Hi everyone, I want to synthesize new derivatives from the reaction of bromonicotinic acid with derivatives of boronic acid by the suzuki reaction. I use Tetrakis(triphenylphosphine)palladium(0)
as a catalyst, dioxane: water as a solvent: (3: 1), K2CO3 as a base, the reaction is carried out under N2, after two hours a black precipitate forms at the bottom of the flask, there are also two liquid phases, crude oil at the bottom of the flask , Analyzed by TLC did not react. where am i wrong
It might be better to change solvent/base if these conditions are not working. Try anhydrous conditions. This article might be of help. Article Suzuki coupling reaction for the solid-phase preparation of ...
Hello Sabina, many thanks for sharing this very interesting chemical problem with the RG community. I'm certainly not a proven exert concerning Suzuki–Miyaura coupling reactions. However, my suggestion would be to change the solvent used in your reaction and avoid the use of water in your system. In this context, please have a look at the following potentially useful article which might help you in your analysis:
Regioselective palladium-catalyzed Suzuki–Miyaura coupling reaction of 2,4,6-trihalogenopyrido[2,3-d]pyrimidines
Article Regioselective palladium-catalyzed Suzuki–Miyaura coupling r...
In this study the authors also use tetrakis(triphenylphosphine)palladium(0)
as the catalyst and K2CO3 as the base, but the reactions are run in toluene as solvent. I would not be surprised if it is the water in your reaction mixture that caused the observed problems. In case that you need the full text of the article, please note that one of the authors has an RG profile (https://www.researchgate.net/profile/Said-Lazar). Thus you can easily contact him via RG and request the full text of the paper directly from him.
Good luck with your research work and best wishes, Frank Edelmann
Also check https://www.sciencedirect.com/science/article/pii/S1631074819300207
Kindly check on this paper.
https://chemrxiv.org/engage/api-gateway/chemrxiv/assets/orp/resource/item/60c74ec4bdbb8909cca39c3b/original/3d-printed-tetrakis-triphenylphosphine-palladium-0-impregnated-stirrer-devices-for-suzuki-miyaura-cross-coupling-reactions.pdf
Hi Sabina,
I had the same problem years ago. I solved it with the following steps.
1. Switch from triphenyl phosphine to 3,3′,3′′-Phosphanetriyltris(benzenesulfonic acid) [TPPTS] trisodium salt plus Pd(dppf)Cl2*CH2Cl2 (4 to one molar ratio of TPPTS to Pd complex).
2. Switch from a reversible amine base to 2-3 equivalents of tetraethylammonium hydroxide, available as a solution in methanol or water (I used methanol). You need enough base to neutralize all the nicotinic acid and one equivalent to pair with the bromide (in one of the reductive elimination steps of the coupling where HBr is liberated). The excess 0.5 to 1.0 of base keeps the mixture basic; this may be important as the boronic acid may be more reactive as the anion, Ar-B(OH)_3(-), which is present in equilibrium amounts when an excess of OH(-) or OMe(-) is present.
3. Why are you seeing a second layer form? The amine you are using is making an alkylammonium bromonicotinate salt that oils out, taking the nicotinic acid out of solution. This oil phase doesn't take up the catalyst. Methanol and tetraethylammonium hydroxide will form a salt that, if it does form a second phase, will be "chaotropic", i.e., will take up small pools of both aqueous and non-aqueous material. With rapid stirring (mechanical stirring preferably), about 1000 rpm, or as high as you can turn up the magnetic stirrer, you should see immediate product formation, complete in about an hour. If this works, please let the RG community know.
PS: Acidic phenols make 2nd phases with amine bases too; to see the effect, combine 2-nitrophenol with triethylamine in a 1:1 molar ratio. Any excess triethylamine floats above a viscous "salt"(or hydrogen-bonded complex) of triethylamine and 2-nitrophenol. Older versions of the Merck Index (prior to the 11th Ed.) formerly mentioned this effect under either the o-nitrophenol entry or the triethylamine entry. Don't know why they took it out. I guess you have to be an old chemist to remember it.
When you are using zero or low-valent metal complexes such as Pd(PPh3)4, Ni(COD)2 or Pd2dba3 (dba = dibenzylidene acetone), you should carry out reactions in non-aqueous medium, strictly under inert atmosphere. Please follow the suggestions made by Edelmann. Use a combination of palladium acetate/PPh3 (excess, you need at least three molecules per palladium to generate Pd(PPh3)2 moiety as an active species. Pd(PPh3)4 also generates the same species through ligand dissociation, but palladium acetate (trimeric in nature) is easy to handle compare to highly sensitive Pd(PPh3)4, unless you are equipped to handle it.
Best wishes
Balakrishna
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