Fluorous tin hydrides: A new family of reagents for use and reuse in radical reactions

Article abstract of DOI:10.1021/ja990069a

Eight members of a new family of highly fluorinated (fluorous) tin hydrides have been synthesized and studied as reagents for radical reactions. Tin hydrides of the general formulas [Rf(CH₂)_n]₃SnH and [Rf-(CH₂)<

Full text of DOI:10.1021/ja990069a

J. Am. Chem. Soc. 1999, 121, 6607-6615
6607
Fluorous Tin Hydrides: A New Family of Reagents for Use and
Reuse in Radical Reactions
Dennis P. Curran,* Sabine Hadida, Sun-Young Kim, and Zhiyong Luo
Contribution from the Department of Chemistry and Center for Combinatorial Chemistry,
UniVersity of Pittsburgh, Pittsburgh, PennsylVania, 15260
ReceiVed January 7, 1999. ReVised Manuscript ReceiVed April 22, 1999
Abstract: Eight members of a new family of highly fluorinated (fluorous) tin hydrides have been synthesized
and studied as reagents for radical reactions. Tin hydrides of the general formulas [Rf(CH2)n]3SnH and [Rf-
(CH2)n]Me2SnH have been prepared where Rf is C4F9, C6F13, C8F17, or C10F21 and n is 2 or 3. These reagents
are highly soluble in fluorinated solvents, and partition coefficients between perfluorohexanes and several
organic solvents have been measured. The reagents are generally useful for reductive radical reactions and
hydrostannation reactions that would typically be conducted with tributyltin hydride. Stoichiometric and catalytic
procedures have been developed, and both feature very easy separation of the tin products from the organic
products by convenient liquid-liquid or solid-liquid extractions. The tin reagents are recovered from reactions
in high yields and are routinely reused. Rate constant measurements suggest that the fluorous tin hydrides are
about as reactive as (or in some cases, slightly more reactive than) tributyltin hydride. The reagents show
excellent potential for large-scale application in “green” (environmentally friendly) processes. In addition,
they are useful for combinatorial and parallel synthesis applications both as reagents and as scavengers in
phase-switching procedures.
Introduction
been introduced with the goal of facilitating separation or
reducing toxicity.5 In the field of radical hydrogen transfer
reactions, these include water-6 and acid-soluble tin hydrides,7
and polymer-bound tin hydrides.8 However, most of these
reagents are rarely used, and only tris-trimethylsilylsilicon
hydride (Chatgilialoglu’s reagent) has emerged as a popular
alternative to tributyltin hydride.9
The organic chemistry of tin is featured in a diverse
assortment of important reactions and is therefore central to the
discipline of organic synthesis.1 Nowhere is this truer than in
radical chemistry, where trialkyltin hydrides, especially tribu-
tyltin hydride, hold a privileged role as reagents for reductive
radical reactions.2 The privileged role of trialkyltin reagents
persists in radical chemistry and elsewhere despite the broadly
acknowledged problems of separation, toxicity, and disposal that
many tin reagents present.1 In tin hydride radical chemistry,
these problems can be reduced though not eliminated by using
increasingly popular catalytic procedures.2,3 However, in other
areas of radical chemistry and in organometallic chemistry
stoichiometric quantities of tin components are often de rigour.
The vexing purification problems have been addressed in two
ways. First, an assortment of workup procedures has been
devised with the goal of removing trialkytin products from
reaction mixtures.4 Unfortunately, most workup methods provide
only for the separation of tin and not for its recovery in a useful
form. Second, a number of alternative classes of reagents have
(4) Representative references: (a) Curran, D. P.; Chang, C.-T. J. Org.
Chem. 1989, 54, 3140. (b) Crich, D.; Sun, S. X. J. Org. Chem. 1996, 61,
7200. (c) Merge, J. M.; Roberts, S. M. Synthesis 1979, 471.
(5) Walton, J. C. Acc. Chem. Res. 1998, 31, 99.
(6) (a) Light, J.; Breslow, R. Tetrahedron Lett. 1990, 31, 2957. (b) Rai,
R.; Collum, D. B. Tetrahedron Lett. 1994, 35, 6221.
(7) (a) Vedejs, E.; Duncan, S. M.; Haight, A. R. J. Org. Chem. 1993,
58, 3046. (b) Clive, D. L. J.; Wang, W. J. Org. Chem. 1995, 60, 2607.
(8) (a) Neumann, W. P.; Peterseim, M. React. Polym. 1993, 20, 189. (b)
Junggebauer, J.; Neumann, W. P. Tetrahedron 1997, 53, 1301. (c) Ruel,
G.; The, N. K.; Dumartin, G.; Delmond, B.; Pereyre, M. J. Organomet.
Chem. 1993, 444, C18.
(9) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188.
(10) (a) Hudlicky, M. Chemistry of Organic Fluorine Compounds, 2nd
ed.; Ellis-Horwood: New York, 1992; p 903. (b) Banks, R. E., Smart, B.
E., Tatlow, J. C., Eds. Organic Fluorine Chemistry: Principles and
Applications, Plenum: New York, 1994; p 644. (c) Zhu, D.-W. Synthesis
1993, 953.
(1) (a) Pereyre, M.; Quitnard, J.-P.; Rahm A. Tin in Organic Synthesis,
Butterworth: London, U.K., 1987; p 342. (b) Davies, A. G. Organotin
Chemistry; VCH: Weinheim, Germany, 1997; p 327. (c) Smith, P. J., Ed.
Chemistry of Tin, 2nd ed.; Blackie: London, U.K., 1997; p 578.
(11) Curran, D. P. Chemtracts: Org. Chem. 1996, 9, 75. This paper
contains a brief overview of the physical and chemical properties of
fluorinated liquids (fluorous solvents) as related to organic synthesis.
(12) (a) Vogt, M. Ph.D. Thesis, University of Aachen, 1991. We thank
Dr. B. Cornils for a copy of this thesis. (b) Klien, W.; Vogt, M.;
Wasserscheid, P.; Driessan-Holscher, B. J. Mol. Catal. 1999, 139, 171.
(13) (a) Horva´th, I. T.; Ra´bai, J. Science 1994, 266, 72. (b) Juliette, J. J.
J.; Horva´th, I. T.; Gladysz, J. A. Angew. Chem., Int. Ed. Engl. 1997, 36,
1610. (c) Guillevic, M. A.; Arif, A. M.; Horva´th, I. T.; Gladysz, J. A. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1612. (d) Li, C. B.; Nolan, S. P.; Horva´th,
I. T. Organometallics 1998, 17, 452. (e) Guillevic, M. A.; Rocaboy, C.;
Arif, A. M.; Horva´th, I. T.; Gladysz, J. A. Organometallics 1998, 17, 707.
(f) Horva´th, I. T.; Kiss, G.; Cook, R. A.; Bond, J. E.; Stevens, P. A.; Ra´bai,
J.; Mozeleski, E. J. J. Am. Chem. Soc. 1998, 120, 3133. (g) Herrera, V.;
deRege, P. J. F.; Horva´th, I. T.; LeHusebo, T.; Hughes, R. P. Inorg. Chem.
Commun. 1998, 1, 197. (h) Kainz, S.; Koch, D.; Baumann, W.; Leitner,
W. Angew. Chem., Int. Ed. Engl. 1997, 36, 1628.
(2) (a) Kuivila, H. G. Acc. Chem. Res. 1968, 1, 299. (b) Giese, B.
Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds;
Pergamon: Oxford, U.K., 1986. (c) Neumann, W. P. Synthesis 1987, 665.
(d) Curran, D. P. Synthesis 1988, 417. (e) Curran, D. P. Synthesis 1988,
479. (f) Curran, D. P. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Ed.; Pergamon: Oxford, U.K., 1991; Vol. 4, p 715. (g) Curran,
D. P. Ibid.; Vol. 4, p 779. (h) Motherwell, W.; Crich, D. Free Radical
Chain Reactions in Organic Synthesis, Academic Press: London, U.K.,
1992; p 259. (i) Rajanbabu, T. V. In Encyclopedia of Reagents for Organic
Synthesis, Paquette, L., Ed.; Wiley: New York, 1995; Vol. 7, p 5016.
(3) (a) Hays, D. S.; Fu, G. C. J. Org. Chem. 1998, 63, 2796. (b) Lopez,
R. M.; Hays, D. S.; Fu, G. C. J. Am. Chem. Soc. 1997, 119, 6949. (c)
Hays, D. S.; Scholl, M.; Fu, G. C. J. Org. Chem. 1996, 61, 6751.
10.1021/ja990069a CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/02/1999

6608 J. Am. Chem. Soc., Vol. 121, No. 28, 1999
Curran et al.
named as a substituent on the perhydrogenated chain. This
aggregated study provides some of the first detailed information
on how the nature and composition of fluorous chains affects
the reactivity and solubility of fluorous reagents.13b,c,f
Results and Discussion
tris(2-Perfluorohexylethyl)tin Hydride. We developed sev-
eral different routes to the initial tin hydride reagent 1a, and
details of these are provided in the Supporting Information.
Equation 1 shows the preferred route to the tin hydride 1a
Figure 1. Fluorous tin hydrides.
(1)
Fluorocarbon liquids are extremely poor solvents for organic
compounds,10,11 and the technique of “fluorous biphasic
catalysis” 12-14 takes advantage of this property to immobilize
a catalyst in a fluorous phase and allow simple reaction and
separation. Starting in 1996, we have published a series of
papers15-17 that has extended and generalized the concept of
the fluorous phase as a strategic alternative to the other
commonly used phases in organic synthesis: the gas phase, the
water phase, the organic liquid phase, and the solid phase. These
simple concepts of fluorous synthesis, phase planning, phase
switching, etc., which apply to both traditional and parallel
(combinatorial) synthesis, have been outlined elsewhere,11,18 and
they will be used here as relevant without extensive reiteration.
This full paper provides complete details of our study of a
new class of fluorous tin hydrides. The work described was
our initial foray into the fluorous field, and it set both the
conceptual and experimental tone for subsequent new directions
both in and beyond tin chemistry. The family of fluorous tin
hydrides described in this work is summarized by structures 1
and 2 (Figure 1). Reagents consist of a tin hydride separated
from a longer perfluorinated chain by a shorter “perhydroge-
nated” spacer. We use the abbreviation “Rfh” to represent such
partially fluorinated/partially hydrogenated chains,11 and the
numbers x and y in “Rfxhy” represent the number of perfluori-
nated and perhydrogenated carbon atoms, respectively. In
naming the compounds, we typically use the convenient, if
unofficial, nomenclature where the perfluoroalkyl chain is
through tin bromide 5a that has been optimized over time and
now can be routinely executed in excellent yield. Grignard
reagent 3a was reacted with phenyl trichlorotin to provide
fluorous phenyl tin compound 4a in 86% isolated yield after
rapid chromatography (or distillation) to free it from small
amounts of the Wurtz coupled dimer (not shown) resulting from
the Grignard reagent. This was then treated with bromine to
provide the crude (but very pure) bromide 5a, which was in
turn directly treated with LiAlH4 in ether. Standard workup and
purification by vacuum distillation provided the tin hydride 1a
in 93-98% yield. Overall yields on a 20-40 g scale range from
80% to 83% for the three steps. The intermediates 4a and 5a
are important compounds in their own right; phenyl tin
compound 4a has been used in fluorous Stille couplings,16a,b,d
while tin bromide 5a is a precursor of an assortment of other
fluorous tin compounds.17
The fluorous tin hydride 1a has unusual properties when
compared to standard organotin compounds, but these properties
are representative of related fluorous tin compounds. Despite
its high molecular weight (1162), it is a crystal clear, free
flowing liquid with a boiling point of 115 °C at about 0.1
mmHg. Despite its vapor pressure, it lacks the unpleasant odor
of alkyltin compounds and indeed has no detectable smell at
all. It is freely soluble in fluorous solvents such as perfluoro-
hexane (FC-72) but sparingly soluble or insoluble in most
organic solvents.
(14) Overviews of FBC: (a) Cornils, B. Angew. Chem., Int. Ed. Engl.
1997, 36, 2057. (b) Horva´th, I. T. Acc. Chem. Res. 1998, 31, 641. (c)
Rutherford, D.; Juliette, J. J. J.; Rocaboy, C.; Horva´th, I. T.; Gladysz, J. A.
Catal. Today 1998, 42, 381.
Tin hydride 1a is sufficiently soluble in CDCl3 to record a
1H NMR spectrum. The tin hydride proton resonates at 5.27
ppm (compared to 4.80 ppm for tributyltin hydride), and two
2-proton multiplets with the expected mutiplicities (coupling
to H and F) are seen at 2.35 and 1.16 ppm. A pleasant harbinger
of things to come was observed when the NMR sample was
allowed to stand in the light overnight; the tin hydride was
converted into the corresponding tin chloride [(C6F13CH2CH2)3-
SnCl], presumably by radical chain reduction of the CDCl3. The
19F NMR spectrum of 1a is first-order and shows individual
resonances for the five difluoromethylene groups and the
trifluoromethyl group with the expected couplings. The unde-
coupled (or H-decoupled) 13C spectrum is less informative; the
two carbons of the ethylene spacer are clearly visible (coupled
to H and F), but the carbons bearing fluorine appear as a forest
of peaks between about 100 and 110 ppm due to coupling to
fluorine. Such spectra would best be recorded with 19F decou-
pling, but we do not currently have this capability. The 119Sn
NMR spectrum shows a single resonance at -84.5 ppm (1J
(15) Tin hydrides: (a) Curran, D. P.; Hadida, S. J. Am. Chem. Soc. 1996,
118, 2531. (b) Horner, J. H.; Martinez, F. N.; Newcomb, M.; Hadida, S.;
Curran, D. P. Tetrahedron Lett. 1997, 38, 2783. (c) Hadida, S.; Super, M.
S.; Beckman, E. J.; Curran, D. P. J. Am. Chem. Soc. 1997, 119, 7406. (d)
Ryu, I.; Niguma, T.; Minakata, S.; Komatsu, M.; Hadida, S.; Curran, D. P.
Tetrahedron Lett. 1997, 38, 7883.
(16) Other tin chemistry: (a) Curran, D. P.; Hoshino, M. J. Org. Chem.
1996, 61, 6480. (b) Larhed, M.; Hoshino, M.; Hadida, S.; Curran, D. P.;
Hallberg, A. J. Org. Chem. 1997, 62, 5583. (c) Curran, D. P.; Hadida, S.;
He, M. J. Org. Chem. 1997, 62, 6714. (d) Hoshino, M.; Degenkolb, P.;
Curran, D. P. J. Org. Chem. 1997, 62, 8341. (e) Spetseris, N.; Hadida, S.;
Curran, D. P.; Meyer, T. Y. Organometallics 1998, 17, 1458. (f) Curran,
D. P.; Luo, Z. Med. Chem. Res. 1998, 8, 261. (g) Curran, D. P.; Luo, Z.;
Degenkolb, P. Biorg. Med Chem. Lett. 1998, 8, 2403. (h) Ryu, I.; Niguma,
T.; Minakata, S.; Komatsu, M.; Luo, Z.; Curran, D. P. Tetrahedron Lett.,
in press.
(17) “Fluorous synthesis” techniques: (a) Studer, A.; Hadida, S.; Ferritto,
R.; Kim, S.-Y.; Jeger, P.; Wipf, P.; Curran, D. P. Science 1997, 275, 823.
(b) Studer, A.; Curran, D. P. Tetrahedron 1997, 53, 6681. (c) Studer, A.;
Jeger, P.; Wipf, P.; Curran, D. P. J. Org. Chem. 1997, 62, 2917. (d) Curran,
D. P.; Ferritto, R.; Hua, Y. Tetrahedron Lett. 1998, 39, 4937. (e) Takeuchi,
S.; Nakamura, Y.; Ohgo, Y.; Curran, D. P. Tetrahedron Lett. 1998, 39,
8691. (f) Linclau, B.; Singh, A.; Curran, D. P. J. Org. Chem., in press.
(18) Curran, D. P. Angew. Chem., Int. Ed. Engl. 1998, 37, 1175.

Fluorous Tin Hydrides
119Sn-H) ) 1835 Hz). The stretching frequency of the tin
J. Am. Chem. Soc., Vol. 121, No. 28, 1999 6609
(
trifluoromethylbenzene (C6H5CF3, benzotrifluoride, hereafter
abbreviated BTF). BTF is a very inexpensive compound
produced on ton scale per year by OxyChem under the trade
name Oxsol2000.20 We find BTF to be a good solvent for
organic reactions both in fluorous settings16-18 and in traditional
settings. 21
Mixing of adamantyl bromide 8, tin hydride 1a, and AIBN
in benzotrifluoride resulted in a homogeneous (to the naked eye)
reaction mixture even at room temperature (eq 3). This mixture
hydrogen bond in the IR is 1842 cm-1 (compared to 1812 for
Bu3SnH). The molecule is amenable to standard EIMS analysis;
it does not show a parent ion but shows important fragment
peaks at m/e 1161 (M+ - H) and 813 (M+ - CH2CH2C6F13).
Despite the success in reducing chloroform with 1a, we
initially had considerable difficulties conducting the simple
reduction of adamantyl bromide to adamantane. We attempted
reductions in organic solvents (like benzene, toluene, and tert-
butyl alcohol), in a fluorous solvent (perfluoromethylcyclohex-
ane, PFMC) a` la Zhu,10 and in biphasic solvent mixtures a` la
Horva´th and Ra´bai.13a In all cases, we observed very slow
conversion of adamantyl bromide to adamantane. It was
necessary to periodically add AIBN to prevent the painfully
slow reactions from stopping entirely. Some reactions were run
at 80 °C for as long as 3 days, but maximum conversions of
adamantyl bromide never exceeded 50%.
(3)
A number of observations suggested that the problem with
these reactions was phase separation. None of the reactions are
homogeneous to the naked eye; adamantyl bromide is not
soluble in perfluoromethylcyclohexane and tin hydride 1a is
not soluble in benzene, toluene, or tert-butyl alcohol. Consistent
with the analysis, better reduction results were obtained in
solvents such as hexane or THF that have some ability to
dissolve the fluorous tin hydride 1a. To confirm that the problem
was solubility, we conducted a “fully fluorous” reduction (eq
2). A solution of perfluorodecyliodide 6 (1 equiv), tin hydride
was heated for 3 h at 80 °C, at which time the peak for
adamantyl bromide 8 in the GC was consumed and a single
new peak was identified as adamantane 9 appeared. The reaction
was cooled, and the BTF was partially evaporated prior to
partitioning between dichloromethane (top) and PFMC. The
layers were separated, and the dichloromethane phase was
washed twice with PFMC. Evaporation of the dichloromethane
phase provided adamantane 9 in 90% yield (as determined by
1
GC). The H NMR spectrum of the product was essentially
(2)
indistinguishable from a commercial sample; no resonances for
methylene protons on a fluorous tin compound could be
detected. Combination of the PFMC phases and evaporation
provided the tin bromide 5a in 95% yield; the 1H NMR spectrum
of this sample was essentially indistinguishable from that made
by bromination of 4a (eq 1). This simple yet crucial experiment
established conditions for reaction and separation that over time
have proven generally useful. This procedure is hereafter called
the “stoichiometric procedure”. In later experiments, we rou-
tinely used perfluorohexane (FC-72) in place of the more
expensive perfluoromethylcyclohexane for the fluorous extrac-
tion solvent.
1a (1.2 equiv), and AIBN (5%) in PFMC was heated at 80 °C.
After 2 h, the peak for iodide 6 in the GC had disappeared and
was replaced by that of 1(H)-perfluorodecane 7, which was
isolated in 73% yield after evaporation of the solvent and flash
chromatography.
Two important implications derive from this simple experi-
ment. First, the success of this homogeneous reduction supports
the suggestion that the poor results in the reduction of adamantyl
bromide can be attributed to phase separation. Due to the
insolubility of the fluorous and organic solvents and reaction
components, there simply is not a high enough concentration
of all needed components in any one phase for the radical chain
to propagate; in essence, termination competes effectively with
propagation and chains are not maintained. The second implica-
tion is that tin hydride 1a and related compounds should be
useful reagents in the branch of organofluorine chemistry that
deals with highly fluorinated compounds. These are often
insoluble or sparingly soluble in organic solvents, but they can
now be reduced in fluorinated solvents with tin hydride 1a.
This series of preliminary experiments pointed to the need
for a reaction solvent that would substantially or completely
dissolve both the fluorous tin hydride 1a and typical organic
compounds. One approach to address the reaction solvent
problem is to use miscible combinations of fluorous and organic
solvents.10,14 However, fluorous solvents are extraordinarily
nonpolar and are poor solvents for organic compounds.19 It
follows that blends of fluorous and organic solvents might not
have the general dissolving capability to be broadly useful in
synthesis. We instead adopted a complementary solution. This
involves the use of a lightly fluorinated organic solvent like
We then surveyed the reduction of a number of different types
of compounds with tin hydride 1a. Additional halides will be
shown below. Reductions of several phenyl selenides, 3°-nitro
compounds, and 2°-xanthates are shown in Figure 2. These were
reduced by the standard procedure to the corresponding products
in the indicated isolated yields after flash chromatography.
1
Importantly, the crude H NMR spectra of the crude organic
fractions never showed resonances that could be attributed to
fluorous products. Thus, in all cases, the liquid-liquid extractive
workup served its purpose admirably.
While the “stoichiometric procedure” is practical and effective
for small-scale work, it will not win any awards for atom
economy;22 tin hydride 1a (MW >1100) is used to deliver a
hydrogen atom (MW ) 1). We therefore developed a catalytic
procedure fashioned after the popular procedure of Stork and
Sher.23 This procedure features a three-phase extraction in the
(20) “Introducing OXSOL2000” Oxychem Specialty Business Group No.
BCG-OX-37, 5/96. Available from Occidental Chemical Corporation. See
also Material Safety Data Sheet (MSDS) M35459.
(21) (a) Ogawa, A.; Curran, D. P. J. Org. Chem. 1997, 62, 450. (b) Maul,
J. P.; Ostrowski, P.; Ublacker, G. A.; Curran, D. P.; Linclau, B. In Modern
Organic SolVents; Knochel, P., Ed.; in press.
(22) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259.
(23) Stork, G.; Sher, P. M. J. Am. Chem. Soc. 1986, 108, 303.
(19) (a) Reichardt, C. SolVents and SolVent Effects in Organic Chemistry;
VCH: Weinheim, Germany, 1988. (b) Reichardt, C. Chem. ReV. 1994, 94,
2319.

6610 J. Am. Chem. Soc., Vol. 121, No. 28, 1999
Curran et al.
(5)
gave diphenylmethylcyclopentane 11a in 72% yield after three-
phase extractive workup and purification by flash chromatog-
raphy, while reductive cyclization of 6-bromo-1-cyano-1-hexene
10b provided cyanomethylcyclopentane 11b in 52% isolated
yield. The isolated yields are comparable to those reported by
Newcomb for tributyltin hydride.24 These results strongly
suggest that a standard radical chain mechanism is operating.
Information on the rate constant for reduction of radicals by 1a
will be presented below along with the rate data of the other
tin hydrides.
Figure 2. Isolated yields and reaction times of reductions by the
“stoichiometric procedure”.
The catalytic procedure can also be used to conduct inter-
molecular reactions, as shown by the series of Giese reactions
in eq 6. These nine experiments (3 halides 12 with 3 alkenes
workup (eq 4). Under the standard “catalytic procedure”,
(4)
(6)
adamantyl bromide was heated at 80 °C in a 1/1 mixture of
benzotrifluoride and tert-butyl alcohol with 10% tin hydride 1a,
1.3 equiv sodium cyanoborohydride (NaCNBH3), and AIBN.
tert-Butyl alcohol is required to aid in the gradual dissolution
of the NaCNBH3. After being heated for 3 h, the mixture was
cooled, concentrated, and partitioned in a three-phase liquid
extraction between water (top), dichloromethane (middle), and
PFMC (bottom). The aqueous phase containing the borohydride
salts was discarded, while the organic and fluorous phases were
evaporated and analyzed. The only detectable product in the
organic phase was adamantane (92% isolated yield). We
estimate detection limits in these experiments on the order of
1%. The tin hydride was recovered from the fluorous phase in
13) were designed to show the useful features of fluorous
reagents for solution phase combinatorial chemistry17,18 and were
conducted in parallel in nine test tubes. After the reaction and
three-phase extractive workup, the organic phase remaining in
the test tube was evaporated to dryness and analyzed. Yields
1
of the nine products 14 in eq 6 were determined by H NMR
spectroscopy against a standard, and purities were all >95%
according to GC analysis. All products 14 were substantially
1
1
free of fluorous compounds as determined by H NMR and
97% yield, and its H NMR spectrum was clean and free of
weighing (due to its high weight, a fluorous tin impurity is
readily detected when the weight yield exceeds the NMR yield).
The whole experiment was reproduced a second time with
similar results. This time 19F NMR spectra of all nine organic
products were also recorded; no spectrum showed any reso-
nance.
In addition to providing added information on the scope of
the tin hydride reagent 1a, this parallel experiment is a simple
example of the power of phase planning.18 The reagents are
chosen and the conditions are designed such that the starting
iodide 12 is completely converted to the reductive addition
product 14 and such that the reductive addition product is the
only product left in the organic liquid phase after workup. The
tin hydride 1a is removed in the fluorous phase (all nine fluorous
products were combined without analysis and saved for later
reuse), the inorganic salts are in the water phase, and the excess
alkene 13 (which is required for a high yield of 14) is removed
by evaporation. From the perspective of library synthesis, the
adamantane resonances.
We conducted a number of experiments to assess the
robustness of this procedure with regard to efficient use of the
tin. We first repeated the reduction of adamantyl bromide under
the standard catalytic procedure and then recovered the tin
hydride and (without analysis or purification) repeated the
reduction of a fresh sample of adamantyl bromide. The tin
hydride was reused five times in this way for a total of six
reductions with the same sample of tin (1.6 mol % tin per
reduction). In each reduction, the yield of adamantane was
essentially quantitative (peak-to-peak conversion in the GC).
Although the purity of the recovered tin fraction was not
analyzed, its weight indicated >95% recovery at each stage.
The first four reactions were completed in 3 h while the last
two took 5 h, suggesting that some degradation of the tin hydride
might be occurring. We also conducted a reduction using 1%
tin hydride, and this provided pure adamantane in 95% yield.
The ability to use 1-10% tin catalyst and to recover the catalyst
is attractive for preparative applications.
(24) (a) Park, S.-U.; Chung, S.-K.; Newcomb, M. J. Am. Chem. Soc.
1986, 108, 240. (b) Newcomb, M.; Varick, T. R.; Ha, C.; Manek, M. B.;
Yue, X. J. Am. Chem. Soc. 1992, 114, 8158. (c) Ha, C.; Horner, J. H.;
Newcomb, M.; Varick, T. R.; Arnold, B. R.; Lusztyk, J. J. Org. Chem.
1993, 58, 1194.
We also conducted a number of preparative reactions where
cyclization products were expected. Reductive cyclization of
6-bromo-1,1-diphenyl-1-hexene 10a (eq 5, catalytic procedure)

Fluorous Tin Hydrides
J. Am. Chem. Soc., Vol. 121, No. 28, 1999 6611
removal of an excess reactant by evaporation is a liability since
it limits the number of reactants that can be input to make a
library. However, excess nonvolatile alkene can be removed
by fluorous switching, as shown below.
(9)
In addition to the reductive removal of functional groups,
the other characteristic radical reaction of tin hydrides is
hydrostannation of multiple bonds.2 To assess this reaction, we
studied the radical addition of fluorous tin hydride 1a to a
number of alkenes and alkynes. Although test reactions with
1a proceeded smoothly in neat conditions, we elected to use a
minimum amount of BTF to ensure homogeneous reaction
mixtures. The reactions shown in eq 7 were carried out by
to yield mixtures of three products (R, cis-â, and trans-â, 25:
45:30 and 5:45:50). In our case, no product coming from the
addition of tin hydride 1a in a trans-â fashion was observed in
1
the crude H NMR spectrum of the reaction mixture.
The addition of fluorous tin hydride 1a to phenyl acetylene
20 was conducted at 25 °C with triethylborane initiation (eq
10).26 The (E) alkene 21 was isolated in 57% yield as the only
(7)
(10)
product of the reaction. The differences in E/Z selectivity in
eqs 9 and 10 and literature results may be due to reversible
additions27 of tin radicals to the products; unactivated alkyne
18 provides the kinetic Z product while activated alkyne 20
provides the equilibrated E product. However, the relative extent
of kinetic and thermodynamic control in these reactions remains
to be elucidated.
That all of the products of these reactions partition into the
fluorous phase preferentially suggests that the hydrostannation
reaction can be used as a means to remove excess alkenes from
reaction mixtures. We used this reaction to introduce the
technique of “fluorous quenching”17a,18 whereby a residual
undesired organic reaction component at the end of a reaction
is switched to the fluorous phase to allow its removal during
workup. We first demonstrated this potential in Giese reactions
such as those shown in eq 6, but now we use nonvolatile radical
acceptors. In two experiments, adamantyl iodide was reductively
added to an excess of benzyl acrylate and styrene with tin
hydride 1a under the standard catalytic conditions (eq 11). After
heating a mixture of the alkene 15a,b, 1.5 equiv of fluorous tin
hydride 1a, and a catalytic amount of AIBN in 0.1 mL of BTF
at 80 °C for 8 h. The solvent was evaporated, and the residue
was partitioned between FC-72 and CH2Cl2. The hydrostanna-
tion products partitioned into the fluorous phase, and after
evaporation of the FC-72, the residue was purified from excess
tin hydride by column chromatography. This provided the
tetraalkytin compounds 16a,b in good to excellent yields (eq
7).
We also studied the hydrostannation of several alkynes. In
the case of activated alkynes such as diethyl acetylenedicar-
boxylate, the reaction was carried out with 1.5 equiv of 1a in
BTF solution at 50 °C for 8 h. The fluorous product 17 was
isolated as a single (Z) isomer in 73% yield from the fluorous
phase after fluorous/organic extraction and column chromatog-
raphy (eq 8).
(11)
three-phase extractive workup, 1H NMR spectra of the residue
from the organic phase showed that the major component of
the mixture was unreacted styrene or benzyl acrylate and the
minor component was the Giese adduct (as expected from the
stoichiometry of the reaction). A similarly generated mixture
was subjected to the hydrostannation with excess tin hydride
1a followed by FC-72/dichloromethane extraction. From the
organic phase we isolated the adducts 14a in 82% (R ) CO2-
Bn) and 67% (R ) Ph) yield, free from the starting alkene (as
(8)
In the case of propargyl alcohol 18, the best results were
obtained when the reaction mixture was heated at 100 °C for 8
h (eq 9). Two products were isolated from the reaction; a minor
product 19b, derived from R-addition of the triple bond, was
isolated in 19% yield and a major one, 19a, from cis-â addition,
was isolated in 36% yield. The addition of triethyl- and
triphenyltin hydride to propargyl alcohol has been reported25
1
assessed by H NMR). Of course, the fluorous product from
(26) Nozaki, K.; Oshima, K.; Utimoto, K. Tetrahedron 1989, 45, 923.
(27) (a) Ferreri, C.; Ballestri, M.; Chatgilialoglu, C. Tetrahedron Lett.
1993, 34, 5147. (b) Chatgilialoglu, C.; Ballestri, M.; Ferreri, C.; Vecchi,
D. J. Org. Chem. 1995, 60, 3826.
(25) Leusink, A. J.; Budding, H. A.; Marsman, J. W. J. Organomet.
Chem. 1967, 9, 285.

6612 J. Am. Chem. Soc., Vol. 121, No. 28, 1999
Table 1. Partition Coefficients of Tin Hydrides
Curran et al.
We conducted a series of experiments to compare the
spectroscopic, solubility, and reactivity properties of these new
reagents. Information about partition coefficients is contained
in Table 1. Partition coefficients were estimated in two pairs of
solvents: FC-72/CH3CN and FC-72/C6H6. In these experiments,
0.5-1.0 g of fluorous tin hydride was partitioned between 10
mL of FC-72 and 10 mL of acetonitrile or benzene. The biphasic
mixture was stirred vigorously for 10 min. The two layers were
separated and evaporated to dryness, and the residue was
weighed. Also listed in Table 1 are two crude measures of the
“fluorousness” of a molecule: the ratio of fluorines to hydrogens
(F/H) and the percent fluorine by molecular weight.
Compound 1c bearing 63 fluorines proved, not surprisingly,
to be highly insoluble in organic solvents. But it was also only
sparingly soluble in BTF and FC-72, and we therefore did not
attempt to measure a partition coefficient. We presume that this
is very high because the denominator (organic solubility) is close
to zero. However, the partition coefficient does not tell the whole
story, as attempted reductions with 1c were largely unsuccessful,
presumably due to its insolubility. In effect, 1c is on the
borderline between a fluorous tin hydride and a “Teflon-bound”
tin hydride. At the other extreme is tributyltin hydride, which
is essentially insoluble in FC-72.
tin hydride
Bu3SnH
1a (Rf6h2)3SnH
1b (Rf4h2)3SnH
1c (Rf10h2)3SnH
1d (Rf6h3)3SnH
1e (Rf4h3)3SnH
2a (Rf6h2)SnMe2H 0.87
2b (Rf8h2)SnMe2H 1.13
2d (Rf10h2)SnMe2H 1.40
F/Ha % Fb FC-72/CH3CN FC-72/C6H6
na
0
64
60
68
62
57
50
54
57
<1/150
160/1
5.8/1
highc
6.4/1
2.3/1
2.4/1
14/1
<1/350
45/1
3.25
2.25
5.25
2.17
1.50
10.5/1
highc
10.0/1
1.2/1
0.7/1
2.5/1
4.7/1
48/1
a Ratio of fluorines to hydrogens. b Percent fluorine by molecular
weight. c Due to low solubility, the partition coefficient measurements
are not reliable.
this reaction cannot be reused directly because it contains a
mixture of tin hydride 1a and hydrostannated products 16.
We also conducted the standard Diels-Alder and nitrile oxide
cycloaddition reactions shown in eq 12 by using excess alkene.
The original tin hydride 1a is also quite fluorous as measured
by partition coefficients, and two or three washes of an organic
solvent with FC-72 are sufficient to remove >99% of this
compound, as shown by the experimental results above.
Shortening of the fluorocarbon tag by two CF2 groups leads to
considerably decreased, but still substantial, coefficients favoring
partitioning of 1b into the fluorous phase. The propylene spacer
reagent 1d bearing C6F13 is also considerably “less fluorous”
than its ethylene spacer analogue. Propylene-spaced reagent 1e
with C4F9 group splits between the organic and fluorous solvents
but still with a preference for the fluorous phase.
With this limited data, it is too early to analyze in detail the
partition coefficient trends as a function of the fluorous chains;
however, one obvious trend that emerges from Table 1 does
appear to be significant: subtraction of two CF2 groups or
insertion of one CH2 group from the basic reagent 1a leads to
an analogue with significantly reduced partition coefficients.
While we have not measured absolute solubilities, it is clear
from the preparative results (see below) that this change in
partition coefficient must be due in large measure to increased
solubility in the organic solvents. This can be a significant
benefit in the reaction chemistry. We have not extensively
measured the partition coefficients of the fluorous products of
the radical reactions, but we do know at least qualitatively that
tin halides are more susceptible to partition into organic solvents
than tin hydrides and that this partitioning can be effected by
other cosolvents.16
The new tin hydrides were fully characterized, and relevant
spectral data are summarized in Table 2 for comparison. These
data include the following: the stretching frequency of the
Sn-H bond in the IR spectrum, the chemical shift of the proton
bonded to tin (1H NMR), and the chemical shift and coupling
constant (to H) of the tin (119Sn NMR). The propylene-spaced
reagents 1d,e and the monofluorous ethylene-spaced reagents
2a-c show values closer to the standard trialkyltin hydrides
than the trifluorous ethylene-spaced reagents 1a-c. The deshield-
ing effect of the (presumably more electronegative) ethylene
spacer on the chemical shift of the hydrogen bonded to tin is
counterintuitive based on inductive effects but is nonetheless
expected based on prior measurements.29
(12)
These reactions were conducted in BTF and were then subjected
to hydrostannation with 1a and fluorous/organic extraction. The
expected cycloadducts were obtained by evaporation of the
organic phase and were free from starting alkene. The fluorous
phases of these reactions contained the respective hydrostannated
products along with residual tin hydride. The simple technique
of fluorous quenching is readily automated and has excellent
potential to expedite solution phase combinatorial and parallel
syntheses.17f
The results so far suggest that, despite its unusual physical
and solubility properties, tin hydride 1a reacts more or less like
a standard trialkytin hydride in radical reactions, provided that
the reactions are not biphasic. However, this is not the case in
ionic reactions. Attempts to reduce simple aldehydes and ketones
in diethyl ether in the presence of Lewis acids under standard
conditions28 were not very successful. Reactions were very
sluggish, and the starting materials were generally recovered.
Since the tin hydride is reasonably soluble in ether, we do not
think that solubility is the problem here. Simple aldehydes such
as benzaldehyde can be reduced by using 20 equiv of ZnCl2
(see Supporting Information), but this procedure is not very
practical or general. Ionic (and even radical) reactions of related
“ethylene-spaced” fluorous allyl stannanes do not give prepara-
tively acceptable results either.16f,g These are clear indications
that the nature of the spacer will be crucial for some applications
in fluorous chemistry.
Other Fluorous Tin Hydrides. To study the effects of the
spacer and the fluorous chain on the reactivity and solubility,
we prepared four related tin hydrides 1b-e bearing three
fluorous chains and three tin hydrides 2a-c bearing one fluorous
chain and two methyl groups. The structures of these reagents
are shown in Figure 1 and Table 1, and the syntheses are detailed
in the Supporting Information.
(28) Leusink, A. J.; Budding, H. A.; Drenth, W. J. Organomet. Chem.
1968, 13, 163.
(29) Duffermont, J.; Maire, J. C. J. Organomet. Chem. 1967, 7, 415.

Fluorous Tin Hydrides
J. Am. Chem. Soc., Vol. 121, No. 28, 1999 6613
Table 2. Selected Spectroscopic Data for Tin Hydrides 1 and 2
72 (3-8 times) and evaporated to provide the crude products,
1
which were substantially pure as assessed by H NMR. Thus,
Sn-H
c
δ SnHa
δ SnHb
J119Sn-H (cm-1
)
while these reagents are “less fluorous” than 1a, it is still
possible to separate them from the reaction products by liquid-
liquid extraction. Although not studied with reagents 1a-d, the
convenient solid-liquid extractive workup described below
could also surely be used.
tin hydride
Me3SnH
Bu3SnH
4.73
1744
1609
1835
1833
4.80 -86.6 (CDCl3)
1812
1842
1862
ndd
1838
1843
1839
1841
1840
1a (Rf6h2)3SnH
1b (Rf4h2)3SnH
1c (Rf10h2)3SnH
1d (Rf6h3)3SnH
1e (Rf4h3)3SnH
2a (Rf6h2)SnMe2H
2b (Rf8h2)SnMe2H
5.27 -84.5 (CDCl3)
5.22 -64.9 (BTF-C6D6) 1858
5.48
ndd
ndd
During the course of these reactions, we noticed that the
propylene-spaced tin hydrides were considerably less stable than
the ethylene-spaced analogues. The reasons for this difference
are not currently clear, but it was confirmed by several simple
experiments. Heating of tin hydride 1a in CDCl3 in the dark
for 18 h resulted in only a small decrease in the intensity of the
SnH signal relative to an integration standard, but the signal
from the tin hydride in 1d had almost completely disappeared
after 18 h in an analogous experiment. The progress of this
4.87 -95.1 (BTF-C6D6) 1583
4.88 -94.2 (BTF-C6D6) 1791
4.75 -86.8 (C6D6)
4.74 -86.8 (C6D6)
ndd
1782
2c (Rf10h2)SnMe2H 4.75 -86.9 (C6D6)
ndd
a From the 1H NMRin CDCl3. b From the 119Sn NMR in CDCl3. c Of
a thin film by FTIR. d Not determined.
To probe the reactivity of these tin hydrides, we conducted
the radical reduction of 2-iodoethylnaphthalene 22 (eq 13) and
1
transformation was followed over time, but the resulting H
NMR spectra were very complex and no decomposition products
could be identified. This thermal instability does not seem to
compromise the utility of the reagents in standard radical
reactions, but it could detract from practicality if the tin product
is not recovered in a pure form after the reaction.
(13)
A similar series of experiments was conducted with the tin
hydrides 2a-c bearing one fluorous chain and two methyl
groups (eqs 13, 14). These compounds all bear ethylene spacers,
and we again used the catalytic procedures which regenerate
the tin hydride. The partition coefficients of these three tin
hydrides are shown in the lower part of Table 1. Compound 2a
does not have partition coefficients that are high enough to
permit simple extractive removal. However, both 2b and 2c
exhibit good partitioning out of acetonitrile and into FC-72. In
all three cases, extraction against acetonitrile is considerably
better than that against benzene.
the cyclization of the aniline derivative 24 (eq 14). Attempts to
Iodides 22 and 24 were then reduced with all three tin
hydrides by the standard catalytic procedure with sodium
cyanoborohydride. Reactions occurred smoothly in tert-butyl
alcohol, and benzotrifluoride was not required as a cosolvent
due to the acceptable organic solubility of these molecules.
Reactions were purified by a simple solid-phase extraction
through fluorous reverse-phase silica gel eluting with aceto-
nitrile.16c,f,g In the case of 2c, evaporation of the acetonitrile
provided pure 2-ethylnaphthalene in 83% yield; no resonances
from the fluorous tin compound were detected in the 1H NMR
spectrum. However, in the products from 2a and 2b, small but
clear resonances for the tin methyl groups and spacer protons
could be identified, thus showing that the separation was not
completely effective. The product from 2a was dried overnight
on a vacuum pump, which resulted in evaporation of both the
product and the tin hydride to leave nothing. This suggested
that less volatile products could be separated from the tin hydride
by vacuum-drying, and indeed reduction of 24 with 2a followed
by vacuum-drying overnight gave 25 in 78% yield free from
fluorous tin residues in the 1H NMR. Reduction with 2c
followed by solid-phase extraction provided pure 25 in 75%
yield. However, neither the simple solid-phase extraction nor
overnight pumping removed all of the fluorous resonances from
(14)
use the tin hydride 1c bearing 63 fluorines were irreproducible
and generally unsuccessful, presumably due to its insolubility.
However, in a separate paper we report that highly fluorous
reagents such as 1c can be coaxed to react under microwave
conditions.30 All of the other tin hydrides were well-behaved.
Indeed, in contrast to tin hydride 1a, we discovered that the
other tin hydrides could be used in the catalytic procedure
without the need for BTF as a cosolvent. While these reactions
were cloudy, suggesting incomplete dissolution of the fluorous
tin components, they all nonetheless worked smoothly and in
good yield. Thus, the increased solubility of these reagents
relative to the prototype 1a is an attractive feature because it
extends the range of solvents that can be used. Reactions were
worked up by the standard three-phase extraction with water,
FC-72, and benzene. The benzene phase was washed with FC-
1
the H NMR spectrum of the product of 2b.
All of the preparative results suggest that the new tin hydrides
show reactivities that are qualitatively similar to those of
standard trialkytin hydrides. Problematic behavior was only
observed when the tin hydride was substantially insoluble in
the reaction medium. To provide a more quantitative measure
of the effects of the fluorous substituents, we measured rate
constants for several of the new tin hydrides using Newcomb’s
(30) Olofsson, K.; Kim, S.-Y.; Larhed, M.; Curran, D. P.; Hallberg, A.
submitted for publication.

6614 J. Am. Chem. Soc., Vol. 121, No. 28, 1999
Table 3. Rate Constants for Tin Hydrides
Curran et al.
R3SnH
overall yield (%)
red/cyc
[(Rf)3SnH] (M)
kH (80) (M-1 s-1
)
average (M-1 s-1
)
(C6F13CH2CH2CH2)3SnH
84
83
64
92
81
0.14
0.43
0.40
0.34
0.48
0.16
0.25
0.19
0.03
0.10
0.07
0.08
0.23
0.03
0.08
0.03
1.0 × 107
1.0 × 107
1.4 × 107
1.0 × 107
1.5 × 107
1.2 × 107
7.3 × 106
1.4 × 107
1.1 × 107
1a
(C4F9CH2CH2)3SnH
1.2 × 107
1b
(C4F9CH2CH2CH2)3SnH
79
75
1.0 × 107
5.2 × 106
1d
64
0.07
0.03
5.1 × 106
5.3 × 106
2c
0.36
0.15
Table 4. Biphasic “Pseudo-Dilution” Experiments
(Rf)3SnH
benzene/FC-72 red/cyc temp overall yield effectivea [(Rf)3SnH] calculatedb [(Rf)3SnH]
results
(C4F9CH2CH2)3SnH
(C6F13CH2CH2CH2)3SnH
1:1
1:1
1:1
1:4
0.28
0.40
1.1
80
80
rt
92
81
0.051
0.082
0.11
0.020
0.020
0.020
0.0054
2.3 times higher
4.1 times higher
5.5 times higher
10.7 times higher
0.28
80
95
0.058
a Calculated by using rate constants in Table 3. b Calculated by using partition coefficients in Table 1.
probe 26.31 The measurements were anchored for 1a by an
absolute determination of the rate constant in the laboratories
of Prof. M. Newcomb.15b This showed kH ) 1 × 107 M-1 s-1
at 80 °C in BTF, while the rate constant for Bu3SnH at 80 °C
is 6 × 106 M-1 s-1. The other substrates were then subjected
to standard competitive experiments with 26 as the cyclizable
probe. BTF was used as the solvent for all of these experiments
since the rate constant for tin hydride 1a was determined in
BTF and since it is the only solvent in which all the tin hydrides
are soluble enough so that we can be confident of the
concentrations. The results of these experiments are shown in
Table 3. All the trifluorous tin hydrides appear to be marginally
more reactive than tributyltin hydride. The difference (less than
a factor of 2) is probably large enough to be real but small
enough so as not to merit extensive discussion or interpretation.
Monofluorous tin hydride 2c was, within experimental error,
of equal reactivity to Bu3SnH.
The combined knowledge of partition coefficients and rate
constants for cyclization provided us with an opportunity to test
ideas about using biphase mixtures as a way to control
concentrations of fluorous tin reagents in an organic phase. The
first example of this has been recently described in asymmetric
protonation chemistry; a prochiral samarium enolate and a
catalytic quantity of a chiral proton source were protected from
a stoichiometric achiral proton source by partitioning of the
achiral proton source into a fluorous phase.17e In radical
chemistry, the use of low concentrations of tin hydride to
conduct slow radical reactions is common, and this can be done
by using either low stationary concentrations or syringe pump
addition. We hypothesized that a biphasic reaction with a
fluorous tin hydride could establish a low, stationary tin hydride
concentration in an organic phase while holding most of the
tin hydride in reserve in the fluorous phase.
To test this possibility, we conducted cyclizations with tin
hydrides 1b and 1d and probe 26 in mixtures of FC-72 and
benzene (Table 4). The use of the cyclizable probe allows us to
measure an “effective tin hydride concentration” if we assume
that the radical cyclizations and reductions take place in the
organic phase. This number can also be calculated by assuming
that the partition coefficients measured in Table 1 are not
temperature-dependent and are not affected by the other reaction
components. In principle, the measured and calculated concen-
trations should be identical. In practice, the comparison of the
measured effective tin hydride concentrations to the calculated
ones suggests that there is clearly a flaw in this simple analysis.
In all cases, we observe significantly more (2-10 times) of the
direct reduction product than the analysis predicts. This trend
holds even in the experiment conducted at room temperature,
suggesting that the effect cannot be attributed to temperature
dependence on partition coefficients. Thus, there is a “pseudo-
dilution” effect in these biphasic experiments, but it is much
smaller than the partition coefficients would suggest.
Conclusions
The extensive reactivity and solubility studies of the eight
tin hydrides reported herein begin to provide some much needed
insight into how to design fluorous reagents with desired
reactivity and separation features. Nicely complementing this
(31) (a) Johnson, C. C.; Horner, J. H.; Tronche, C.; Newcomb, M. J.
Am. Chem. Soc. 1995, 117, 1684. (b) Tronche, C.; Martinez, F. N.; Horner,
J. H.; Newcomb, M.; Senn, M.; Giese, B. Tetrahedron Lett. 1996, 37, 5845.

Fluorous Tin Hydrides
J. Am. Chem. Soc., Vol. 121, No. 28, 1999 6615
work in the organotin area are detailed studies of assorted
fluorous phosphines and derived organometallic complexes by
Horva´th, Gladysz, and others.13,14
number of other solutions to the reaction solvent problem that
do not require the use of fluorinated solvents. Oxygenated
solvents such as THF and ether have reasonably good dissolving
power for fluorous compounds. Additionally, the strategy of
using partially fluorinated solvents (exemplified by BTF) looks
especially general. Other partially fluorinated solvents that are
commercially available include para-chlorobenzotrifluoride,
trifluoroethanol, and 1,2,2-trifluoro-1,1,2-trichoroethane. Finally,
perhaps the most expedient strategy for standard synthesis
applications is simply to use the more lightly fluorinated
reagents, which have expanded solubility in the full range of
organic solvents.
On the basis of early work, both we14b and Horva´th suggested
that molecules bearing about 60% fluorine by molecular weight
would partition well into fluorous solvents. While this remains
a useful guideline, the data in Table 1 clearly show that the %F
is only one factor determining partition coefficients. For
example, the addition of one methylene group to 1a to give 1d
reduces the fluorine content from 64% to 62%, yet the partition
coefficient of 1d into CH3CN is more than 10 times smaller
than 1a. In contrast, 1b and 1e (which also differ by a CH2
group) have rather similar partition coefficients. The mono-
fluorous tin hydride with the longest (C10F21) chain is only 57%
F, yet it exhibits much higher partition coefficients than 1d (62%
F). So it is clear that, even with relatively nonpolar molecules,
partition coefficients depend on structures and not just fluorine
content. The partition coefficients also vary from solvent to
solvent, with higher partitioning usually (but not always)
observed out of acetonitrile compared to benzene. We classify
both acetonitrile and benzene (as well as other aromatic solvents)
as relatively “anti-fluorous”; that is, they have relatively poor
capability to dissolve polyfluorinated molecules.
This work with tin hydrides provides a prototype for rendering
a standard “organic” reagent fluorous. The result of the process
is not a single reagent but instead a family of reagents with
tunable reactivity and solubility properties. The chemistry
described here for tin hydrides serves as a model for other types
of organotin reagents, some of which have already been made
and studied.16 Suitable fluorous tin reagents mimic the reactivity
of their organic parents, but they are readily separated from
organic products and can routinely be reused. The issue of
toxicity is still an open question, and while there is some reason
to believe that these reagents could be less toxic than alkyl tin
compounds, this notion has not yet been tested experimentally.
In the meantime, we recommend that fluorous tin reagents be
handled with the standard precautions used for regular alkyltin
reagents. Special care should be taken with the monofluorous
series 2; even if these fluorous compounds do prove to have
reduced toxicity, there is still the potential that the fluorous chain
would be lost in the environment or by metabolism. This would
generate fragments Me2SnXY, which are well-known to be
toxic.1
Taken together, the work with tin reagents and phosphines
suggests that three perfluorohexylethyl chains bring together
the features needed to make fluorous reagents with very high
partition coefficients. These high partition coefficients result,
at least in part, from low solubilities in organic solvents.
Subtraction of two CF2 groups or addition of one CH2 group
results in molecules that retain substantial solubility in fluorous
solvents but have increased solubility in organic solvents. This
results in lower partition coefficients, so more extractions are
needed if reactions are worked up by liquid-liquid methods.
However, the solid-liquid extractions provide a convenient
alternative when liquid-liquid extractions become impractical.
Going in the other direction, the simultaneous lengthening of
the three chains to C10F21 results in reagents that are essentially
insoluble in organic solvents and are not very soluble in fluorous
solvents, either.
Although they have not yet been studied extensively, the tin
hydrides bearing one fluorous chain provide a new direction in
the fluorous field. Reducing the number of chains from three
to one should provide reagents that more closely resemble the
parents, and these reagents also show better solubility in organic
solvents. Even reagents bearing a single long fluorinated chain
show good solubility properties in both fluorous and organic
solvents. Indeed, reagent 2c has proved popular in our group
for conducting preparative radical cyclizations.
Although calculations in the phosphine series suggested that
an ethylene spacer should provide a reasonable insulation of
the phosphorus atom of (RfCH2CH2)3P from the perfluoroalkyl
group, the effects of this group are nonetheless readily de-
tected.13,14 In the tin series, spacer effects seem especially
significant. Reagents such as 1a bearing three fluorous chains
and ethylene spacers can be used in tin hydride radical
chemistry, but they do not work well in radical allylations or
ionic reactions. Early work suggests that the propylene-spaced
reagents are much better for these types of reactions.16f,g
While early work in the fluorous field focused on biphasic
reaction conditions with fluorous solvents, there are now a
Although still in its infancy, fluorous chemistry stands poised
to impact across the discipline of organic synthesis from small-
scale parallel synthesis to process chemistry. The attraction of
fluorous methods is that they couple synthesis and separation.17
While a number of other general methods to do this are now
emerging, the features of fluorous chemistry (stability of
perfluorocarbon fragments, ease of synthesis, tunability by
substituent effects, etc.) suggest that there is still vast untapped
potential.
Acknowledgment. This work was funded primarily by the
National Institutes of Health, and we thank the National Science
Foundation for partial support. S.H. thanks the Ministerio de
Educacion y Ciencia of Spain for a postdoctoral fellowship. We
also thank CombiChem, Merck, Warner-Lambert, and Hewlett-
Packard for supporting the University of Pittsburgh Center for
Combinatorial Chemistry. We are grateful to Elf Atochem for
providing many of the perfluoroalkylethyl iodides used in this
work. Dedicated to Keith Ingold, a poineer in modern radical
chemistry, on the occasion of his seventieth birthday.
Supporting Information Available: Complete details on
the preparation and characterization of all fluorous tin com-
pounds and experimental procedures for their use. This material
is available free of charge via the Internet at http://pubs.acs.org.
JA990069A