All target structures 1-9 are assembled by Sonogashira reactions as key steps. The Sonogashira reaction is a transition metal catalyzed cross coupling reaction, and is an efficient method to build up OPE structures.[151-153] For the understanding of the outcome of the following reactions, the mechanism will be briefly discussed.
The Sonogashira reaction is a palladium catalyzed coupling reaction co- catalyzed by a copper(+I) salt.[154] The catalytic cycle is displayed in Scheme 2. The acetylene is deprotonated by the amine base forming an acetylide and an amine salt as side product. To stabilize the acetylide and increase its nucleophilicity, the copper salt is required as a co-catalyst while forming the copper acetylide. The first step in the main catalytic cycle is an oxidative addition (a in Scheme 2). The active catalyst is an electron deficient palladium(0) species (Pd1) to which the halide bearing reagent is introduced and the palladium is oxidized (Pd2). The oxidative addition is the rate limiting step of the reaction. In a transmetallation step (b in Scheme 2) the palladium complex Pd3 is formed. Followed by the reductive elimination, the cross- coupled product is relieved and the active palladium catalyst is regenerated.
Pd0(PPh 3)4 Cu R' CuX R' amine amine HX Pd0L2 Pd+2 X R L L Pd+2 R L L R' R R' R X a b c Pd1 Pd2 Pd3 -2PPh3
Scheme 2: Catalytic cycle of a Sonogashira reaction. a: oxidative addition, b: transmetallation, c: reductive elimination. R = aryl. R’ = aryl, alkenyl, alkyl, SiR’’3. X = I, Br, OTf.
The most widely used catalysts are [Pd(PPh3)2Cl2] and [Pd(PPh3)4]. CuI is used as
co-catalyst. As base, amine bases are employed either directly as solvent or as reagents. There are many variables that dictate the overall efficiency of the catalytic cycle, including catalysts, amine base, solvent and the electronic and steric
characteristics of the organic electrophile and alkyne. Electron-deficient organic halides are more reactive to cross-couplings than electron-rich, while the opposite is true for alkynes.[154-156] The general reactivity order of the sp2 species is aryl iodide > aryl triflate ≥ aryl bromide >> aryl chloride.[154, 157]
For the assembly of target structure 1-9, several Sonogashira reactions were performed. The reaction conditions found to be generally applicable to most of these couplings were the following:
The acetylene and the aryl-iodide were dissolved in a 5:1 mixture of dry THF and diisopropylamine. 10 mol% [Pd(PPh3)4] and 10 mol% CuI were added and the
reaction mixture was stirred until complete at room temperature. The extent of the reaction was followed by thin layer chromatography (TLC). The reaction mixture was then evaporated, absorbed on silica gel and purified by column chromatography (CC). To prevent oxidative diacetylene-formation, the solvent mixture was degassed before use, and the reaction was performed under an inert argon atmosphere. These reaction conditions are in the following referred to as the standard Sonogashira conditions and where no further clarification is stated these conditions were applied.
Applying synthetic strategy I the symmetric compounds 1 and 3 were assembled in a single Sonogashira reaction (Scheme 3). 1-Acetylsulfanyl-4-iodobenzene (10)[158] and 1-4-bisethynylbenzene (11) were treated with the standard conditions.[159] After workup the crude was purified by CC to yield compound 1 as a beige solid in 79% yield.
Scheme 3: Synthesis of symmetric rod 1 and 3 following synthetic strategy I.
The dipyridine functionalized OPE derivative 3 was synthesized applying the standard conditions to 11 and commercially available 4-bromo pyridine (HCl-salt) (12). The substitution of the bromide required elevated reaction temperatures and
therefore the reaction was performed at 47 °C. After workup and CC compound 3 was isolated in a 67 % yield.
Target molecules 2 and 4 were synthesized applying synthetic strategy II. The electron withdrawing character of bromopyridines enabled monocoupling to 1,4-bisethynylbenzene (11). As the pyridines are electron poor aromatics, they withdraw electrons from the conjugated system which leads to a deactivation of the free acetylene in 13 and 15 and reduces the reactivity of a second coupling. Therefore 13 and 15 are achievable in acceptable yields in only one step. 4-Bromopyridine or 3-bromopyridine and 1,4-bisethynylbenzene were treated with the standard conditions at 45 °C. The mono coupled products 13 and 15 were isolated after workup and CC in 41% yield each. In a second Sonogashira reaction
13 and 15 were coupled with building block 10 and the two target molecules 2 and 4
were isolated in 87% and 76% yield as beige solids (Scheme 4).
The assembly of the monothiolated OPE 5 could not be performed efficiently by a comparable selective coupling strategy. For example, if bromo-benzene is reacted with 1,4-bisethynylbenzene (11) the monocoupled 1-ethynyl-4-(phenylethynyl)- benzene (17) was only isolated in 5 % yield. Therefore a stepwise synthesis is inevitable and synthetic strategy III was considered for the synthesis of 5.
N S O N N Br (PPh3)4Pd CuI (i-Pr)2NH THF 45°C 41% (PPh3)4Pd CuI (i-Pr)2NH THF rt 87% N N Br (PPh3)4Pd CuI (i-Pr)2NH THF 45°C 41% (PPh3)4Pd CuI (i-Pr)2NH THF rt 76% N S O 10 10 11 11 2 4 13 15 Br THF 60°C 5% 12 14 (PPh3)4Pd CuI (i-Pr)2NH 11 17 16
1-Bromo-4-iodobenzene (18) was treated with trimethylsilane-acetylene (TMS-acetylene) in a Sonogashira reaction using the standard conditions. The iodide-bromide selectivity in metal catalyzed coupling reactions is nicely reflected in this example, as 4-bromo-1-(2-trimethylsilyl-ethynyl)benzene (19) was isolated in 92% yield. 19 was then coupled with ethynylbenzene to give 20 in 64% yield. The TMS-protection group of the acetylene was cleaved with fluoride ions using tetrabutylammonium fluoride (TBAF). 20 was dissolved in THF and treated with a 1 M TBAF solution (in THF containing 5% water) at 0°C to yield the free acetylene 21 in good yield. In a final Sonogashira reaction 21 was coupled with 10 to give OPE 5 in a 79% yield as a beige solid.
Scheme 5: Synthesis of compound 5.
Compound 6 bears a 2,5-substituted pyridine as a central unit. The electron withdrawing character of pyridine towards the ortho and para-positions, activates the oxidative addition of 2,5-dibromopyridine in 2-position. Therefore, 2,5-dibromo- pyridine can be selectively substituted at the 2-position.[160] So if 2,5-dibromopyridine (22) is treated with ethynylbenzene in a Sonogashira reaction, 23 is observed as the main product in quantitative yields. The bromide 23 was coupled with 1-ethynyl-4- acetylsulfanylbenzene (29)[161] which directly led to the target structure 6, but only in very low yield (Scheme 6). Elevated temperatures were required for the substitution of the bromide which led to decomposition of building block 29. The acetyl protection group of the thiol is not stable under these harsher reaction conditions. To improve the outcome of this reaction, the thiol needs to be protected with a more stable protection group, or the bromide needs to be exchanged with iodide such that the reaction can be performed at room temperature.
N S O N Br N Br Br (PPh3)2Cl2Pd CuI NEt3 rt quant. (PPh3)4Pd CuI (i-Pr)2NH THF 55°C 2% 6 23 Ph 22 S O 29
Scheme 6: Synthesis of compound 5. Pyridine activates the bromide in alpha position and therefore the compound 23 is selectively formed.
For the synthesis of target molecule 7 different strategies were envisaged. The most straightforward pathway would have been synthetic strategy II. However, coupling pentafluoroiodobenzene with 1,4-bisethynylbenzene did not lead to the desired mono-coupled building block 1-((4-ethynylphenyl)ethynyl)-pentafluoro- benzene. Therefore a stepwise assembly was required and two different strategies (IV and V in Scheme 7) were considered. In the synthetic strategy IV the acetylene functionalized pentafluorobenzene 24, which is available directly from a Corey-Fuchs reaction sequence from the commercially available corresponding aldehyde, is coupled with the corresponding halide 25. On the other side, building block 27 can be assembled by a coupling-deprotecting sequence, and later coupled to the commercially available pentafluoroiodobenzene (26) (strategy V in Scheme 7).[162]
Scheme 7: Synthetic strategy IV and V for the assembly of target structure 7.
1-ethynyl-pentafluorobenzene (24) was synthesized with a Corey-Fuchs reaction starting from pentafluorobenzaldehyde (28) (Scheme 8)[163-165]. Therefore,
carbontetrabromide and triphenylphosphine were dissolved in dichloromethane. The aldehyde was added at 0 °C and the reaction mixture was stirred for 30 minutes. To remove the salts that form, the reaction mixture was filtrated over a silica gel plug. After evaporation of the solvents, the mixture was purified by CC to obtain 29 as a colorless solid. 29 has a high vapor pressure and needs to be handled with care to
prevent sublimation on the rotary evaporator or at high vacuum. Therefore dichloromethane was chosen as the eluent for column chromatography. If hexane:ethylacetate is used as an eluent system, the product is lost while evaporating the solvents. In a second step the dibromo-olefine is treated with two equivalents of lithiumdiisopropylamine (LDA) which leads to formation of the vinylcarbenoid. After an H-shift, the acetylene is formed and immediately deprotonated with the second equivalent LDA and the lithium salt is formed. After aqueous workup the free acetylene is obtained. To form LDA, diisopropylamine was dissolved in dry THF, and n-BuLi was added as a 1.6 molar solution in hexane at -78 °C. The freshly formed LDA was then transferred by a cannula to a -78 °C cold solution of the dibromo-olefine in dry THF. After stirring for 40 minutes at -78 °C and one hour at room temperature the reaction mixture was quenched with water. After work up and CC, the acetylene 24 was obtained as a colorless solid in 95% yield. Again, pentafluoro-ethynyl (24) has to be handled with care to prevent sublimation.
Scheme 8: Synthesis of building block 24 and 25.
The corresponding building block 25 was synthesized starting from the previously described 1-bromo-4-(2-trimethylsilylethynyl)benzene (19). After deprotection with TBAF, 32 was coupled in a Sonogashira reaction to 1-acetylsulfanyl-4-iodobenzene (10) to afford building block 25 in 80% yield.
Scheme 9: Attempted synthesis of target structure 7.
With both building blocks 24 and 25 in hand, the final Sonogashira coupling was aimed. However, all attempts for the synthesis of the fluorinated OPE through this
route failed (Scheme 9). One explanation could be that the perfluorinated benzene unit of 24 reduces the nucleophilicity of the acetylene, and disables it towards a
Sonogashira reaction with a bromide.
Scheme 10: Synthesis of target structure 7.
As an alternative pathway, synthetic strategy V was considered. Building block 27[166, 167] was coupled with commercially available pentafluoroiodobenzene (26) in a Sonogashira reaction and indeed, the desired fluoro functionalized OPE 7 was obtained in 32 % yield (Scheme 10).[162]
S O S O I (PPh3)4Pd CuI (i-Pr)2NH THF rt 87% 8 10 28 S O S O I (PPh3)4Pd CuI (i-Pr)2NH THF 37 °C 85% 9 10 29 S O S O
Scheme 11: Synthesis of the short OPEs 8 and 9.
The short OPEs 8 and 9 were readily accessible in one step. Coupling of 1- acetylsulfanyl-4-iodobenzene (10) to either ethynylbenzene (28) or 1-ethynyl-4- acetylsulfanylbenzene (29) led to the desired compounds 8 and 9 in 87 % and 85 %, respectively.
All compounds were fully characterized by melting point, TLC, 1H-NMR-spectra,
13C-NMR-spectra and mass spectroscopy (EI, MALDI-ToF or FAB). The elemental
analysis of the OPE structures were off, therefore the purity of the compounds was further proved by gel permeation chromatography (GPC) in an HPLC setup. The absorption spectra recorded in dichloromethane are depicted in Figure 42.
Figure 42: Absorption spectra of 1- 8 in dichloromethane.
All OPEs 1-7 have an absorption maximum between 320-332 nm with a shoulder at 340-351 nm. The pyridine containing compounds 2, 3, 4, and 6 further show a shoulder at 374-378 nm. The short OPE 8 has an absorption maximum at 293 nm with a shoulder at 310 nm.
The transport investigation experiments of the synthesized compounds 1-8 will be discussed in the following sections.