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19F NMR spectroscopy of polyhalonaphthalenes
Journal of Fluorine Chemistry 105 (2000) 35±40
19
F NMR spectroscopy of polyhalonaphthalenes Part V. Halex reactions of polychloroisoquinolines Raymond S. Matthews*, Adam N. Matthews High Force Research, Bowburn, Durham DH6 5PF, UK Received 21 January 1999; accepted 13 March 2000
Abstract Nucleophilic ¯uoride ¯uoro-dechlorination of four isoquinolines (5,6,7,8-tetrachloro-,3,5,6,7,8-pentachloro-,3,4,5,6,7,8-hexachloro- and 1,3,4,5,6,7,8-heptachloro-isoquinoline) led to the preparation of 15 new polychloropoly¯uoro isoquinolines by reaction with caesium ¯uoride in DMSO at 1008C. The product from the perchloroisoquinoline was an inseparable mixture of C9Cl7ÿnFnN where n is 1±3. The order of reactivity in 1,3,4,5,6,7,8-heptachloro-isoquinoline [10] to nucleophilic attack by ¯uoride was 1 @ 6 7 8 > 3 5 > 4 # 2000 Elsevier Science S.A. All rights reserved. Keywords: Halex; Nucleophilic; Isoquinoline; Polychloroisoquinolines; Polyhaloisoquinolines; Fluorine NMR; Through-space
1. Introduction Nucleophilic ¯uoride ion exchanges in polyhalocompounds are ostensibly `non-selective' although the preceeding quinoline study [1] at 1008C shows that these reactions are more predictable than previously believed. Fluorine (F2) reactions can be non-speci®c but Hutchinson and Sandford [2] recently noted that the such exothermic reactions can now be controlled and could be described as selective. Brooke [3] has reviewed the known nucleophilic and electrophilic reactions of poly¯uoroaromatic and poly¯uoroheterocylic compounds, covering the literature until 1996. Halex reactions with potassium ¯uoride in sulpholane at 2008C were reported by Fuller [4] in 1965. Chambers et al. [5] reported the synthesis of hepta¯uoroquinoline and hepta¯uoroisoquinoline with KF in sulpholane in 1966. Su et al. [6] reported the carbon-13 shifts of mono and dichloroisoquinolines in 1978 whilst we reported the separation and C13 NMR of the hexachloro and pentachloroisoquinolines in 1989 [7]. The partial anodic ¯uorination of the hydrocarbons (isoquinoline, 1,10-phenanthroline and quinoline) in Et3N3HF reputedly only took place in the carbocyclic ring [8]. Recently, Konno et al. [9] investigated the use of Et4NF4HF as the support electrolyte in partial ¯uorination. Whether dryness is a necessity in these Halex ¯uorinations is debatable. Clark and Nightingale [10] have investigated the use of methylhexamethyltetramine ¯uoride *
Corresponding author.
for ¯uorodenitration in chlorocyanonitrobenzenes, where the ¯uoride source is the dihydrate which still selectively brings about denitration. Chambers et al. [11] have explored the potential of TDAE (tetrakis-dimethylamino-ethylene di¯uoride) for dry ¯uoride ion generation without a solvent or `dissolved in the reagent'. The most notable drawbacks with the known weak sources of ¯uoride ions are: poor solubility poor activity and moisture. whilst the more powerful fluorinating reagents tend to react `explosively' [12]. Here, we report the result of an investigation of the partially ¯uorinated isoquinolines, applying the same 19F substituent chemical shifts (SCSs) and the same solutionstate methodology [13]. The products of Halex reactions with CsF in aprotic dry DMSO at 1008C were identi®ed in an NMR tube. Presumably, the ¯uoride ion in solution will be exchanging readily at 1008C and exist in a bath of receptor sites, mostly the caesium cationic sites. 2. Experimental details Compounds are numbered as they appear in this article with IUPAC systematic ring numbering. 19F NMR spectra were measured on a Varian Mercury 200 at 188.18 MHz,
0022-1139/00/$ ± see front matter # 2000 Elsevier Science S.A. All rights reserved. PII: S 0 0 2 2 - 1 1 3 9 ( 0 0 ) 0 0 2 6 0 - 8
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R.S. Matthews, A.N. Matthews / Journal of Fluorine Chemistry 105 (2000) 35±40
both in dry d6-DMSO and d-chloroform, referenced to CFCl3 in CDCl3. Reactions (10 mg of a compound and 50 mg caesium ¯uoride, an excess) were followed for 96 h at 1008C in 1 cm3 of d6-DMSO. Samples were cooled to 228C for spectroscopic measurement. All our compounds had the correct integrals.
The systematic names for 1±19 are as follows: 1 5,6,7,8-Tetrachloroisoquinoline 2 5,7,8-Trichloro-6-fluoroisoquinoline 3 5,6,7-Trichloro-8-fluoroisoquinoline 4 5,7-Dichloro-6,8-difluoroisoquinoline 5 3,5,6,7,8-Pentachloroisoquinoline 6 3,5,7,8-Tetrachloro-6-fluoroisoquinoline 7 3,5,6,7-Tetrachloro-8-fluoroisoquinoline 8 3,6,8-Trichloro-6,8-difluoroisoquinoline 9 3,4,5,6,7,8-Hexachloroisoquinoline 10 1,3,4,5,6,7,8-Heptachloroisoquinoline 11 3,4,5,6,7,8-Hexachloro-1-fluoroisoquinoline 12 3,4,5,6,7-Pentachloro-1,8-difluoroisoquinoline 13 3,4,5,7-Tetrachloro-1,6,8-trifluoroisoquinoline 14 1,3,4,5,6,7-Hexachloro-8-fluoroisoquinoline 15 1,4,5,6,7,8-Hexachloro-3-fluoroisoquinoline 16 1,3,4,5,7,8-Hexachloro-6-fluoroisoquinoline 17 1,3,4,6,7,8-Hexachloro-5-fluoroisoquinoline 18 1,3,4,6,8-Pentachloro-5,7-difluoroisoquinoline 19 1,3,4,5,6,8-Hexachloro-7-fluoroisoquinoline
3. Assignment of
19
F spectra
(A) The reaction of 5,6,7,8-tetrachloroisoquinoline {1} with caesium ¯uoride in DMSO at 1008C. The 19F shifts from run A are summarised in Table 1. Two products were visible after 20 min at 1008C and assigned to the F6 product (ÿ104.86 ppm) {2} and F8 product (ÿ119.13 ppm) {3}. It is notable at this point that all the previously-reported 19F shifts of polychloromono¯uoronaphthalenes were in the range ÿ100 to ÿ110 ppm. The Table 1 Summary of shifts in reaction (A) DMSO ÿ104.86 ÿ108.12 ÿ119.13 ÿ121.86
F6 F6 F8 F8
{2} {4}, JF6,F85.5 Hz {3} {4}, JF6,F85.5 Hz
Scheme 1. NIMs prediction for the 19F shifts of two alternative structures for compound {4}: either 5,7-difluoro-6,8-dichloroisoquinoline (top structure) or 5,7-dichloro-6,8-difluoroisoquinoline (middle structure). The experimental shifts are superimposed on the correct structure (bottom structure).
peaks for compounds {2} and {3} were in the approximate ratio 60/40 and can be assigned directly or via our assignment of compound {4} below. Two peaks (1:1) of a third new compound subsequently appeared. Both peaks were doublets (JF6,F85.5 Hz) and 3 ppm down-shift of compounds {2} and {3}, a typical meta-coupling and typical down-shifts on both ¯uorines. A NIMs (Nitrogen insertion method) prediction for the 19F shifts of compound {4} was attempted for the two alternative structures, both the carbocyclic meta di¯uoro-isomers (Scheme 1). 19 F NIMs are the `real experimental differences in a single spectrum' for a mixture of octa¯uoronaphthalene and hepta¯uoroisoquinoline in either CDCl3 or dry DMSO (all seven values are given in Table 4). The 19F shifts for octa¯uoronaphthalene CDCl3 were ÿ145.59 and ÿ154.05 ppm with respect to internal CFCl3; the assignment for hepta¯uoroisoquinoline was reported in 1976 [14]. The peaks for octa¯uoronaphthalene were always sharp under these wide-shift observations. 19 F NIMs describes the hypothetical insertion of a nitrogen atom in a naphthalene molecule (6,8-dichloro-5,7di¯uoronaphthalene) where the 19F shifts of our model
R.S. Matthews, A.N. Matthews / Journal of Fluorine Chemistry 105 (2000) 35±40
naphthalene are known [15]. The b-¯uorine shift was chosen for this prediction because 1. the b-fluorine does not have a peri-problem and 2. they are more remote from the site of change. Thus, for F(6), the predicted value of ÿ105.7 ppm in accord with the experimental value of ÿ108.1 ppm of the second structure and discord for an F(7) assignment of the first structure. The new compound {4} must be 5,7-dichloro-6,8difluoroisoquinoline. (B) The reaction of 3,5,6,7,8-pentachloroisoquinoline {5} with caesium ¯uoride in DMSO at 1008C. The starting material appeared pure by proton NMR (separation in [7]). The reaction appeared to progress quickly. After 12 h, a broad peak at ÿ140 ppm was attributable to ¯uoride ion. A typical spectrum could be described as follows in Table 2. After 20 min, two peaks were visible and were assigned to the mono-substituted products {6} and {7} where the integration ratio was 70:30%. Reaction at C6 again dominated this sequence. The assignment of the shifts of products {6} and {7} follows the logic used in the above reaction. After 18 h, the peaks at ÿ105 and ÿ120 ppm indicate the 6,8-meta di¯uoro-compound {8} via the 4-bond meta JF6,F86.0 Hz. Such values would be described as through-bond and not through-space, although a throughspace contribution to the meta-coupling could not be ruled out. At this stage C3 was only just beginning to react and a compound containing F3 was a minor component in the mixture. Peaks at ÿ106 and ÿ125 were unattributed. Both the chlorines, at C6 and C8, in the carbocyclic ring proved more reactive than the `isolated' chlorine at C3 in the heterocyclic ring. (C) Reaction of 3,4,5,6,7,8-hexachloroisoquinoline {9} with caesium ¯uoride in DMSO at 1008C. Only very slow exchanges occurred between 3,4,5,6,7,8hexachloroisoquinoline {9} and ¯uoride. Two sharp peaks appeared at ÿ100.5 and ÿ123.92 ppm. Fluoride ion peaks were visible at ÿ100 and ÿ144 ppm. (D) The reaction of 1,3,4,5,6,7,8-heptachloroisoquinoline {10} with caesium ¯uoride in DMSO at 1008C. The starting material appeared pure by proton NMR with no proton peaks. The reaction progressed quite smoothly, quickly and showed many products after 1 h. A typical, complicated spectrum is described in Table 3. Table 2 Summary of shifts in reaction (B) DMSO ÿ102.26 ÿ105.34 ÿ106.09 ÿ117.39 ÿ119.65 ÿ125.32
F6 {6} F6, JF6,F86.0 Hz {8} F8 {7} F8, JF6,F86.0 Hz {8}
37
Table 3 Summary of shifts in reaction (D) DMSO ÿ54.16 F1 s {11} ÿ58.9 F1, JF1,F889.6 Hz {12} ÿ58.95 F1, JF1,F886.9H z {13} ÿ66.84 F3 s {15} ÿ67.16 m ÿ93.67 F6 s {16} ÿ97.03 F6, J6.0 Hz {13} ÿ103.85 s F8 {14} ÿ104.85 s F5 {17} ÿ106.85, JF1,F889.6 Hz F8 {12} ÿ107.00 d, JF5,F77.1 Hz F5 {18} ÿ108.16 d ÿ108.69 s F7 {19} ÿ109.5 dd, JF1,F886.9, JF6,F86.0 Hz F8 {13} ÿ111.62 d, JF5,F77.1 Hz F7 {18} ÿ111.75 dd
The single exchange product (1-¯uoro-) {11} dominated (65% see Table 5) the early spectra and appeared to lead to many di¯uoro-compounds in a complex mixture, one of which was the 1,8-di¯uoro-pentachloroisoquinoline {12} with a doublet at ÿ59 ppm and a sharp doublet at ÿ106 ppm where the F,F coupling is 89.6 Hz. A doublet of doublets at ÿ109 displayed a through-space coupling JFF of 86.9 Hz and was F8 of the F1,F6,F8-tri¯uoro compound {13} with peaks at ÿ59, ÿ97 and ÿ109 ppm. Through-space F,F coupling constants are those greater than 50 Hz (all positive), whereas through-bond are less than 40 Hz in these aromatic systems [15]. For example, 32.2 Hz, attributed to a para F,F coupling in the heterocyclic ring, was the largest through-bond coupling. 19F NIMS style predictions for compound {13} 1,6,8-tri¯uoropentachloroisoquinoline are presented in Scheme 2, using the original 19F NIMs values in Table 4 (for hepta¯uoroisoquinoline) and the new NIMs values from the 19F shifts of compound {4} in reaction A above i.e. F6 SCS for NIMs at position-2
6:2 ppm
F8 SCS for NIMs at position-2
0:4 ppm
In Scheme 2, the 19F shift of F1 is not predicted accurately by the NIMs method (being adjacent to the N atom) and is Table 4 Nitrogen insertion method SCSs in ppm for heptafluoroisoquinoline [15] Position
CDCl3
DMSO
F1 F3 F4 F5 F6 F7 F8
83.52 57.68 ÿ9.68 ÿ0.0 9.06 0.57 6.19
83.40 55.46 ÿ9.05 ÿ0.41 8.57 0.89 5.63
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R.S. Matthews, A.N. Matthews / Journal of Fluorine Chemistry 105 (2000) 35±40
Scheme 2. 19F NIMS style predictions for compound {13} using the original 19F NIMs values in Table 4 (top structure) and the new NIMs values from 19F shifts of reaction (A) (middle structure). The experimental 19 F shifts of compound {13} (1,6,8-trifluoropentachloroisoquinoline) are given (lower structure).
thus excluded from our NIMs table. The SCS method, based on the experimental shift in hepta¯uoroisoquinoline [15], proved more accurate. That value was ÿ62.9 ppm, adjusted by 9 ppm for a peri chlorine SCS (in italics) giving a prediction of ÿ53.9 ppm. In compound {11} 3,4,5,6,7,8hexachloro-1-¯uoroisoquinoline, F1 is found at ÿ54.1 ppm. The peri-SCS (Cl to F), for an a-¯uorine, were ÿ7.6 ppm for F4 in hepta¯uoroquinoline [16], ÿ9.0 ppm for F5 in
hepta¯uoroquinoline [16] and ÿ6.44, ÿ6.85, ÿ7.98 ppm in Part 1 [1] for polychloronaphthalenes. Experimentally, for hepta¯uoroisoquinoline, we found ÿ4.8 ppm for F1 and ÿ3.0 ppm for F8. It was probable that the monosubstituted F8 {14} was a sharp singlet at ÿ104 ppm. Single exchange at C3, adjacent to the nitrogen atom, led to compound {15} 1,4,5,6,7,8-hexachloro-3-¯uoroisoquinoline. 19F prediction was based on the shift of F3 in hepta¯uoroisoquinoline [15] at ÿ98.5 ppm, adjusted for an ortho¯uorine to chlorine SCS (25.8 ppm), to give a prediction of ÿ72.3 ppm. A small peak was found at ÿ66.8 ppm. Possible single exchange at C4 in compound {10} would give hexachloro-4-¯uoroisoquinoline which was not found in our spectrum. 19 F prediction for F4 led to: ÿ155.93 ppm in hepta¯uoroisoquinoline [15]; 25.8 ppm adjusted for an ortho-chlorine (25.8 ppm) and ÿ130.1 ppm. No peaks were visible in the region ÿ125 to ÿ135 ppm. A further singly-substituted compound was 1,3,4,5,7,8hexachloro-6-¯uoroisoquinoline {16}, a singlet at ÿ93.7 and 3 ppm upshift from F6 in compound {13}. Singlysubstituted peaks for F5 {17} and F7 {18} were traced by both being 3 ppm upshift from the di¯uorinated compound {19} which displayed a coupling of 7.1 Hz. The initial reactions of heptachloroisoquinoline {10} are shown in Scheme 3, including compounds {10}, {11}, {12} and {13}. Interestingly the reaction is dominated by sequential exchange at F1, then F8, then F6. Other sequences/ compounds are not found in our spectra. So far these shifts are internally consistent. For example, meta SCSs were ÿ2.50 ppm 0.5 ppm throughout this study. At the end of 96 h, the F1 compounds had formed oligomers. 4. Relative reactivity at the different sites in heptachloroisoquinoline {10} The relative reactivities of the seven sites in heptachloroisoquinoline {10} are summarised in Table 5. The 19F integrals, for this speci®c reaction, were measured from the initial spectra (15 min after the reaction started).
Table 5 Summary of integrals for initial attack in heptachloroisoquinoline {10} Position F1 F3 F4 F5 F6 F7 F8
19
F Chemical shifts (ppm) ÿ54.16 ÿ66.83b ÿ104.85 ÿ93.7 ÿ108.69 ÿ103.85
a b
For the parent hydrocarbon isoquinoline. Overlapping peaks.
Integrals (%)
Proton shifts (ppm) [17]a
Hyperfine splittings [18]a
HMO electron density [19]a
65 4 0 4 8 6 7
9.14 8.45 7.50 7.70 7.56 7.48 7.85
5.38 0.37 4.01 3.95 3.26 0.04 6.26
0.8261 0.7022 1.0609 1.0776 0.9425 0.9251 1.0378
R.S. Matthews, A.N. Matthews / Journal of Fluorine Chemistry 105 (2000) 35±40
39
Scheme 3. Sequential fluoride exchange in compound {10} (top of scheme) led to compounds {11} {12} and {13}.
For {10}, the nucleophilic sequence of attack was 1 @ 6 7 8 > 3 5 > 4. Position 1 is the most reactive centre and Position 3 is surprisingly unreactive, despite being adjacent to the ring nitrogen. At Position 3, the positive `adjacent-N' effect [20±22] overpowers the negative b-naphthalenic effect. The lack of reactivity in Positions 3 and 7 accords with smaller hyper®ne splittings and higher electron density (Table 5) at those sites. In per¯uoronaphthalene (C10F8) nucleophilic attack occur s mostly at the b-position (Position 2) whilst the a-position is less active. In the hepta¯uoroisoquinoline (C9F7N) the 6position is most reactive to the thiolate ion [23], one exchange giving 100% of the 6-isomer. The nature of the nucleophile has a substantial effect on the orientation of the attack [22]. In perchloronaphthalene (C10Cl8) nucleophilic attack occurs mostly at the a-position (Position 1). The b-position is less reactive. For the hydrocarbon isoquinoline, the electrophilic order of reactivity (which should be the reverse of nucleophilic attack) was [17] 4>57>8>3@1
for d-exchange
and 5>8>7>4>63@1
for nitration:
References [1] R.S. Matthews, J. Fluor. Chem. 91 (1998) 203 (Part IV). [2] J. Hutchinson, G. Sandford, Topics Current Chem. 193 (1997) 1. [3] G.M. Brooke, J. Fluor. Chem. 86 (1997) 1. [4] G. Fuller, J. Chem. Soc. (1965) 6264. [5] R.D. Chambers, M. Hole, W.K.R. Musgrave. R.A. Storey, B. Iddon, J. Chem. Soc. C (1966) 2331. [6] J. Su, E. Siew, E.V. Brown, S.L. Smith, Org. Magnetic Resonance 11 (1978) 565. [7] R.S. Matthews, M. Jones, J. Banks, Magnetic Resonance Chem. 27 (1989) 841. [8] J.H.H. Meurs, W. Ellenberg, Tetrahedron 47 (1991) 705. [9] A. Konno, M. Shimojo, T. Fuchigami, J. Fluor. Chem. 87 (1998) 163. [10] J.H. Clark, D.J. Nightingale, J. Fluor. Chem. 78 (1996) 91. [11] R.D. Chambers, S. Nishimura, G. Sandford, J. Fluor. Chem. 87 (1998) 68. [12] A.J. Woytek, Abstr. Papers ACS 207 (1) (1994) 1.
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R.S. Matthews, A.N. Matthews / Journal of Fluorine Chemistry 105 (2000) 35±40
[13] R.S. Matthews, J. Fluor. Chem. 48 (1990) 7. [14] R.S. Matthews, Org. Magnetic Resonance 8 (1976) 628. [15] G.W. Gribble, D.J. Keavy, E.R. Olson, I.D. Rae, A. Staffa, T.E. Herr, M.B. Ferraro, R.H. Contreras, Magnetic Resonance Chem. 29 (1991) 422. [16] R.S. Matthews, Org. Magnetic Resonance 8 (1976) 240. [17] W. Brugel, Handbook of NMR Parameters, Vol. 2, Heyden, Paris, p. 617. [18] G. Grethe, Heterocyclic Compounds: Isoquinoline, Vol. 36, Wiley, New York, 1981, p. 30.
[19] G. Grethe, Heterocyclic Compounds: Isoquinoline, Vol. 36, Wiley, New York, 1981, p. 20. [20] R.D. Chambers, M.J. Seabury, D.L.H. Williams, J. Chem. Soc., Perkin Trans. 1 (1988) 251. [21] R.D. Chambers, M.J. Seabury, N. Hughes, D.L.H. Williams, J. Chem. Soc., Perkin Trans. 1 (1988) 258. [22] R.D. Chambers, J.A.H. McBr ide, W.K.R. Musgrave, J. Chem. Soc. C (1968) 2116. [23] G.M. Brooke, R.D. Chambers, C. Drury, M. Bower, J. Chem. Soc. Perkin Trans. 1 (1993) 2201.
19
F NMR spectroscopy of polyhalonaphthalenes Part V. Halex reactions of polychloroisoquinolines Raymond S. Matthews*, Adam N. Matthews High Force Research, Bowburn, Durham DH6 5PF, UK Received 21 January 1999; accepted 13 March 2000
Abstract Nucleophilic ¯uoride ¯uoro-dechlorination of four isoquinolines (5,6,7,8-tetrachloro-,3,5,6,7,8-pentachloro-,3,4,5,6,7,8-hexachloro- and 1,3,4,5,6,7,8-heptachloro-isoquinoline) led to the preparation of 15 new polychloropoly¯uoro isoquinolines by reaction with caesium ¯uoride in DMSO at 1008C. The product from the perchloroisoquinoline was an inseparable mixture of C9Cl7ÿnFnN where n is 1±3. The order of reactivity in 1,3,4,5,6,7,8-heptachloro-isoquinoline [10] to nucleophilic attack by ¯uoride was 1 @ 6 7 8 > 3 5 > 4 # 2000 Elsevier Science S.A. All rights reserved. Keywords: Halex; Nucleophilic; Isoquinoline; Polychloroisoquinolines; Polyhaloisoquinolines; Fluorine NMR; Through-space
1. Introduction Nucleophilic ¯uoride ion exchanges in polyhalocompounds are ostensibly `non-selective' although the preceeding quinoline study [1] at 1008C shows that these reactions are more predictable than previously believed. Fluorine (F2) reactions can be non-speci®c but Hutchinson and Sandford [2] recently noted that the such exothermic reactions can now be controlled and could be described as selective. Brooke [3] has reviewed the known nucleophilic and electrophilic reactions of poly¯uoroaromatic and poly¯uoroheterocylic compounds, covering the literature until 1996. Halex reactions with potassium ¯uoride in sulpholane at 2008C were reported by Fuller [4] in 1965. Chambers et al. [5] reported the synthesis of hepta¯uoroquinoline and hepta¯uoroisoquinoline with KF in sulpholane in 1966. Su et al. [6] reported the carbon-13 shifts of mono and dichloroisoquinolines in 1978 whilst we reported the separation and C13 NMR of the hexachloro and pentachloroisoquinolines in 1989 [7]. The partial anodic ¯uorination of the hydrocarbons (isoquinoline, 1,10-phenanthroline and quinoline) in Et3N3HF reputedly only took place in the carbocyclic ring [8]. Recently, Konno et al. [9] investigated the use of Et4NF4HF as the support electrolyte in partial ¯uorination. Whether dryness is a necessity in these Halex ¯uorinations is debatable. Clark and Nightingale [10] have investigated the use of methylhexamethyltetramine ¯uoride *
Corresponding author.
for ¯uorodenitration in chlorocyanonitrobenzenes, where the ¯uoride source is the dihydrate which still selectively brings about denitration. Chambers et al. [11] have explored the potential of TDAE (tetrakis-dimethylamino-ethylene di¯uoride) for dry ¯uoride ion generation without a solvent or `dissolved in the reagent'. The most notable drawbacks with the known weak sources of ¯uoride ions are: poor solubility poor activity and moisture. whilst the more powerful fluorinating reagents tend to react `explosively' [12]. Here, we report the result of an investigation of the partially ¯uorinated isoquinolines, applying the same 19F substituent chemical shifts (SCSs) and the same solutionstate methodology [13]. The products of Halex reactions with CsF in aprotic dry DMSO at 1008C were identi®ed in an NMR tube. Presumably, the ¯uoride ion in solution will be exchanging readily at 1008C and exist in a bath of receptor sites, mostly the caesium cationic sites. 2. Experimental details Compounds are numbered as they appear in this article with IUPAC systematic ring numbering. 19F NMR spectra were measured on a Varian Mercury 200 at 188.18 MHz,
0022-1139/00/$ ± see front matter # 2000 Elsevier Science S.A. All rights reserved. PII: S 0 0 2 2 - 1 1 3 9 ( 0 0 ) 0 0 2 6 0 - 8
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R.S. Matthews, A.N. Matthews / Journal of Fluorine Chemistry 105 (2000) 35±40
both in dry d6-DMSO and d-chloroform, referenced to CFCl3 in CDCl3. Reactions (10 mg of a compound and 50 mg caesium ¯uoride, an excess) were followed for 96 h at 1008C in 1 cm3 of d6-DMSO. Samples were cooled to 228C for spectroscopic measurement. All our compounds had the correct integrals.
The systematic names for 1±19 are as follows: 1 5,6,7,8-Tetrachloroisoquinoline 2 5,7,8-Trichloro-6-fluoroisoquinoline 3 5,6,7-Trichloro-8-fluoroisoquinoline 4 5,7-Dichloro-6,8-difluoroisoquinoline 5 3,5,6,7,8-Pentachloroisoquinoline 6 3,5,7,8-Tetrachloro-6-fluoroisoquinoline 7 3,5,6,7-Tetrachloro-8-fluoroisoquinoline 8 3,6,8-Trichloro-6,8-difluoroisoquinoline 9 3,4,5,6,7,8-Hexachloroisoquinoline 10 1,3,4,5,6,7,8-Heptachloroisoquinoline 11 3,4,5,6,7,8-Hexachloro-1-fluoroisoquinoline 12 3,4,5,6,7-Pentachloro-1,8-difluoroisoquinoline 13 3,4,5,7-Tetrachloro-1,6,8-trifluoroisoquinoline 14 1,3,4,5,6,7-Hexachloro-8-fluoroisoquinoline 15 1,4,5,6,7,8-Hexachloro-3-fluoroisoquinoline 16 1,3,4,5,7,8-Hexachloro-6-fluoroisoquinoline 17 1,3,4,6,7,8-Hexachloro-5-fluoroisoquinoline 18 1,3,4,6,8-Pentachloro-5,7-difluoroisoquinoline 19 1,3,4,5,6,8-Hexachloro-7-fluoroisoquinoline
3. Assignment of
19
F spectra
(A) The reaction of 5,6,7,8-tetrachloroisoquinoline {1} with caesium ¯uoride in DMSO at 1008C. The 19F shifts from run A are summarised in Table 1. Two products were visible after 20 min at 1008C and assigned to the F6 product (ÿ104.86 ppm) {2} and F8 product (ÿ119.13 ppm) {3}. It is notable at this point that all the previously-reported 19F shifts of polychloromono¯uoronaphthalenes were in the range ÿ100 to ÿ110 ppm. The Table 1 Summary of shifts in reaction (A) DMSO ÿ104.86 ÿ108.12 ÿ119.13 ÿ121.86
F6 F6 F8 F8
{2} {4}, JF6,F85.5 Hz {3} {4}, JF6,F85.5 Hz
Scheme 1. NIMs prediction for the 19F shifts of two alternative structures for compound {4}: either 5,7-difluoro-6,8-dichloroisoquinoline (top structure) or 5,7-dichloro-6,8-difluoroisoquinoline (middle structure). The experimental shifts are superimposed on the correct structure (bottom structure).
peaks for compounds {2} and {3} were in the approximate ratio 60/40 and can be assigned directly or via our assignment of compound {4} below. Two peaks (1:1) of a third new compound subsequently appeared. Both peaks were doublets (JF6,F85.5 Hz) and 3 ppm down-shift of compounds {2} and {3}, a typical meta-coupling and typical down-shifts on both ¯uorines. A NIMs (Nitrogen insertion method) prediction for the 19F shifts of compound {4} was attempted for the two alternative structures, both the carbocyclic meta di¯uoro-isomers (Scheme 1). 19 F NIMs are the `real experimental differences in a single spectrum' for a mixture of octa¯uoronaphthalene and hepta¯uoroisoquinoline in either CDCl3 or dry DMSO (all seven values are given in Table 4). The 19F shifts for octa¯uoronaphthalene CDCl3 were ÿ145.59 and ÿ154.05 ppm with respect to internal CFCl3; the assignment for hepta¯uoroisoquinoline was reported in 1976 [14]. The peaks for octa¯uoronaphthalene were always sharp under these wide-shift observations. 19 F NIMs describes the hypothetical insertion of a nitrogen atom in a naphthalene molecule (6,8-dichloro-5,7di¯uoronaphthalene) where the 19F shifts of our model
R.S. Matthews, A.N. Matthews / Journal of Fluorine Chemistry 105 (2000) 35±40
naphthalene are known [15]. The b-¯uorine shift was chosen for this prediction because 1. the b-fluorine does not have a peri-problem and 2. they are more remote from the site of change. Thus, for F(6), the predicted value of ÿ105.7 ppm in accord with the experimental value of ÿ108.1 ppm of the second structure and discord for an F(7) assignment of the first structure. The new compound {4} must be 5,7-dichloro-6,8difluoroisoquinoline. (B) The reaction of 3,5,6,7,8-pentachloroisoquinoline {5} with caesium ¯uoride in DMSO at 1008C. The starting material appeared pure by proton NMR (separation in [7]). The reaction appeared to progress quickly. After 12 h, a broad peak at ÿ140 ppm was attributable to ¯uoride ion. A typical spectrum could be described as follows in Table 2. After 20 min, two peaks were visible and were assigned to the mono-substituted products {6} and {7} where the integration ratio was 70:30%. Reaction at C6 again dominated this sequence. The assignment of the shifts of products {6} and {7} follows the logic used in the above reaction. After 18 h, the peaks at ÿ105 and ÿ120 ppm indicate the 6,8-meta di¯uoro-compound {8} via the 4-bond meta JF6,F86.0 Hz. Such values would be described as through-bond and not through-space, although a throughspace contribution to the meta-coupling could not be ruled out. At this stage C3 was only just beginning to react and a compound containing F3 was a minor component in the mixture. Peaks at ÿ106 and ÿ125 were unattributed. Both the chlorines, at C6 and C8, in the carbocyclic ring proved more reactive than the `isolated' chlorine at C3 in the heterocyclic ring. (C) Reaction of 3,4,5,6,7,8-hexachloroisoquinoline {9} with caesium ¯uoride in DMSO at 1008C. Only very slow exchanges occurred between 3,4,5,6,7,8hexachloroisoquinoline {9} and ¯uoride. Two sharp peaks appeared at ÿ100.5 and ÿ123.92 ppm. Fluoride ion peaks were visible at ÿ100 and ÿ144 ppm. (D) The reaction of 1,3,4,5,6,7,8-heptachloroisoquinoline {10} with caesium ¯uoride in DMSO at 1008C. The starting material appeared pure by proton NMR with no proton peaks. The reaction progressed quite smoothly, quickly and showed many products after 1 h. A typical, complicated spectrum is described in Table 3. Table 2 Summary of shifts in reaction (B) DMSO ÿ102.26 ÿ105.34 ÿ106.09 ÿ117.39 ÿ119.65 ÿ125.32
F6 {6} F6, JF6,F86.0 Hz {8} F8 {7} F8, JF6,F86.0 Hz {8}
37
Table 3 Summary of shifts in reaction (D) DMSO ÿ54.16 F1 s {11} ÿ58.9 F1, JF1,F889.6 Hz {12} ÿ58.95 F1, JF1,F886.9H z {13} ÿ66.84 F3 s {15} ÿ67.16 m ÿ93.67 F6 s {16} ÿ97.03 F6, J6.0 Hz {13} ÿ103.85 s F8 {14} ÿ104.85 s F5 {17} ÿ106.85, JF1,F889.6 Hz F8 {12} ÿ107.00 d, JF5,F77.1 Hz F5 {18} ÿ108.16 d ÿ108.69 s F7 {19} ÿ109.5 dd, JF1,F886.9, JF6,F86.0 Hz F8 {13} ÿ111.62 d, JF5,F77.1 Hz F7 {18} ÿ111.75 dd
The single exchange product (1-¯uoro-) {11} dominated (65% see Table 5) the early spectra and appeared to lead to many di¯uoro-compounds in a complex mixture, one of which was the 1,8-di¯uoro-pentachloroisoquinoline {12} with a doublet at ÿ59 ppm and a sharp doublet at ÿ106 ppm where the F,F coupling is 89.6 Hz. A doublet of doublets at ÿ109 displayed a through-space coupling JFF of 86.9 Hz and was F8 of the F1,F6,F8-tri¯uoro compound {13} with peaks at ÿ59, ÿ97 and ÿ109 ppm. Through-space F,F coupling constants are those greater than 50 Hz (all positive), whereas through-bond are less than 40 Hz in these aromatic systems [15]. For example, 32.2 Hz, attributed to a para F,F coupling in the heterocyclic ring, was the largest through-bond coupling. 19F NIMS style predictions for compound {13} 1,6,8-tri¯uoropentachloroisoquinoline are presented in Scheme 2, using the original 19F NIMs values in Table 4 (for hepta¯uoroisoquinoline) and the new NIMs values from the 19F shifts of compound {4} in reaction A above i.e. F6 SCS for NIMs at position-2
6:2 ppm
F8 SCS for NIMs at position-2
0:4 ppm
In Scheme 2, the 19F shift of F1 is not predicted accurately by the NIMs method (being adjacent to the N atom) and is Table 4 Nitrogen insertion method SCSs in ppm for heptafluoroisoquinoline [15] Position
CDCl3
DMSO
F1 F3 F4 F5 F6 F7 F8
83.52 57.68 ÿ9.68 ÿ0.0 9.06 0.57 6.19
83.40 55.46 ÿ9.05 ÿ0.41 8.57 0.89 5.63
38
R.S. Matthews, A.N. Matthews / Journal of Fluorine Chemistry 105 (2000) 35±40
Scheme 2. 19F NIMS style predictions for compound {13} using the original 19F NIMs values in Table 4 (top structure) and the new NIMs values from 19F shifts of reaction (A) (middle structure). The experimental 19 F shifts of compound {13} (1,6,8-trifluoropentachloroisoquinoline) are given (lower structure).
thus excluded from our NIMs table. The SCS method, based on the experimental shift in hepta¯uoroisoquinoline [15], proved more accurate. That value was ÿ62.9 ppm, adjusted by 9 ppm for a peri chlorine SCS (in italics) giving a prediction of ÿ53.9 ppm. In compound {11} 3,4,5,6,7,8hexachloro-1-¯uoroisoquinoline, F1 is found at ÿ54.1 ppm. The peri-SCS (Cl to F), for an a-¯uorine, were ÿ7.6 ppm for F4 in hepta¯uoroquinoline [16], ÿ9.0 ppm for F5 in
hepta¯uoroquinoline [16] and ÿ6.44, ÿ6.85, ÿ7.98 ppm in Part 1 [1] for polychloronaphthalenes. Experimentally, for hepta¯uoroisoquinoline, we found ÿ4.8 ppm for F1 and ÿ3.0 ppm for F8. It was probable that the monosubstituted F8 {14} was a sharp singlet at ÿ104 ppm. Single exchange at C3, adjacent to the nitrogen atom, led to compound {15} 1,4,5,6,7,8-hexachloro-3-¯uoroisoquinoline. 19F prediction was based on the shift of F3 in hepta¯uoroisoquinoline [15] at ÿ98.5 ppm, adjusted for an ortho¯uorine to chlorine SCS (25.8 ppm), to give a prediction of ÿ72.3 ppm. A small peak was found at ÿ66.8 ppm. Possible single exchange at C4 in compound {10} would give hexachloro-4-¯uoroisoquinoline which was not found in our spectrum. 19 F prediction for F4 led to: ÿ155.93 ppm in hepta¯uoroisoquinoline [15]; 25.8 ppm adjusted for an ortho-chlorine (25.8 ppm) and ÿ130.1 ppm. No peaks were visible in the region ÿ125 to ÿ135 ppm. A further singly-substituted compound was 1,3,4,5,7,8hexachloro-6-¯uoroisoquinoline {16}, a singlet at ÿ93.7 and 3 ppm upshift from F6 in compound {13}. Singlysubstituted peaks for F5 {17} and F7 {18} were traced by both being 3 ppm upshift from the di¯uorinated compound {19} which displayed a coupling of 7.1 Hz. The initial reactions of heptachloroisoquinoline {10} are shown in Scheme 3, including compounds {10}, {11}, {12} and {13}. Interestingly the reaction is dominated by sequential exchange at F1, then F8, then F6. Other sequences/ compounds are not found in our spectra. So far these shifts are internally consistent. For example, meta SCSs were ÿ2.50 ppm 0.5 ppm throughout this study. At the end of 96 h, the F1 compounds had formed oligomers. 4. Relative reactivity at the different sites in heptachloroisoquinoline {10} The relative reactivities of the seven sites in heptachloroisoquinoline {10} are summarised in Table 5. The 19F integrals, for this speci®c reaction, were measured from the initial spectra (15 min after the reaction started).
Table 5 Summary of integrals for initial attack in heptachloroisoquinoline {10} Position F1 F3 F4 F5 F6 F7 F8
19
F Chemical shifts (ppm) ÿ54.16 ÿ66.83b ÿ104.85 ÿ93.7 ÿ108.69 ÿ103.85
a b
For the parent hydrocarbon isoquinoline. Overlapping peaks.
Integrals (%)
Proton shifts (ppm) [17]a
Hyperfine splittings [18]a
HMO electron density [19]a
65 4 0 4 8 6 7
9.14 8.45 7.50 7.70 7.56 7.48 7.85
5.38 0.37 4.01 3.95 3.26 0.04 6.26
0.8261 0.7022 1.0609 1.0776 0.9425 0.9251 1.0378
R.S. Matthews, A.N. Matthews / Journal of Fluorine Chemistry 105 (2000) 35±40
39
Scheme 3. Sequential fluoride exchange in compound {10} (top of scheme) led to compounds {11} {12} and {13}.
For {10}, the nucleophilic sequence of attack was 1 @ 6 7 8 > 3 5 > 4. Position 1 is the most reactive centre and Position 3 is surprisingly unreactive, despite being adjacent to the ring nitrogen. At Position 3, the positive `adjacent-N' effect [20±22] overpowers the negative b-naphthalenic effect. The lack of reactivity in Positions 3 and 7 accords with smaller hyper®ne splittings and higher electron density (Table 5) at those sites. In per¯uoronaphthalene (C10F8) nucleophilic attack occur s mostly at the b-position (Position 2) whilst the a-position is less active. In the hepta¯uoroisoquinoline (C9F7N) the 6position is most reactive to the thiolate ion [23], one exchange giving 100% of the 6-isomer. The nature of the nucleophile has a substantial effect on the orientation of the attack [22]. In perchloronaphthalene (C10Cl8) nucleophilic attack occurs mostly at the a-position (Position 1). The b-position is less reactive. For the hydrocarbon isoquinoline, the electrophilic order of reactivity (which should be the reverse of nucleophilic attack) was [17] 4>57>8>3@1
for d-exchange
and 5>8>7>4>63@1
for nitration:
References [1] R.S. Matthews, J. Fluor. Chem. 91 (1998) 203 (Part IV). [2] J. Hutchinson, G. Sandford, Topics Current Chem. 193 (1997) 1. [3] G.M. Brooke, J. Fluor. Chem. 86 (1997) 1. [4] G. Fuller, J. Chem. Soc. (1965) 6264. [5] R.D. Chambers, M. Hole, W.K.R. Musgrave. R.A. Storey, B. Iddon, J. Chem. Soc. C (1966) 2331. [6] J. Su, E. Siew, E.V. Brown, S.L. Smith, Org. Magnetic Resonance 11 (1978) 565. [7] R.S. Matthews, M. Jones, J. Banks, Magnetic Resonance Chem. 27 (1989) 841. [8] J.H.H. Meurs, W. Ellenberg, Tetrahedron 47 (1991) 705. [9] A. Konno, M. Shimojo, T. Fuchigami, J. Fluor. Chem. 87 (1998) 163. [10] J.H. Clark, D.J. Nightingale, J. Fluor. Chem. 78 (1996) 91. [11] R.D. Chambers, S. Nishimura, G. Sandford, J. Fluor. Chem. 87 (1998) 68. [12] A.J. Woytek, Abstr. Papers ACS 207 (1) (1994) 1.
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[13] R.S. Matthews, J. Fluor. Chem. 48 (1990) 7. [14] R.S. Matthews, Org. Magnetic Resonance 8 (1976) 628. [15] G.W. Gribble, D.J. Keavy, E.R. Olson, I.D. Rae, A. Staffa, T.E. Herr, M.B. Ferraro, R.H. Contreras, Magnetic Resonance Chem. 29 (1991) 422. [16] R.S. Matthews, Org. Magnetic Resonance 8 (1976) 240. [17] W. Brugel, Handbook of NMR Parameters, Vol. 2, Heyden, Paris, p. 617. [18] G. Grethe, Heterocyclic Compounds: Isoquinoline, Vol. 36, Wiley, New York, 1981, p. 30.
[19] G. Grethe, Heterocyclic Compounds: Isoquinoline, Vol. 36, Wiley, New York, 1981, p. 20. [20] R.D. Chambers, M.J. Seabury, D.L.H. Williams, J. Chem. Soc., Perkin Trans. 1 (1988) 251. [21] R.D. Chambers, M.J. Seabury, N. Hughes, D.L.H. Williams, J. Chem. Soc., Perkin Trans. 1 (1988) 258. [22] R.D. Chambers, J.A.H. McBr ide, W.K.R. Musgrave, J. Chem. Soc. C (1968) 2116. [23] G.M. Brooke, R.D. Chambers, C. Drury, M. Bower, J. Chem. Soc. Perkin Trans. 1 (1993) 2201.