1.2. Sources of materials
Perfluoroalkyl iodides, 1 (RF ¼ n-C6F13 and n-C8F17; and
RF ¼ C6, C8 and C10 chains in equimolar mixture) are a gift
1
are ascertained by GC (when appropriate), IR, H NMR;
11 The endo-6-iodo norbornane anhydride (33) is hydrolyzed in
aqueous NaOH solution at 70 8C. The sodium salt is acidified to the
diacid 34 (99% yield). The iodine atom is unaffected. For this to
happen, intramolecular substitution by the carbanion (or the
carboxylate ion) at endo-C(6)-I, could not have occurred [6,7,10,31].
and by elemental analyses. Pure liquids are obtained by
distillation in an 18 in., stainless steel spinning band column
(A; Nester-Faust) or a 3 ft, platinum mesh spinning band
column (B; Nester-Faust).

N.O. Brace / Journal of Fluorine Chemistry 123 (2003) 237–248
243
3.2. Radical addition of perfluoroalkyl iodides (1) to
prop-2-en-1-yl-2-butane-1,4-dioic acid anhydride (2), and
to but-3-en-2-yl-2-butane-1,4-dioic acid anhydride (3);
preparation of 3-(perfluoroalkyl)-2-iodoalkyl-2-butane-1,
4-dioic acid anhydride (4a,b and 5a,b) (Scheme 1)
followed by D remaining. Exothermic reaction occurs and
the mixture is cooled as necessary (turns red in color). After
1.5 h, the excess 1 is stripped (water pump), and excessive
foaming occurs. This leaves solid 4a,b (C6, C8, C10 homo-
logues), 68.3 g, 99.9% yield and conversion. Re-crystallized
from CCl4, mp: sinter 89 8C, mp 91–95–109 8C (clear).
Anal. Calcd. for C15H8F17IO3 (4a,b; average C8): C,
26.3; H, 1.18; F, 47.1; I, 18.5. Found: C, 25.9; H, 1.21; F,
46.1; I, 18.6.
3.2.1. 3-(Perfluorohexyl)-2-iodopropyl-2-butane-1,4-dioic
acid anhydride (4) (Table 1, entry 1)
The reactants (1, n-C6F13I and AIBN) are stirred under
nitrogen in a 100 ml flask immersed in a heated, stirred bath.
Anhydride 2 (14 ml) is added drop wise at 63–70 8C during
15 min, and forms a cloudy mixture. After 25 min, and
11 ml of 2 are added, temperature rises to 82 8C, and
continues to 132 8C in 2 min, as the flask is removed from
the bath. The clear mixture is cooled to 82 8C, the remaining
2 is added drop wise, and the flask is heated at 82 8C for
1.5 h. A 3.0 g sample shows unreacted 2; thus, AIBN
(0.61 mmol) and 1 (11.0 mmol) are added, and after 5 h
at 70–92 8C, the flask is set up for distillation (water pump).
Unreacted 1 (8.33 g, 18.7 mmol, 100% of theory) is recov-
ered. The solid 4a,b (diastereomers) remains (56.0 g; 99.6%
conversion and yield) mp 83–88 8C. Re-crystallization from
CCl4/HCCl3, yields pure 4a,b, mp (sinter 84 8C) 85–88 8C.
1H NMR: d 2.06–2.6, broad m, 2H, CHICH2; d 4.20 and
4.80, 1H total, 1:1, complex m, CHI (diastereomers). Anal.
Calcd. for C13H8F13IO3: C, 26.6; H, 1.38; F, 42.1; I, 21.7.
Found: C, 27.0; H, 1.27; F, 41.6; I, 21.0.
3.2.5. RFI (C6) adds to anhydride 3 (AIBN);
4-(perfluorohexyl)-3-iodo-2-butyl-2-butane-1,4-dioic
anhydride (5a,b) (Table 1, entry 6)
The conditions of Section 3.2.1 are employed. At the water
pump, excess 1 (11.0 g; 24.7 mmol) distills, and 5a,b remains
as a viscous oil, 28.3 g (94.4% conversion and 99.4% yield).
1H NMR: d 1.05, 1.08, and 1.15, complex m, total 3H, CH3
(diastereomers); d 4.37–4.5, complex m, 1H, CHI (diaster-
eomers). Anal. Calcd. for C14H10F13IO3: C, 28.0; H,1.68, F,
39.7; I, 21.2. Found: C, 28.6; H, 1.78; F, 39.7; I, 20.7.
3.3. Reactions of 3-(perfluorohexyl)2-iodo-propyl-2-
butane-1,4-dioic acid anhydride (4a,b)
3.3.1. The reductive dehalogenation of anhydride 4a,b by
zinc and acid to ethyl 3-(perfluorohexyl)propyl-2-butane-
1-oic acid-4-oate (half ester 7); and diester 8 (Scheme 2)
A mixture of 4a,b (RF ¼ C6F13; 23.3 g, 50.0 mmol), zinc
(30–40 mesh, 19.5 g, 298 mmol, added in two portions) and
ethanol (118 g, 2.6 mol, 150 ml; moles EtOH/4a, 4b ¼ 52)
is stirred by a magnet bar at 73–76 8C, as HCl (g, anhydrous)
is bubbled below the surface of the liquid by means of a glass
tube. A gas bubbler device filled with oil is used to monitor
the flow of HCl. After 5 min, the flow of HCl is stopped, and
in 10 min, it is turned on again, briefly. As the solution
becomes colorless, the surface of the zinc is covered with gas
bubbles, and the mixture is foamy with evolved gases (H2,
HCl). The heat is removed during this rapid, exothermic
reaction at 76 8C. After 1.5 h, the colorless mixture is
cooled, and the liquid is decanted into 100 ml of water.
The aqueous layer is extracted twice with benzene, with
CCl4 (each, 25 ml), and the solvent is added to the heavy oil
3.2.2. 3-(Perfluorooctyl)-2-iodopropyl-2-butane-1,4-dioic
acid anhydride (4a,b) (Table 1, entry 2)
At 72 8C (bath), the reaction occurs exothermally, and it is
cooled as necessary. After heating for 2 h, the mixture of 4a,b
is cooled and solidifies (39.9 g, 100% recovery; mp (sinter
96 8C) 114–117 8C; IR: 2). Solid 4a,b is slurried with ligroine
(30 ml; bp 60–70 8C) and acetic anhydride (1.0 ml; to prevent
hydrolysis), and filtered. The 4a,b is dried; corrected weight
1
34.2 g (99.7% yield and conversion). H NMR: d 4.28 and
4.61, 1:1 multiplets of CHI. Re-crystallization of 1.3 g gives
0.586 g of pure 4a,b, 1:1 diastereomers, mp 115–116 8C.
Anal. Calcd. for C15H8F17IO3: C, 26.3; H, 1.18; F, 47.1; I,
18.5. Found: C, 26.3; H, 1.08; F, 46.5; I, 18.3.
1
3.2.3. Benzoyl peroxide induced reaction, thiol 1¼C8
(4a,b) (Table 1, entry 3)
layer, 25.76 g (100% conversion as 7); H NMR: chiefly 7;
some 8 and 9). The solution is dried (MgSO4), and distilled in
column A at the water pump, to give three fractions: (1) bp
109–154 8C/14 mm, total, 2.11 g; fraction (2), bp 131–
148 8C/14 mm, 1.09 g; NMR: a mixture of 2 and 8, 44/56,
from integration of signals d 1.26 and 4.18 (CH3CH2O); and
d 5.10 and 5.70 (CH2¼CH in 2); and, fraction (3), bp 148–
Thiol 1 and half of B is stirred at 100 8C, while 2 is added
drop wise (half h), followed by B remaining. Exothermic
reaction occurs and the mixture is cooled as necessary. After
0.75 h at 100 8C, the mixture is cooled to 89 8C and turns
solid. Unreacted 1 is stripped to leave 4a,b, 38.6 g, 96.7%
yield and conversion. 1H NMR: a mixture of diasteromers of
4a,b; unreacted 2 is absent.
154 8C/14 mm, 0.85 g; n2D5 1.3726; IR, nC¼O 1780 cmꢂ1
,
1
strong, COOH, and 1735, strong, COOEt [18]. H NMR: a
mixture of 7 and 8. The residue (weight 22.0 g) (86.9% as 7)
is mostly 7 (80%) and 8 (20%) by integration. Some 9 is
3.2.4. bis-tert-Butyl peroxide; thiol 1¼C6, C8, C10,
equimolar; average C8 and 2 (Table 1, entry 4)
indicated by IR: nOH in bonded COOH, 3200–3000 cmꢂ1
;
Thiol 1 (C6, C8, C10, equimolar; average C8) and half of
D is stirred at 125 8C, while 2 is added drop wise (half h),
1860, 1800, anhydride, as in succinic anhydride; 1780,
strong, COOH, monomer; 1735, very strong, COOEt.

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N.O. Brace / Journal of Fluorine Chemistry 123 (2003) 237–248
1
1H NMR: d 1.3, t, J ¼ 7 Hz, CH3CH2; d 1.8, m, CH2; d 2.0–
3.5, multiplets, RFCH2, CH2, CH; d 4.22, q ꢁ q, 2H,
CO2CH2CH3; 5.5, m, 1H, COOH, exchangeable. The sam-
ple (IR, NMR and elemental analysis) is primarily 7, with
some 8 and 9. No CHI, nor CH¼CH is present.
Anal. Calcd. for C15H15F13O4: C, 35.5; H, 3.0; F, 48.6.
Found: C, 36.6; H, 3.0; F, 48.0.
(COOH, COOEt); H NMR: same as above for 10; CHF
anal, same as for 10. Fraction (2) (2.83 g) a mixture of 10
(mostly) and 11. IR: nC¼O, 1765, g-lactone, 1700–
1750 cmꢂ1, COOH, COOEt. H NMR: in addition to the
1
signals of 10 (including 10.0, bonded OH) as in (1), signals
for 11 are present as in (3). Fraction (3) (1.51 g) is cis- and
trans-11. Total recovery of products, 4.74 g, 37.6% of theory.
One eluate fraction of (3) is evaporated separately to white
solid, mp 103–108 8C. This is pure cis-11; IR: 1765 cmꢂ1; 1H
NMR of cis-11 (see Scheme 4 for structure; cf. Scheme 7,
20a): d 5.02, t, Ha; Ja;b ¼ 6 Hz ¼ Ja;c ¼ ca: 6 Hz. The coin-
cidence of coupling constants suggests that the bulky sub-
stituents of cis-11 twist away from each and distort the bond
angles in such a way as to minimize the shielding difference
3.3.2. Dehydrohalogenation of 4a,b by KOH in aqueous
ethanol to potassium 2-[3(perfluorohexyl)-2-
E-propenyl]butane-1,4-dioc acid (10, K salt), and ethyl
2-[3-(perfluorohexyl)-E-2-propenyl]-1-oic acid-4-oate
(10, half ester) (Scheme 4)
To a stirred solution of KOH (5.1 g, 0.0909 mol) in water
(20 ml, 1.11 mol) and ethanol (90 ml, 1.53 mol), at 25 8C, is
added anhydride 4a,b (18.0 g, 0.0307 mol; mols
EtOH:4a,b ¼ 50; KOH:4a,b ¼ 3; H2O:4a,b ¼ 30), and stir-
ring continued for 6.5 h. The clear solution of 10 (K salts)
and KI foams, and is weakly basic; it is evaporated slowly in
a beaker to a soft solid, wt 17.1 g (10, 82% as K salt). The
surface tension in water at 0.1 wt.% is 15.7 dyn/cm at 25 8C.
A 1.0 g portion of the K salts is shaken while adding 2 M
HCl to a pH 3, extracted into ether, the solution dried and
passed down alumina. Fractions are eluted with CH2Cl2,
acetone and then CH3OH, and evaporated to white solid (10;
half ester). IR: nOH, bonded COOH; nC¼O, 1760, ester;
1710, COOH, dimer; nC¼C, 1650 (RFCH¼CH, trans),
1
in Hb and Hc. H NMR of trans-11: d 4.80, d ꢁ d, Ha;
Ja;b ¼ 10 Hz and Ja;c ¼ 6 Hz; the bulky substituents are trans
(cf. Scheme 7, 21a,b). Weak signals for the (di)ethyl ester are
present, but no exchangeable H is seen in the NMR.
Anal. Calcd. for C15H13F13O4 (11): C, 35.7; H, 2.6; F,
49.0. Found (fraction 1): C, 34.7; H, 2.5; F, 49.4. Found
(fraction 3): C, 33.0; H, 2.3; F, 49.0.
3.3.4. Reductive deiodination of anhydride 5a,b to ethyl
4-(perfluorohexyl)-2-butyl-2-butane-1-oate-4-oic acid
(half ester 14a,b) (Scheme 5)
Anhydride 5a,b (n-C6F13; 20.0 g, 0.0333 mol, 0.266 M),
ethanol (100 ml; 78.5 g, 1.96 mol, 15.7 M), HBr (10.0 ml,
48 wt.%, 14.9 g total weight; thus, HBr, 7.15 g, 0.0884 mol,
0.71 M; HBr:5a,b ¼ 2:65 mol), water (in HBr solution;
7.75 g, 0.430 mol, 0.344 M; water:5 ¼ 12:9 mol), and zinc
(20–40 mesh, 6.5 g, 0.10 mol) is stirred at 78 8C. The
solution becomes colorless in five min, zinc (6.5 g; total
0.2 mol; Zn:5a,b ¼ 6:0 mol) is added after 10 min, and
stirring continued for 1 h. When decanted into 100 ml of
water, an oil (19.4 g, 0.0341 mol as 1a,b, impure) separates.
The aqueous layer is extracted with ether and benzene
(together), combined with the oil and shaken with sodium
bisulfite solution. The colorless solution is dried, and the
solvent distilled (column A) to 104 8C (Tpot); the viscous
gum, weight 18.3 g, is further pumped down to 80 8C/
10 mm for 1/2 h to give 14a,b (16.24 g, 93.9% conversion;
sample 1). IR and NMR are consistent with impure 14a,b
(COOH and COOEt position isomers), and there is no
1
1640, 1615 [10,16,18]. H NMR (100 MHz): d 1.28, q, t,
3H, OCH2CH3; d 4.22, q, 2H, OCH2CH3; d 5.72, dxt, 1H,
3
CHa; Ja;b ¼ 16 Hz, Ja;CF ¼ 12 Hz; in the segment,
2
3
CF2CHa¼CHbCH2(c), the high Ja;b ¼ 16 Hz indicates a
3
trans isomer; d 6.34, dxt, CHb; Jb;CH ¼ 7 Hz; d 10.7, m,
2
broad, exchangeable, COOH.
Anal. Calcd. for C15H13F13O4: C, 35.7; H, 2.6; F, 49.0.
Found: C, 35.6; H, 2.6; F, 48.1.
3.3.3. Conversion of half ester 10 to cis and trans-g-
lactone (11) by acid induced lactonization
(Scheme 4, Eqs. (c) and (d))
The remaining 10 (16.0 g, 0.025 mol of 10 K salt; and KI,
ca 0.025 mol) is stirred into H2SO4 (9.0 ml, 50% aq. solu-
tion; 0.046 mol; H2SO4:10 ¼ 1:8 mol) to give a dark,
gummy liquid. Water (20 ml) is added and stirred (magnet
bar) for 1/2 h. The gummy liquid mixture of acids and 11 is
washed twice by decantation with ice/water. The strongly
acidic wash liquid is extracted with ether, then with CH2Cl2,
and evaporated to give 0.1 g of solid. The combined organic
layer is extracted with NaHSO3 solution (now colorless),
dried and evaporated to an orange, viscous gum, 7.0 g (63%
recovery as 10 or 11). The mixture is re-dissolved in CH2Cl2,
passed down an alumina column (5 in: ꢁ 1=2 in.), and
washed successively with 100 ml each of ether, acetone
and CH3OH, while taking 30 ml eluates. The three com-
bined solvent fractions are examined by IR, NMR and
elemental analysis. Combined fraction (1) (2.00 g) contains
10, chiefly. IR: nC¼C, 1650; nC¼O, 1700–1750 cmꢂ1
1
CH¼CH, and no g-lactone. H NMR (see Scheme 5 for
notation): d 1.00, 3 H, d ꢁ d, CH3CHe, diastereoisomers;
1.26, t, 3 H, OCH2CH3; 2.44–3.26, complex m, 8H, CH2(a),
CH2(b); CH2(c), H(e), H(d); 4.16, q, 2 H, OCH2CH3; 9.44,
broad, exchangeable, CO2H. The spectrum is consistent with
a 1:1 mixture of two diastereomers of 14a,b.
Anal. Calcd. for C16H17F13O3 (14a,b): C, 36.9; H, 3.3; F,
47.5; I, 0.0. Found: C, 35.1; H, 3.2; F, 45.5; I, 1.22. Anal.
Calcd. for C14H10F13IO3 (5): C, 28.0; H, 1.7; F, 39.7, I, 21.2.
The elemental anal shows ca. 5.7 wt.% of unreacted 5
(or equivalent) is present. In order to react with and remove
5, NaOH (0.030 mol) in water (25 ml) is added to a portion
(81.5%) of the material, and the mixture heated to 80 8C for

N.O. Brace / Journal of Fluorine Chemistry 123 (2003) 237–248
245
2 h to form a thick paste. This is dissolved in 50 ml of water,
made acid with 6N HCl (17 ml; 0.1 mol), and extracted with
ether (twice), benzene, and NaHSO3 solution, to remove the
iodine (dark red color; some of the half ester 14 may have
reacted and dissolved in the basic solution, and lost). The dry
extract is again distilled and pumped down to 90 8C/10 mm
for 1 h. The viscous gum remaining (14a,b, 11.63 g; 88.8%
recovery) contains ca. 20% of the diacid formed during the
hydrolysis reaction, Calculated from the integrals in the
NMR (82.5% yield and conversion).
(17.5 mmol, 0.11 M), 12 (8.3 mmol, 0.054 M), and 13, K
salt (13.6 mmol, 0.88 M dissolved in water, 20 ml).
The mixture is added, while stirring (magnet bar), to ethanol
(100 ml, 1.96 mol, 60 eq., 12.6 M) and water (20 ml).
Water is added to give a homogenous liquid (total water
2.2 mol, 91 eq., 14 M). The liquid volume is 155 ml.
While stirring, HBr (48 wt.%, 20 ml, 29.8 g; actual HBr,
14.3 g, 0.177 mol, 1.14 M; HBr/5a,b þ 13 ¼ 5:45 mol)
and zinc (6.5 g, 0.10 mol) are added, and the mixture is
heated. At 62 8C, it becomes colorless, and gas evolves. In
10 min, additional zinc (6.5 g, 0.10 mol; 0.20 mol total;
Zn/5a,b þ 13 ¼ 6:15 mol) is added, and the colorless solu-
tion is stirred at 80 8C for 3 h. The solution is decanted from
Zn into 100 ml of water, and g-lactone (16), 17.6 g
(0.034 mol, 88% recovery) is extracted with benzene
(70 ml), but does not dissolve. Ether (30 ml) is added, and
the clear layer is washed with sodium bisulfite solution to
remove the iodine (red color), and dried (MgSO4). Solvents
are distilled (column A) to 102 8C (pot temperature) to leave
half ester 14 and g-lactone (16a,b) isomers, as a colorless oil.
IR: nOH, 3500–3000 cmꢂ1, heavy, bonded OH of COOH,
14; nC¼O, very strong, 1780, g-lactone; 1735, COOEt,
16a,b. The mixture is re-dissolved in benzene and ether,
extracted with NaHCO3/Na2CO3 solution (to pH 8) to
remove 14, and distilled (column A) at the water
pump. Fractions: (1), bp 138–150 8C/9.5 mm, 0.64 g; (2),
bp 170–179 8C/11.0 mm, 6.86 g, and (3), bp 174 8C/11 mm,
5.24 g; (4) hold up, 1.18 g, white solid (total 14.0 g). The
yield of 16a,b (0.0270 mol) is 87% based on the 5a; b þ 13
(0.0311 mol) used in the zinc reduction. IR (1)–(3): nC¼O,
very strong, 1780 cmꢂ1, g-lactone; 1735, COOEt; but no
bonded OH of CO2H. 1H NMR (see Scheme 6 for notation):
Fractions (2) and (3) are a 16a,b isomer mixture, not pure.
Fraction (4) is re-crystallized from ligroine/ethanol to give
pure cis-isomer 16a, 0.16 g, mp 78–80 8C. IR (16a): nOH,
none; nC¼O, 1770 cmꢂ1, very strong; 1735, same, ester. 1H
NMR (16a; see Scheme 6 for notation): d 1.19, d, 3H,
CH3 cis to RFCH2; 1.28, t, 3 H, CH3CH2O; 2.0–2.9, complex,
6H, CH2(c), CH2(e), Hd, Hb; 4.19, q, 2H, CH3CH2O; 4.26, d
Anal Calcd. for C16H17F13O3 (14a,b): C, 36.9; H, 3.3; F,
47.5. Found: C, 36.7; H, 3.3; F, 47.0.
3.3.5. Catalytic deiodination of anhydride 5a,b over Pd/C
and H2 to 4-(perfluorohexyl)-2-butyl-2-butane-1,4-dioic
acid anhydride (12); reaction of 5a,b with K2CO3 to give
ethyl 4-(perfluorohexyl)-2-butyl-2-butane-1,4-dioic acid, K
salt (13) (Scheme 6, Part I)
Anhydride 5a,b (n-C6F13; 27.1 g, 0.0383 mol; contains 3,
1.04 g; 6.83 mmol), K2CO3 (6.91 g, 0.0500 mol), ethyl
acetate (anhydrous, 100 ml) and 5% Pd/C (5.00 g) are
charged to a Parr hydrogenator bottle, evacuated and filled
three times with H2 to 50 psi. When shaken, the black slurry
begins to foam in 15 min, and plugs the valve and the vent.
Shaking is continued for 2.5 h (no apparent loss in pressure),
the bottle stopper is loosened, and a burst of H2 and slurry
vents into the surroundings. The remainder is rinsed from the
bottle onto a Buchner funnel with ethyl acetate (50 ml). The
black filter cake on the Buchner funnel is rinsed with portions
of water (total 100 ml), and dried, wt 6.37 g (1.4 g excess).
The filtrate of K salts foams and forms a gel when cooled. The
water is evapd and leaves a white solid (KI; 13, K salt), 13.6 g
(ca. 13.6 mmol of 13 or KI; from total mmol of 5 þ 12). The
original (ethyl acetate) clear liquid filtrate is evaporated for
1 h in a rotary evaporator to 40 8C/20 mm. The viscous oil,
weight 17.0 g, is a mixture of 5 (ca. 62%; 10.5 g, 17.5 mmol,
45.7%recovery on5), ethylacetate(15 mol%), and anhydride
12 (ca. 23 mol%; 3.4 g, 7.2 mmol, 18.7% conversion on 5),
from iodine anal and NMR. IR (smear on KBr): nOH,
3200 cmꢂ1, weak, bonded OH of COOH; nC¼O, 1860,
1790, very strong, 12 anhydride; 1735, 5, COOEt. 1H
NMR: d 4.37, 5.22, d ꢁ d, CHI of 5a,b (diastereomers);
integrates to ca. 60% of the total integral; ethyl acetate
is ca. 15 mol% of the total. The iodine analysis is
13.2/21:2 ¼ 62:2% of 5a,b remaining in the sample.
3
3
3
ꢁ d ꢁ d, Ha; JHaHb ¼ 9:3 Hz, JHaHc ¼ 7:2 Hz; JHaHc
¼
3:3 Hz. The NMR spectrum is consistent with a single
isomer 16a; both the clean signals observed in the methyl
region, and the simple clarity of the signal for Ha when the
RFCH2 signal is irradiated, indicate a single isomer. The
observed 3Ja;b of 9.3 Hz suggests that Ha and Hb are cis to one
another.
Anal. Calcd. for C14H11F13O3 (12): C, 35.5; H, 2.3; F, 52.1;
I, 0.0. Anal. Calcd. forC14H10F13IO3 (5a,b):C, 28.0;H, 1.7; F,
39.7, I, 21.2. Found: C, 33.1; H, 2.5; F, 39.9; I, 13.2.
Anal. Calcd. for C16H15F13O4 (16a): C, 37.1; H, 2.92; F,
47.7. Found: C, 37.1; H, 3.0; F, 46.5.
3.3.6. Esterification of anhydride 12 to half ester 14; and,
of anhydride 5a,b and K salt 13 to half ester, 15; zinc
induced lactonization of 15 to 2-ethoxycarbonyl-3-methyl-
4-(perfluorohexyl)methyl-4-hydroxybutanoic acid
g-lactone (16a,b) (Scheme 6, Part II)
3.4. Free radical addition of 1-iodoperfluorooctane (1) to
ethyl 3,3-bis-carboethoxy-hex-5-enoate (17); ethyl [5-iodo-
6-(perfluorooctyl)-3,3-bis-carboethoxy]hexanoate (18)
(Scheme 7, Part I, Eq. (1))
The reactants (above experiment, assuming that all of
5a,b and/or its products are recovered) comprise: 5a,b
1-Iodoperfluorooctane (1, 81.9 g, 40.8 ml, 150 mmol;
passed down Al2O3), 17 (27.4 g, 95.8 mmol; re-distilled)

246
N.O. Brace / Journal of Fluorine Chemistry 123 (2003) 237–248
and AIBN (0.328 g, 2.00 mmol) are charged to a Fischer–
Porter pressure tube, cooled to ꢂ78 8C, evacuated and filled
with nitrogen three times, and heated in an oil bath at 70.0 8C
for 23 h, while stirring by a magnet bar. The colorless, clear
liquid changes to a yellow color when opened to the atmo-
sphere (109.1 g, 100 wt.% recovery). Distillation at the
water pump gives 1, bp 72–67 8C/32 mm (Tpot up to
100 8C) 32.3 g, 59.1 mmol, (94.9% conversion of 1 to
18); ꢂ78 8C trap, 2.0 g (EtI, ?); pot liquid (18), weight
19a,b, 109.2 g; 98.6% recovery) is set up for distillation at
the water pump. Very dark vapors (I2, HI) distill with 1, bp
62–59 8C/21–16 mm, Tpot, up to 108 8C, 18.4 g (0.0338 mol
as 1). Hence, 0.116 mol (77.5% of theory of 1) is consumed,
remains in 19a,b, or is lost. The 19a,b pot residue, and rinse
of tube and flask (evaporated, 2.15 g), total weight (1),
1
77.3 g, 0.0956 mol (94.7% of theory as 19a,b). IR and H
NMR: 19a,b, 1:1. The cold trap (ꢂ78 8C) contains two
layers; the smaller lower layer is solid at ꢂ78 8C (total
weight, 13.0 g; 0.0833 mol, 84.9% as EtI). Impure 19a,b
(70.0 g) is re-crystallized from ligroine (200 ml); (1) 44.3 g,
1
74.8 g, 93.8% conversion. H NMR: mixture of 17 (trace)
and 18; no g-lactone (19a,b).
1
mp 61–3 8C. H NMR: 19a,b 1:1.
3.4.1. Adduct 18 is heated to give iodoethane and cis- and
trans-4-(perfluorooctyl)methyl-2-carboethoxymethyl-2-
carboxy-4-hydroxysuccinic acid lactone (19a,b)
Anal. Calcd. for C20H17F17O6 (19a,b): C, 35.5; H, 2.58 F,
47.8; I, 0.0. Anal. Calcd. for C22H22F17IO6 (18): C, 31.7; H,
2.67; F, 38.8; I, 15.2. Anal. Calcd. for C8F17I (1): C, 17.6; F,
59.1; I, 23.3. Found (impure 19a,b): C, 33. 1; H, 2.42; F,
47.0, I, 2.45. I: 2.45:15:2 ¼ 16:1 wt.% of 18, if present; I:
2.45:23:3 ¼ 10:5% of 1, if present.
(Scheme 7, Part I, Eq. (2))
The impure 18 (74.8 g, 0.0893 mol) is heated in an oil bath
to Tv 82 8C/0.05–0.65 mm; Tpot ¼ 142–146 8C (ca. 1 h).
Iodoethane (total, 10.5 g, 67.3 mmol; 70.2% of theory)
collects in the dry ice trap. MS: m=e ¼ 156 (mol ion),
141 (–CH3), 127 (–I), 126, 29 (CH3CH2) and 27 (CH3C).
The residual oil 19a,b solidifies on cooling and is collected
on a Buchner funnel, weight 59.50 g (0.0880 mol, 98.5% of
theory as g-lactone 19a,b), mp 59–65 8ꢂC1. IR (KBr):
nCH2¼CH (trace), 3090, 1640 and 990 cm ; nC¼O (vs)
1780 cmꢂ1, g-lactone, 19; nC¼O (vs) 1740 cmꢂ1, ester. 1H
NMR: 19a,b; from the areas of d 2.22 (Hc) and 4.98 (Ha),
isomer 19a:19b ¼ 60/40. A 1 g portion of impure 19a,b
is re-crystallized from ligroine (bp 60–70 8C; 20 ml).
Solid 19a,b is collected: (1) weight 0.614 g, mp (sinter
55 8C) 56–59 8C; (2) 0.225 g, mp (sinter 59 8C) 60–
65 8C; (3) 0.0672 g, mp 59–62 8C. IR (Nujol mull): nC¼O
The trap liquid (12.6 g) is re-distilled in column A; (1),
bp 63–66 8C, 3.4 g; two immiscible liquids, and (2),
bp 66 8C (73 8C pot temp), 5.88 g, also two liquids; lit:
iodoethane, bp 69–73 8C, mp ꢂ108 8C [32,33]. MS,
iodoethane, chiefly. Water is not present (negative test).
The lower layer may be 1-H-perfluorooctane; lit: (perfluor-
ooctane): bp 103 8C, mp ꢂ25 8C [34]. The oil residue,
3.4 g (1).
3.4.3. Ethyl 5-iodo-6-perfluorooctyl-3,3-bis-
carboethoxyhexanoate (18) and conversion to
g-lactone (19a,b) (Scheme 7, Part I)
The experiment (Part I, Step 1) is repeated. Recovered, re-
distilled 1 (41.0 g, 75.0 mmol), 17 (14.3 g, 50.0 mmol) and
AIBN (0.164 g, 1.00 mmol) are heated, while stirring, in an
oil bath at 70.0 8C for 17 h. IR: 18, no g-lactone at
1780 cmꢂ1, and unreacted 17. Distillation gives 1, bp
31–37 8C/0.01 mm, Tpot 39–55 8C (29.4 g, 54.0 mmol;
hence, 21 mmol (42%) of 17 is consumed, and/or converted
to 18. The residual oil (17, 18; 26.3 g). A 4.56 g portion of
the residual oil (0.173 fraction; ca. 3.60 mmol of 17
and 4.24 mmol of 18) is heated for a half hr at 116–
143 8C/26 mm and distilled. This affords 17, bp 105–
108 8C/0.15–0.10 mm, 1.03 g, 3.60 mmol, n2D6 1.4330; and
solid residue 19a,b, 2.67 g, 3.95 mmol (93.7% yield); mp
(sinter 49 8C) 53–59 8C. The cold trap contains iodoethane
(0.439 g, 2.81 mmol, 78% conversion).
(vs), 1780, 1735 cmꢂ1, equal intensity. H NMR (sample
1
(1); see Scheme 7 for structures; cf. Scheme 4, 11a; and
Scheme 6, 16a): d 1.28, 1.30, t ꢁ t, 1:1 area, six protons, two
3
2
CH3CH2O; d 2.22, Hc, d ꢁ d, JHc;HA ¼ 9 Hz; JHc;HB
¼
14 Hz; d 2.22–3.36, complex m, Hb, RFCH2, CH2(e)COOEt;
d 4.28, qxq, 4 H, 2 ꢁ CH3CH2O; d 5.08, m, 1H, Ha diaster-
eomers. The NMR data are consistent with 1:1 isomers
19a,b, and either g-lactone or d-lactone structure. However,
IR clearly identifies 19a,b as a g-lactone.
Anal. Calcd. for C22H22F17IO6 (18): C, 31.7; H, 2.67; F,
38.8; I, 15.2. Anal. Calcd. for C20H17F17O6 (19a,b): C, 35.5;
H, 2.58; F, 47.8. Found (impure 19a,b): C, 36.4; H, 2.68; F,
42.6; I, 1.91. I: 1.91:15:2 ¼ 12:6 wt.% of 18. Found (19a,b,
re-crystallized (1)): C, 35.2; H, 2.48; F, 47.6.
3.5. Hydrolysis of 19a,b by NaOH to cis- and trans-2-
carboxymethyl-2-carboxy-4-hydroxy-4-(per-
fluorooctyl)methyl-butanoic acid g-lactone (20a,b)
(Scheme 7, Part II)
3.4.2. Benzoyl peroxide induced radical addition of RFI (1)
to 17, and lactonization of adduct 18 to g-lactone (19a,b)
(Scheme 7, Part I, Eq. (3))
As in Part I, Step (1), 1 (n-C8F17; 81.9 g, 0.150 mol), 17
(28.1 g, 98.2 mmol) and benzoyl peroxide (0.484 g,
2.00 mmol) (sealed pressure tube) is stirred and heated at
99.0 8C in an oil bath for 3.5 h. Within 25 min, the mixture
turns red, and in 1 h, dark purple in color (I2). Iodoethane
refluxes. The tube is cooled and the product (EtI, 1 and
A solution of NaOH (2.00 g, 50.0 mmol) in water (12 ml)
and ethanol (28 ml) is added to 19a,b (90% pure, 8.18 g, ca.
9.00 mmol), while stirring at 50 8C. The pasty mass is kept
at 70 8C for 5.5 h, and allowed to stand at 35 8C for 18 h.
Water (20 ml) is added, and after 5 h, the solution is poured

N.O. Brace / Journal of Fluorine Chemistry 123 (2003) 237–248
247
into dilute HCl (10 ml of 6N HCl in 100 ml of water), while
stirring vigorously at 27 8C. The strongly acidic, soft gel of
20a,b filters very slowly on a Buchner funnel; the soft solid
20a,b is dried in air, and over P2O5 in a vacuum desiccator,
weight 6.88 g (100% recovery), mp 143 8C (dec). The
impure 20a,b dissolves in hot acetone (50 ml), treated with
carbon powder, and evapd to 25 ml; CC14 (25 ml) is added
and then cooled. Crystalline 20a,b is collected, rinsed with
solvent and dried, first at 25 8C in air, and at 60 8C/16 h to
give (1) wt 3.50 g, mp (sinter 136 8C) 136.5 8C (dec). IR:
same as 20a,b below, except nC¼O: 1770 cmꢂ1, 1765
(COOH, monomer), 1730 and 1700 (COOH, dimer),
dCH, 1320 only. 1H NMR (see Scheme 7, Part II):
20a,b, richest in 20a, and a little of another substance.
The mother liquor gives (2) 20a,b and an unknown, prob-
ably 21, weight 1.106 g, mp (sinter 139 8C) mp 147 8C
(dec, ca. 1/2); then mp 176 8C (no dec); (3), 20a,b, weight
0.692 g, mp (sinter 133 8C) 141–42 8C (dec). Total 20a,b
(and unknown) is 5.30 g, 8.54 mmol, 94.9% yield. The
samples of 20a,b decarboxylate to 21a,b when heated;
in no. 2, the higher mp substance does not decarboxylate,
and thus may be 21.
2.07 g, mp (sinter 142 8C) 145–147 8C (dec). Similarly,
20a,b (4) wt, 0.581 g, mp (sinter 140 8C) 144–145 8C (dec);
and (5), 0.301 g, soft solid. Total recovery of 20a,b is 97.7%
of theory based on original 19a,b. IR, KCl disc; 20a (2):
bonded nOH, 3200–2800 cmꢂ1; nC¼O, 1770, 1730; d CH
1420, 1380,1370, 1330, and 1325; nCF, 1250–1180; and
bands at 965, 900, 740, 710, 705, 650, 600, 555, 540, and
440. H NMR [100.1 MHz, DMSO-d solution; 20a, (2)]:
The d 2.20 and 4.96 regions integrate 1:1, and thus, it is a
single isomer. Specifically, it is 20a with the d ꢁ d upfield
from the rest of the aliphatic moiety. For assignments see
20a,b (1) above.
6
1
Anal. Calcd. for C16H9F17O6: C, 31.0; H, 1.46; F, 52.1.
Found (20a,b; no. 1 of Section 3.5): C, 31.2; H, 1.29; F,
52.8, 52.9. Found (20a,b; 70/30 of 3.5.1): C, 30.0; H, 1.41;
F, 49.7. Found [20a (2) of 3.5.1]: C, 30.9; H, 1.43; F, 51.6.
3.5.2. Alkylation of ethyl (2-ethoxycarbonyl)-1,3-
propanedioate (22) by 2-propenyl bromide to give ethyl
3,3-(bis-ethoxycarbonyl)-hex-5-enoate;
CH2¼CHCH2C(CO2Et)2CH2CO2Et (17)
Sodium (4.6 g, 0.20 mol, cut under toluene) is added to
ethanol (100 ml, distilled into the reactor from sodium
ethoxide solution) while stirring under a nitrogen atmo-
sphere, and at a rate to maintain reflux. After all had reacted
and dissolved, ethyl 1-ethoxycarbonylsuccinate, (22,
49.3 g, 0.200 mol; prepared above) is added dropwise dur-
ing 25 min at 50–52 8C. A suspension of the enolate salt is
formed. Allyl bromide (24.2 g, 0.200 mol) is added during
12 min at 40–78 8C. A precipitate of sodium bromide
appears and heat is evolved. The temperature is kept at
82 8C (reflux) for 1 h, and the reaction mixture becomes
neutral. Ethanol is removed (rotary-evaporator) at the water
pump, heating to 40 8C. Water (50 ml) is added and the
product is extracted into benzene (two times 25 ml). The oil
layer is shaken with water (15 ml) and dried over magne-
sium sulfate. Distillation in column B affords 17: (1) bp
100–110 8C/0.35 mm, 2.78 g, n2D5 1.4390 (90% pure); (2) bp
114–115 8C/0.43 mm, n2D5 1.4405, 49.1 g (100% pure), total
3.5.1. Hydrolysis of 19a,b by KOH in water (no ethanol) at
1
75–80 8C; isolation of pure isomer 20a, H NMR results
(Scheme 7, Part II)
As in 3.5.0, 19a,b (8.32 g, 11.1 mm; ca. 90% pure) is
added, while stirring at 35 8C, to KOH (3.09 g, 55.0 mmol,
2.8 M) in 12 ml of water (no alcohol); the mixture clears at
75 8C, and is stirred for 7 h at 75–80 8C. It is poured slowly
into dilute HCl (12 ml 6N HCl and 80 ml of water). The
solid 20a,b is collected and dried as above; 20a,b (1) wt,
6.96 g (10.1 mmol, 100%), mp 145–146 8C (dec),
unchanged in a sealed tube. IR (Nujol mull): nC¼O,
1
1770; 1730 (COOH, dimer) only. H NMR (20a,b; no. 1;
cf. Scheme 4, 11a,b and Scheme 6, 19a,b): d 1.20, t,
CH3CH2O, a small amount of 19a,b; 2.24, d ꢁ d, Hc in
3
2
20a; JðHcHaÞ ¼ 9 Hz, JðHaHbÞ ¼ 14 Hz; 20a:20b ¼ 70/
30; 2.46–3.27, broad complex m, Hb, RFCH2, Hc in 20b;
2.96, s, 2 H, CH2COOH; 4.14, complex m, CH3CH2O, a
small amount from 19a,b; 4.98, broad m, Ha; 9.90, very
broad m, exchangeable, 2H, COOH. The signal at d 2.24 (d
ꢁ d) for Hc in 20a integrates to less than one proton relative
to the Ha signal at d 4.98. Alkyl groups are known to
produce an upfield shift on cis-protons in five-membered
rings [19]. cis-C¼O functionalities also produce upfield
shifts, but the examples cited indicate the effect of an alkyl
group is larger [19]. The large 3J value indicates that the d
2.24 signal must have a proton cis to the proton giving rise
to the signal (i.e. as in 20a in Scheme 7). A 5.00 g portion of
20a,b (no. 1) is re-crystallized from hot 1:1 acetone/CCl4 as
above to give sample 20a (2), weight, 1.24 g, mp 150 8C
(dec); recheck, mp 151–152 8C (dec); NMR shows it
is a single substance. The mother liquor concentration
is adjusted in hot acetone solution by adding a little
CCl4 to incipient cloudiness, then cooled; 20a,b (3) weight,
yield (95%); and (3) residue, 0.70 g. IR: nC¼O 1735 cmꢂ1
,
ester; nC¼C 1645 cmꢂ1. NMR (17): d 1.28, 2t, 9H,
2CH3CH2O, and one CH2CO2CH2CH3; d 2.78, d, 2H,
CH2¼CHCH2; d 2.93, s, 2H, CH2CO2CH2CH3; d 4.12,
4.20, 2q, 4H, (CH3CH2O)2C–; d 5.08, d, fine splitting,
2H, HbHc of HbHcC¼CHaCH2; d 5.70, complex m, Ha of
HbHcC¼CHaCH2. Double irradiation is used to show cou-
pling between sets of protons.
Anal. Calcd. for C14H22O6: C, 58.7; H, 7.75. Found: C,
59.0; H, 8.05.
Acknowledgements
It is a pleasure to acknowledge assistance by Dr. Ronald
Rodebaugh in the acquisition and interpretation of NMR
data.

248
N.O. Brace / Journal of Fluorine Chemistry 123 (2003) 237–248
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