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DOI: 10.1002/qsar.200640046
Abstract
The reaction of hexafluoroacetone sesquihydrate (1, 2 mmol) with a mixture of 3-perfluor-
oalkyl-propanols (CnF2n þ 1 (CH2)3OH; 2a – d: n ¼ 4, 6, 8, 10; 1 mmol each) in an ether solu-
tion using the classical Ph3P/diisopropyl azodicarboxylate reagent pair afforded a mixture
of ten ketals [(CF3)2C(O(CH2)3CnF2n þ 1)2, 3{a – d} {a – d}]. The mixture of the ten fluoro-
philic ketals was easily separated from side products using fluorous extraction (FC-72/
CH3OH). The composition of this fluorous ketal mixture was quantitatively analyzed by
GC, and the results obtained were in agreement with predictable trends based on a
statistical model. A method for collective fluorophilicity determination of the individual
fluorous ketals was supplemented with the calculation of fluorous isotherms and the
analysis of gas chromatographic elution orders.
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Mixture Synthesis of Fluorous Ketals&
Table 3. Retention times of the individual components of the Table 4. Fluorous partition coefficent and fluorophilicity data of
mixture of ten ketalsa. ketals 3{a – d} {a – d}.
Entry 3aa 3ab 3bb 3ac 3bc 3ad 3cc 3bd 3cd 3dd Entry R1, R2 Pexpa f ¼ lnPexp Pmixb f ¼ lnPmix n1 þ n2
R1@R2 4-4 4-6 6-6 4-8 6-8 4-10 8-8 6-10 8-10 10-10 3aa {4, 4} 11.3 2.42 12.5 2.53 8
tRet (min) 8.60 10.41 12.02 12.10 13.51 13.64 14.80 14.87 16.01 17.07 3ab {4, 6}, {6, 4} – – 23.2 3.14 10
a
3ac {4, 8}, {8, 4} – – 44.7 3.80 12
Ether 2.99 min; BTF 3.52 min.
3bb {6, 6} 44.6 3.80 45.2 3.81 12
3ad {4, 10}, {10, 4} – – 82.6 4.41 14
3bc {6, 8}, {8, 6} – – 81.9 4.41 14
the values for 4-4, 6-6, 6-8, 6-10, 8-8, 8-10, and 10-10, the 3bd {6, 10}, {10, 6} – – 141 4.95 16
GC analysis of a sample of the mixture of ten ketals af- 3cc {8, 8} 142 4.96 144 4.97 16
forded the missing last three figures for the 4-6, 4-8, and 4- 3cd {8, 10}, {10, 8} – – 240 5.48 18
3dd {10, 10} 186 5.23 330 5.80 20
10 components (Figure 1, Table 3).
a
These fluorous ketals leave the highly apolar stationary Individual determination, cf. [11c] (experimental, 10 mg of the single ke-
tal per 1:1 mL toluene/CF3C6F11).
phase GC column in the order of their increasing fluorous b
Collective determination (experimental, 100 mg mixture of ten ketals
contents. It should be noted that among isomeric ketal per 1 : 1 mL toluene/CF3C6F11).
pairs (6-6, 4-8; 6-8, 4-10; and 8-8, 6-10) the one with a lon-
ger tail displays somewhat larger retention time. The base-
line separation of these isomers also deserves attention isotherms with a group contribution method as described
(Figure 1), although the mechanism of the latter separa- earlier [11c].
tion selectivity phenomenon is not yet well understood. The results obtained for molar volumes (Vm, Barton,
The above evaluation of the reactivity of the homolo- Vm, de Wolf) using either Barton or de Wolf parameters are
gous alcohols in ether solution revealed that the mixture very similar. However, the calculated cohesions (dBarton, dde
of alcohols 2a – d in this media behaves as an ideal solu- Wolf) have significant differences in the two sources (cf.
tion. Under nonideal conditions, such statistical result is [11c], Table 5).
hardly expected to occur. Although we found here that specific fluorophilicity val-
We thought that collective determination of fluorous ues have good linear correlation with both the Hildebrand
partition coefficients for each individual ketal component [14] and the de Wolf et al. [8f] cohesion parameters (Ta-
in the mixture of ten sample could be a probe of their ble 5), the former fluorous isotherm (Figure 2) has a seri-
phase behavior. Moreover, such collective method for the ous error of displaying increasing specific fluorophilicity
determination of PFBS values could result in the saving of with increasing calculated Hildebrand parameter (Eq. 1).
significant amount of GC instrument occupation time.
Our preliminary results showed that this novel method fspec, Barton ¼ 58.559 þ 4.478 dBarton (1)
affords agreeable figures to those determined earlier using
single samples of the symmetrical ketal components (Ta- Only the latter de Wolf isotherm (Figure 3) displays real
ble 4). physical meanings: the lower the soluteGs cohesion param-
Fluorous partition coefficients of the symmetrical ketals eter, the larger the specific fluorophilicity of the solute
(3aa, 3bb, 3cc, and 3dd) obtained using either single or col- (Eq. 2).
lective determinations have rather good matching.
To show the linear correlation between specific fluoro- fspec, de Wolf ¼ 14.2901.032 dde Wolf (2)
philicity and cohesion parameter, we calculated fluorous
Table 5. Specific fluorophilicity values and calculated cohesion parameters of ketals 3a,b.
Entry 3-R1, R2 P f ¼ ln P dBarton ( MPa1/2) Vm, Barton (cm3/mol) fspec, Barton dde Wolf ( MPa1/2) Vm, de Wolf (cm3/mol) fspec, de Wolf
{4, 4} 12.5 2.53 13.33 453 1.09 12.72 443 1.12
{4, 6} 23.2 3.14 13.36 499 1.23 12.61 489 1.26
{4, 8} 44.7 3.80 13.38 545 1.366 12.51 535 1.391
{6, 6} 45.2 3.81 13.38 545 1.371 12.51 535 1.395
{4, 10} 82.6 4.41 13.40 591 1.464 12.43 581 1.488
{6, 8} 81.9 4.41 13.40 591 1.46 12.43 581 1.485
{6, 10} 141 4.95 13.42 637 1.52 12.37 628 1.545
{8, 8} 143.5 4.97 13.42 637 1.53 12.37 628 1.551
{8, 10} 240 5.48 13.43 683 1.57 12.30 674 1.59
{10, 10} 330 5.79 13.44 729 1.56 12.24 720 1.58
a
fspec, Barton ¼ A þ B*dBarton (for definitions, cf. [11c, 14]).
b
fspec, de Wolf ¼ A þ B*dde Wolf (for definitions, cf. [8f, 11c]).
QSAR Comb. Sci. 00, 0000, No. &, 1 – 5 www.qcs.wiley-vch.de L 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim &3&
These are not the final page numbers! ÞÞ
Full Papers József Rábai et al.
Table 6. Regression and statistical parameters of fluorous iso- Baseline separations were achieved even for isomeric
therms for ketals 3{a – d} {a – d}. fluorous ketals using GC with a 50 m capillary column
Method A B R2 S.D. N holding a very apolar crosslinked methylsilicon gum sta-
tionary phase.
Barton 58.559 4.478 0.9569 0.0343 10
de Wolf 14.29031 1.032 0.9476 0.0370 10
4 Experimental Section
Mixture of Ten Ketals (3aa, 3ab, 3ac, 3ad, 3bb, 3bc, 3bd,
3cc, 3cd, 3dd)
3 Conclusions
To a stirred solution of 1*0.5H2O (0.386 g, 2.00 mmol), 2a
Fluorous isotherms are only the first approximations for (0.280 g, 1.00 mmol), 2b (0.380 g, 1.00 mmol), 2c (0.480 g,
the treatment of the fluorous partition phenomenon. This 1.00 mmol), 2d (0.580 g, 1.00 mmol), and Ph3P (1.572 g,
“paper-and-pencil” method gives better performance with 6.00 mmol) in absolute ether (20 mL) is added at 0 – 5 8C a
the use of de Wolf cohesion increments [8f] in particular solution of Diisopropyl Azodicarboxylate (DIAD, 1.212 g,
for fluorine rich molecules [11c]. 6.0 mmol) in absolute ether (5 mL) during 30 min. Then it
The homologous series of perfluoroalkyl propanols dis- is stirred at r.t. overnight and the solvent evaporated. The
play very similar reactivities in a homogeneous solution residue was partitioned between CH3OH (5 mL) and FC-
phase reaction and have predictable fluorophilicities as 72 (3 5 mL). The separated FC-72 phase consecutively is
proved by mixture synthesis of ketals and collective parti- washed with CH3OH (3 2 mL), then the fluorous solvent
tion coefficient determinations, respectively. is distilled off at 1 atm (bath temperature 75 8C).
&4& L 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.qcs.wiley-vch.de QSAR Comb. Sci. 00, 0000, No. &, 1 – 5
ÝÝ These are not the final page numbers!
Mixture Synthesis of Fluorous Ketals&
Yield: 1.89 g (94%) colorless oil. 1H NMR: d 2.0 (m, [4] Y. Oderaotoshi, Q. Zhang, Z. Luo, D. P. Curran, Science
CH2CH2O), 2.21 (m, CF2CH2), 3.84 (t, CH2O); 13C NMR 2001, 291, 1766 – 1769.
(partial): d 20.9, 27.7, 63.7; 19F NMR: d 76.3 (s, C(CF3)2), [5] a) P. G. Boswell, P. BWhlmann, J. Am. Chem. Soc. 2005, 127,
8958 – 8959; b) P. G. Boswell, E. C. Lugert, J. Rábai, E. A.
82.2, 82.4, 115.5, 122.7, 123.7, 124.5, 125.5, Amin, P. BWhlmann, J. Am. Chem. Soc. 2005, 127, 16976 –
127.2; IR (BaF2, film): 2978w, 1231s, 1147s. 16984.
[6] a) E. de Wolf, G. van Koten, B.-J. Deelman, Chem. Soc.
Rev. 1999, 28, 37 – 41; b) R. D. Fish, Chem. Eur. J. 1999, 5,
Mixture of Six Ketals (3bb, 3cc, 3dd, 3bc, 3bd, 3cd) 1677 – 1680; c) M. Cavazzini, F. Montanari, G. Pozzi, S. Qui-
To a stirred solution of 1*0.5H2O (0.29 g, 1.50 mmol), 2b ci, J. Fluorine Chem. 1999, 94, 183 – 193.
[7] a) I. T. Horváth, G. Kiss, R. A. Cook, J. E. Bond, P. A. Ste-
(0.38 g, 1.00 mmol), 2c (0.48 g, 1.00 mmol), 2d (0.58 g,
vens, J. Rábai, E. J. Mozeleski, J. Am. Chem. Soc. 1998, 120,
1.00 mmol), and Ph3P (1.18 g, 4.50 mmol) in absolute ether 3133 – 3143; b) L. P. Barthel-Rosa, J. A. Gladysz, Coord.
(15 mL) is added at 0 – 5 8C a solution of DIAD (1.01 g, Chem. Rev. 1999, 192, 587 – 605; c) Z. Szlávik, G. Tárkányi,
5.0 mmol) in absolute ether (5 mL) during 30 min. Then it Á. Gçmçry, G. Tarczay, J. Rábai, J. Fluorine Chem. 2001,
is stirred at r.t. overnight and the solvent evaporated at at- 108, 7 – 14.
mospheric pressure. The residue was partitioned between [8] a) L. E. Kiss, J. Rábai, L. Varga, I. Kçvesdi, I. Synlett 1998,
1243 – 1245; b) V. Herrera, P. J. F. de Rege, I. T. Horváth,
CH3OH (5 mL) and FC-72 (3 5 mL). The separated FC-
T. L. Husebo, R. P. Hughes, Inorg. Chem. Commun. 1998, 1,
72 phase consecutively is washed with CH3OH (3 2 mL), 197 – 199; c) Z. Szlávik, G. Tárkányi, Gy. Tarczay, Á. Gçmç-
then the fluorous solvent is distilled off at ambient pres- ry, J. Rábai, J. Fluorine Chem. 1999, 98, 83 – 87; d) L. E.
sure (bath temp. 75 8C). Kiss, I. Kçvesdi, J. Rábai, J. Fluorine Chem. 2001, 108, 95 –
Yield: 1.47 g (89%) colorless oil. 1H NMR: d 2.0 (m, 109; e) J. A. Gladysz, C. Emnet, J. Rábai, Partition Coeffi-
CH2CH2O), 2.23 (m, CF2CH2), 3.84 (t, CH2O); 13C NMR cents Involving Fluorous Solvents, in: J. A. Gladysz, D. P.
(partial): d 21.0, 27.7, 63.7; 19F NMR: d 76.2 (s, C(CF3)2), Curran, I. T. Horváth (Eds.), Handbook of Fluorous
Chemistry, Wiley-VCH, Weinheim, 2004, pp. 56 – 100; f) E.
82.1, 115.3, 122.6, 123.6, 124.4, 127.1; IR de Wolf, P. Ruelle, J. van den Broeke, B.-J. Deelman, G.
(BaF2, film): 2878w, 1225s, 1147s. van Koten, J. Phys. Chem. B 2004, 108, 1458 – 1466.
[9] a) E. G. Hope, A. M. Stuart, J. Fluorine Chem. 1999, 100,
75 – 83; b) A. P. Dobbs, C. McGregor-Johnson, Tetrahedron
Acknowledgements Lett. 2002, 43, 2807 – 2810; c) R. Dembinski, Approaches to
the Fluorous Mitsunobu Reaction, in: J. A. Gladysz, D. P.
Curran, I. T. Horváth (Eds.), Handbook of Fluorous
We thank the Hungarian Scientific Research Foundation
Chemistry, Wiley-VCH, Weinheim, 2004, pp. 190 – 202; d) S.
(OTKA T 043738) for financial support. A.-M. B. thanks Dandapani, D. P. Curran, J. Org. Chem. 2004, 69, 8751 –
the Gedeon Richter Centenary Foundation for a half-year 8757; e) D. P. Curran, X. Wang, Q. Zhang, J. Org. Chem.
fellowship. 2005, 70, 3716 – 3719.
[10] http://www.fluorous.com.
[11] a) J. Rábai, D. Szabó, E. K. Borbás, I. Kçvesi, I. Kçvesdi,
A. Csámpai, Á. Gçmçry, V. E. Pashinnik, Yu. G. Shermolo-
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QSAR Comb. Sci. 00, 0000, No. &, 1 – 5 www.qcs.wiley-vch.de L 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim &5&
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