PRACTICAL SYNTHETIC PROCEDURES 1

3-(Perfluoroalkyl)propanols: Valuable Building Blocks for Fluorous

Chemistry
3-(Perfluor alkyl)propanols:ValuableBuildingBlocksforFluor usCRábai,*
József hemistry Csongor Szíjjártó, Peter Ivanko, Dénes Szabó
Department of Organic Chemistry, Institute of Chemistry, Eötvös Loránd University, P. O. Box 32,

PSP
1518, Budapest 112, Hungary
Fax +36(1)3722592; E-mail: rabai@elte.hu

X
Received 26 February 2007; revised 3 April 2007
Dedicated to Professor Neal O. Brace
No

Abstract: 2-Iodo-3-(perfluoroalkyl)propanols are obtained in excellent yields and several-hundred-gram quantities by the controlled radi-
cal addition of commercially available n-perfluoroalkyl and perfluoroisoalkyl iodides to allyl alcohol. Their consecutive reduction with hy-
drazine hydrate and Raney nickel catalyst in methanol afforded the corresponding 3-(perfluoroalkyl)propanols in high yields and purity.
Key words: alkyl halides, alcohols, fluorine, reductive dehalogenation, transfer hydrogenation

Procedure 1 Procedure 2

AIBN, aq K2S2O5, I Raney Ni, N2H4⋅H2O,

OH 80–90 °C, 2 h MeOH, 0–10 °C, 2 h
RF-I + RF OH RF OH
83–98% 65–95%
1a–f 2 3a–f 4a–f

RF = n-C4F9 (a), n-C6F13 (b), (CF3)2CF(CF2)4 (c),

n-C8F17 (d); (CF3)2CF(CF2)6 (e), n-C10F21 (f)

Scheme 1

Since the 1994 launching of the fluorous biphasic system Procedures

concept,1 and the consecutive elaboration of fluorous
synthesis2 and fluorous mixture synthesis strategies,3 a The synthesis of F-propanols often involves the use of flu-
variety of fluorous monofunctional organic precursors orinated building blocks; perfluoroalkanecarboxylic acids
have been prepared for the synthesis of more complex flu- (RFCO2H), perfluoroalkanesulfonyl chlorides (RFSO2Cl),
orous molecules.4 Fluorous chemistry now spans across and perfluoroalkyl iodides (RFI). These precursors are
biphasic catalysis to high-throughput synthesis of small manufactured on an industrial scale and some of them are
molecules and the separation and immobilization of bio- accessible as bulk chemicals.
molecules, including peptides, oligosaccharides, oligonu- 4,4,4-Trifluorobutan-1-ol (4, RF = CF3), the prototype of
cleotides, and glycopeptides.5 all fluorous propanols, has been prepared by the lithium
In this strategy ponytails with perfluoroalkyl segments aluminum hydride reduction of fluorinated aldehydes, ac-
[e.g., CnF2n+1(CH2)m, n = 4,6,8 and m 2] are appended to ids, and esters.10 Homologues with longer chains
target molecules, which then encode their fluorous char- (RF = C3F7, C6F13, C7F15) were also made by the reduction
acter, while the (CH2)m segments serve to insulate the ac- of fluorinated carboxylic acid derivatives, accessible by
tive site from the electron-withdrawing fluorines.6 multistep syntheses.11
3-(Perfluoroalkyl)propan-1-ols are receiving increasing Another strategy for the synthesis of the title alcohols in-
attention, since they constitute essential part of an emerg- volves the radical addition of perfluoroalkyl iodides 1 to
ing inventory of fluorous tools.7 Moreover, such alcohols allyl alcohol (2) or esters thereof, followed by dehaloge-
have been used for the synthesis of novel fluorous re- nation of the formed adducts 3. Thus, perfluoropropyl io-
agents, reactants, catalysts, chiral auxiliaries, scavengers, dide undergoes addition to allyl alcohol (2) using
protecting groups, and displaceable tags.8 ultraviolet activation, but several days of irradiation are
Although some of them are commercially available, their necessary for high conversions.12 Alternatively, a method
prices justifies the need to disclose optimized procedures of using azonitrile initiators for the addition of RFI to alk-
for the syntheses of these alcohols.9 enes has been disclosed by Brace,13 providing higher con-
version of RFI within hours.14 Thus, the reaction of
perfluoropropyl or perfluorohexyl iodide and allyl acetate
SYNTHESIS 2007, No. 1, pp 0001–0004xx. 207 under similar conditions afforded 2-iodo-3-(perfluoro-
Advanced online publication: xx.xx.2007 alkyl)propyl acetates, which were then reduced with lith-
DOI: 10.1055/s-2007-xxxxx; Art ID: T04007SS ium aluminum hydride to afford the corresponding
© Georg Thieme Verlag Stuttgart · New York alcohols 4a and 4b.15

Imprimatur:
T04007SS.fm, 5/3/07
Date, Signature
2 J. Rábai et al.
The synthesis of fluorous propanols has been improved by
the substitution of allyl alcohol/triallyl borate for allyl ac-
etate and tributyltin hydride for lithium aluminum hydride
in the reduction step.16 A great improvement in the rate of
addition of perfluoroalkyl iodides to allyl alcohol was
achieved by the synergic action of sodium metabisulfite
and 2,2¢-azobis(isobutyronitrile) as discussed by Gamba-
retto.16d Although the latter alterations resulted in higher
isolated yields, the removal of minute traces of toxic orga-
notin halide residues required additional purifications
steps.17
Scope and Limitations
We thought that transfer hydrogenation with hydrazine
hydrate/Raney nickel would be the reagent of choice for
the reductive dehalogenation of 3, since many examples
are disclosed for this transformation in the patent litera-
ture using hydrogen and a catalyst at elevated pressures
and temperatures in the presence of an appropriate base.18
We noticed that the addition of perfluoroalkyl iodides to
allyl alcohol can further be improved if the introduction of
the radical initiator is continuous, instead of in one por-
tion. While Gambaretto controlled the exothermic reac-
tion by the addition rate of 2 to the stirred and preheated
mixture of 1, 2,2¢-azobis(isobutyronitrile), and aqueous
sodium metabisulfite, we used continuous addition of a
solution of a solution of the initiator 2,2¢-azobis(isobuty-
ronitrile) in allyl alcohol (2). This slight modification al-
lowed the optimal reaction temperature to be easily
maintained and resulted in higher isolated yields and GC
purity of adducts 3.
The addition of liquid perfluoroalkyl iodides 1a–e afford-
ed iodohydrins 3a–e in 83–98% yields as shown in
Scheme 1 and detailed in the general procedure. Since the
optimal temperature of 2,2¢-azobis(isobutyronitrile) initi-
ation is about 80 °C, perfluoroalkyl iodides with lower
boiling point (CF3I, –22.5 °C; C2F5I, 12–13 °C; n-C3F7I,
41 °C) are not suitable for Procedure 1, unless a pressure
reactor is used.
Another limiting case for using Procedure 1 could be the
higher melting point of the adduct 3 than the optimal
working temperature of the radical initiator, as it was
found for 3f; 64% conversion of 1f was observed and
longer heating and additional initiator and allyl alcohol
were necessary to reach 99% conversion of 1f.
All of the fluorous iodohydrins 3a–d, but 3f, were readily
soluble in methanol and reacted with hydrazine hydrate
and Raney nickel catalyst under optimized conditions to
furnish the title alcohols in 65–95% yields (Scheme 1,
Procedure 2). For the less soluble 3f, the methanol–tet-
rahydrofuran solvent system and a longer reaction time
were applied. We observed that using lower temperatures
for the reductions resulted in the formation of more pure
crude products, which then were easily separated from the
less volatile side products by vacuum distillation.
Synthesis 2007, No. 1, 1–4 © Thieme Stuttgart · New York
PRACTICAL SYNTHETIC PROCEDURES
This method can be used in many laboratories since it
needs only standard laboratory glassware and equipment,
it is more atom-efficient than the tributyltin hydride pro-
tocol, and the hazards of using lithium aluminum hydride/
polyfluorinated substrate mixtures are eliminated.19
In summary, we have shown that a series of homologous
3-(perfluoroalkyl)propan-1-ols can be prepared from
readily available starting materials. In addition, the io-
dohydrin intermediates obtained here are valuable precur-
sors for the synthesis of other monofunctional fluorous
reagents, such as 3-(perfluoroalkyl)allyl alcohols
(RFCH=CHCH2OH) and 3-(perfluoroalkyl)prop-1-enes
(RFCH2CH=CH2).20
Et2O, MeOH, THF, and hydrazine hydrate (A.R. grades) were pur-
chased from Reanal. AIBN and Raney Ni (F-83440) were supplied
by Fluka. 1a (98%), 1b (99%), 1c (97%), 1d (98%), 1e (98%), and
1f (97%) were purchased from Fluorochem Ltd. 1H, 13C and 19F
NMR spectra (CDCl3 or acetone-d6, TMS) were recorded on Bruker
Avance 250 spectrometer. All reaction steps were monitored by GC
(Hewlett-Packard 5890 Series II, PONA: 50 m capillary, H2 carrier
gas, FID detection). Melting points: Boetius (uncorrected).
Iodohydrins 3; General Procedure
To a 1-L, 3-necked flask, fitted with thermometer, dropping funnel,
magnetic stirrer bar, and condenser with an argon bypass, was add-
ed the perfluoroalkyl iodide 1 (1.00 mol) and K2S2O5 (70 g, 315
mmol) dissolved in H2O (200 mL). It was flushed with argon, then
the mixture was heated to 65–70 °C and a soln of AIBN (5.0 g, 30
mmol) dissolved in allyl alcohol (2, 87 g, 105 mL, 1.5 mol) was
added with stirring at a rate to keep the temperature at 75–80 °C
thus controlling the slightly exothermic reaction; this addition usu-
ally takes 2.5–3 h. To complete the conversion of 1 (GC monitor-
ing), it was stirred at 80 °C for 1 h, then at 100 °C for 10 min. The
mixture was poured into H2O, and then worked up. The solid prod-
ucts were isolated by filtration, washed with H2O and dried in air;
while the liquid ones were extracted with Et2O (3 × 150 mL) and
purified by fractional distillation in vacuum. Analytical samples of
the solid iodohydrins (GC 98%) can be obtained by recrystalliza-
tion (boiling benzene, 1.3 mL g–1).
2-Iodo-3-(perfluorobutyl)propan-1-ol (3a)
The reaction was performed according to the general procedure us-
ing 1a (185 g, 92 mL, 535 mmol) and K2S2O5 (37.5 g, 168 mmol)
in H2O (107 mL) with 2 (56.3 mL, 804 mmol) and AIBN (2.68 g,
16 mmol). Pale-yellow oil; yield: 180 g (83%); GC: 97.5%; bp 105–
110 °C/21 mbar (Lit.15a 57–58 °C/1 mbar).
1
H NMR (CDCl3): d = 4.44 (m, 1 H, CHI), 3.83 (m, 2 H), 2.90 (m,
2 H, CH2CHI), 2.46 (br s, 1 H).
13
C NMR (CDCl3): d = 21.9 (C2), 37.7 (t, C3), 68.3 (C1).
19
F NMR (CDCl3): d = –81.7 (m, 3 F), –114.3 (q, 2 F), –125.1 (m,
2 F), –126.6 (m, 2 F).
2-Iodo-3-(perfluorohexyl)propan-1-ol (3b)
The reaction was performed according to the general procedure us-
ing 1b (1500 g, 735 mL, 3.36 mol) and K2S2O5 (90 g, 405 mmol) in
H2O (300 mL) with 2 (255 mL, 3.75 mol) and AIBN (9.0 g, 55
mmol). Yield: 1592 g (94%), GC: 96.4%. Recrystallization (ben-
zene) gave white crystals, mp 46–48 °C (Lit.21 44 °C). The spectro-
scopic data were in agreement with those reported by Gambaretto et
al.16d
PRACTICAL SYNTHETIC PROCEDURES3-(Perfluoroalkyl)propanols: Valuable Building Blocks for Fluorous Chemistry 3
2-Iodo-3-(perfluoro-5-methylhexyl)propan-1-ol (3c)
The reaction was performed according to the general procedure us-
ing 1c (10 g, 4.90 mL, 20 mmol) and K2S2O5 (1.4 g, 6.3 mmol) in
H2O (10 mL) with 2 (2.1 mL, 31 mmol) and AIBN (0.10 g, 0.6
mmol). Colorless oil solidifies on cooling;22 yield: 9.81 g (88%),
GC: 96%; mp 16–20 °C.
1
H NMR (CDCl3): d = 4.4 (m, 1 H, CHI), 3.8 (m, 2 H, CH2OH), 2.9
(m, 2 H, CH2CHI), 2.2 (br s, 1 H, CH2OH).
13
C NMR (CDCl3): d = 22.0 (C2), 37.8 (t, C3), 68.3 (C1).
19
F NMR (CDCl3): d = –72.4 (m, 6 F), –114.0 (td, 2 F), –115.7 (m,
2 F), –121.2 (m, 2 F), –123.6 (m, 2 F), –186.7 (m, 1 F).
2-Iodo-3-(perfluorooctyl)propan-1-ol (3d)
The reaction was performed according to the general procedure us-
ing 1d (545 g, 267 mL, 1 mol). Pale-yellow solid; yield: 592 g
(98%), GC: 94.2%; mp 91–92 °C. Recrystallization (benzene) gave
white crystals, GC: 98%, mp 93–94 °C (Lit.16b 93–94 °C). The
spectroscopic data were in agreement with those reported by Gam-
baretto et al.16d
2-Iodo-3-(perfluoro-7-methyloctyl)propan-1-ol (3e)
The reaction was performed according to the general procedure us-
ing 1e (50 g, 83.9 mmol) and K2S2O5 (5.8 g, 26 mmol) in H2O (35
mL) with 2 (7.3 g, 8.8 mL, 126 mmol) and AIBN (0.42 g, 0.25
mmol). Yield: 53.6 g (98%); GC: 96.2%. Recrystallization (ben-
zene) gave white crystals (43.2 g, 84%); GC: 99%; mp 69–70 °C.
1
H NMR (CDCl3): d = 4.4 (m, 1 H, CHI), 3.8 (m, 2 H, CH2OH), 2.9
(m, 2 H, CH2CHI), 2.3 (br s, 1 H, CH2OH).
13
C NMR (CDCl3): d = 22.1 (C2), 37.8 (t, C3), 68.2 (C1).
19
F NMR (CDCl3): d = –72.5 (m, 6 F), –114.0 (td, 2 F), –115.7 (m,
2 F), –121.3 (m, 2 F), –122.2 (m, 4 F), –124.1 (m, 2 F), –186.7 (m,
1 F).
2-Iodo-(3-perfluorodecyl)propan-1-ol (3f)
The reaction was started according to the general procedure using
1f (32.3 g, 50 mmol) and K2S2O5 (3.5 g, 16 mmol) in H2O (10 mL)
with 2 (5.2 mL, 75 mmol) and AIBN (0.25 g, 1.5 mmol). When the
addition of 2 was completed the mixture became a solid mass (GC:
1f ~36%). After 3 h stirring at 80 °C more AIBN (0.25 g) was added
and kept at 80 °C for 2 h (GC: 1f ~20%). More AIBN (0.25 g) dis-
solved in 2 (2.6 mL, 38 mmol) was added and kept at 80 °C for 3 h
(GC: 1f ~2%). Finally, it was heated to 100 °C and stirred for 15
min (GC: 1f £1%); then worked up. Yield: 33.1 g (94%), GC: 96%;
mp 123–125 °C (isooctane).
1
H NMR (acetone-d6): d = 4.77 (br s, OH, 1 H), 2.85 (2 m, 2 H, RF-
CH2), 3.85 (d m, 2 H, CH2OH), 4.35 (m, 1 H, CHI).
13
C NMR (acetone-d6): d = 19.9 (C2), 37.5 (t, C3), 68.6 (C1).
19
F NMR (acetone-d6): d = 93.5 (m, 3 F), 61.1 (q, 2 F), 52.9 (m, 10
F), 51.9 (m, 2 F), 51.0 (m, 2 F), 48.4 (m, 2 F).
3-(Perfluorohexyl)propan-1-ol (4b); Typical Procedure
To a 4-L, 3-necked flask, fitted with stirrer, reflux condenser, pres-
sure-equalizing dropping funnel, thermometer and argon bypass,
was added MeOH (750 mL), in a flow of argon a suspension of
Raney Ni (48 g) in MeOH (200 mL), 3b (504 g, 1.00 mol), and
MeOH (450 mL). The mixture was cooled with an ice-water bath to
keep the internal temperature below 10 °C during the addition (3 h)
of a soln of hydrazine hydrate (121 g, 2.41 mol) in MeOH (300 mL).
The mixture was stirred at r.t. for 1.5 h for complete conversion of
3b (GC monitoring). Next, the mixture was filtered through a Celite
pad under an argon flow, the used Raney Ni catalyst quenched with
H2O, while the filtrate was diluted with ice-water (6 L). The crude
product was completely settled out standing overnight as a lower
oily phase from the clear upper aqueous layer. They were separated,
and the H2O phase was saved for Et2O extraction if needed, until
workup finished. The fluorous layer was taken up in some Et2O,
washed with H2O (3 × 50 mL), and dried (Na2SO4). After filtration,
the solvent was evaporated and the crude oil was purified by vacu-
um distillation to give the product as a colorless oil; yield: 311 g
(82%); GC: 99.0%; bp 84–86 °C/26.7 mbar (as reported, Lit.23).
The spectroscopic data were in agreement with a sample prepared
previously in this laboratory.16c
3-(Perfluorobutyl)propan-1-ol (4a)
The reaction was performed according to the typical procedure us-
ing 3a (50 g, 124 mmol). Yield: 28.2 g (82%), collected under argon
as colorless oil, GC: 98%; bp 64 °C/26.7 mbar (as reported, Lit.23).
1
H NMR (CDCl3): d = 1.80–1.91 (m, 2 H, 2 H2), 2.09–2.31 (m, 2
H, 2 H3), 2.51 (br s, OH), 3.72 (t, 3JHH = 6.2 Hz, 2 H, 2 H1).
13
C NMR (CDCl3): d = 23.5 (C2), 27.7 (t, C3), 61.5 (C1).
19
F NMR (CDCl3): d = –81.9 (m, 3 F), –115.4 (m, 2 F), –125.2 (m,
2 F), –126.9 (m, 2 F).
3-(Perfluoro-5-methylhexyl)propan-1-ol (4c)
The reaction was performed according to the typical procedure us-
ing 3c (8.46 g, 15.3 mmol) to give the product as a colorless oil;
yield: 4.25 g (65%); GC: 96.5%. Short-path distilled at 26.7 mbar/
145–150 °C (bath temperature).
1
H NMR (CDCl3): d = 1.80–1.95 (m, 2 H, 2 H2), 2.08 (s, OH), 2.09–
2.32 (m, 2 H, 2 H3), 3.73 (t, 3JHH = 5.7Hz, 2 H, 2 H1).
13
C NMR (CDCl3): d = 23.7 (C2), 27.9 (t, C3), 61.7 (C1).
19
F NMR (CDCl3): d = –72.6 (m, 6 F), –115.0 (td, 2 F), –115.7 (m,
2 F), –121.3 (m, 2 F), –123.7 (m, 2 F), –186.7 (m, 1 F).
3-(Perfluorooctyl)propan-1-ol (4d)
The reaction was performed according to the typical procedure us-
ing 3d (500 g, 828 mmol) giving the product as a colorless melt or
white solid; yield: 310 g (78%); GC: 99.1%; bp 82–83 °C/0.13
mbar; mp 42 °C (as reported, Lit.23). The spectroscopic data were in
agreement with a sample prepared previously in this laboratory.16c
3-(Perfluoro-7-methyloctyl)propan-1-ol (4e)
The reaction was performed according to the typical procedure us-
ing 3d (42 g, 64 mmol) giving the product as a white solid; yield: 32
g (95%); GC: 97.4%; mp 42–43 °C.
1
H NMR (CDCl3): d = 1.80–1.92 (m, 2 H, 2 H2), 2.09–2.32 (m, 2
H, 2 H3), 3.74 (t, 3JHH = 6.2 Hz, 2 H, 2 H1).
13
C NMR (CDCl3): d = 23.5 (C2), 27.7 (t, C3), 61.5 (C1).
19
F NMR (CDCl3): d = –72.6 (m, 6 F), –115.0 (td, 2 F), –115.7 (m,
2 F), –121.4 (m, 2 F), –122.2 (m, 4 F), –124.1 (m, 2 F), –186.7 (m,
1 F).
3-(Perfluorodecyl)propan-1-ol (4f)
The reaction was performed according to the typical procedure un-
der an argon flow; using a mixture of iodohydrin 3f (200 g, 284
mmol), THF (430 mL), and Raney Ni (14 g, 0.24 g-atom) in MeOH
(85 mL), and hydrazine hydrate (34 g, 685 mmol) in MeOH (85 mL)
at 10 °C for 2 h and at 20 °C for 18 h. 12 M HCl (68 mL), H2O (500
mL) and Et2O (250 mL) were added consecutively to the stirred
mixture over 30 min. Then it was filtered on Celite and the clear fil-
trate was separated to organic and aqueous layers. The aqueous
phase was extracted with Et2O (2 × 200 mL) and added to the or-
ganic layer. The combined extracts were washed with H2O (3 × 500
mL) and dried (Na2SO4). After filtration, the solvent was evaporat-
ed and the crude melt was purified by vacuum distillation to give a
colorless melt or white solid; yield: 106 g (80%); GC: 98.1%; bp
110 °C/0.13 mbar; mp 86–89 °C (as reported, Lit.23). The spectro-
scopic data were in agreement with a sample prepared previously in
this laboratory.16c
Synthesis 2007, No. 1, 1–4 © Thieme Stuttgart · New York
4 J. Rábai et al.
Acknowledgment
We thank the Hungarian Scientific Research Foundation (OTKA
K62191, T34871) and the European Contract of Research Training
Network (‘Fluorous Phase’ HPRN-CT-2000-00002) for support.
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(12) Moore, L. D. J. Chem. Eng. Data 1964, 9, 251; and
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Brandstadter, S. M.; Chien, J.; Cohn, M.; Edwards, B. E.;
Hedrick, V.; Jackson, A.; Leman, G.; Ameduri, B.; Kostov,
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213355.
(16) (a) Metzger, J. O.; Mahler, R.; Schmidt, A. Liebigs Ann.
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(17) For replacement of toxic organotin hydrides and/or removal
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1998, 37, 3072; Angew. Chem. 1998, 110, 3272. (b) Studer,
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borate/Bu3SnH protocol, see: (c) Rábai, J.; Kövesi, I.;
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(c) Ukihashi, K.; Hayashi, T. JP 7,022,523, 1970; Chem.
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(21) Lahiouhel, D.; Ameduri, B.; Boutevin, B. J. Fluorine Chem.
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(22) For an analogous synthesis of 3c with bp 88–90 °C/1.7–2.0
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PRACTICAL SYNTHETIC PROCEDURES3-(Perfluoroalkyl)propanols: Valuable Building Blocks for Fluorous Chemistry 5

I
RFI RF OH RF OH
83–98% 65–95%

RF = CnF2n+1, n = 4, 6–10

graphical abstract

Synthesis 2007, No. 1, 1–4 © Thieme Stuttgart · New York