Org Prep Daily

February 24, 2008

Arnold Salt

Filed under: procedures — milkshake @ 5:33 pm


Anhydrous DMF 160mL in a 0.5L round flask was cooled on ice bath and neat POCl3 40 mL (436mmol) was added greadually over 10 min period (exothermic). The mixture was warmed up to RT, bromoacetic acid solid 19.00g (136.7 mmol, Aldrich 99%+) was added quickly in one portion (hygroscopic, wear gloves – bromoacetic acid and POCl3 are nasty). The flask was equipped with a reflux condenser and the mixture was stirred under Ar on oil bath at 90C for 9 hours. The mixture turned orange, with a slow CO2 evolution. The mixture was cooled to RT, DMF was distilled out on highvac (RT to 90C at 0.5 Torr) and the obtained thick residue was treated with ice-cold water 100mL on a sonicator bath. An exothermic hydrolysis commenced. When all residue dissolved and the mixture cooled to RT, solid sodium hexafluorophosphate 46.2g (275 mmol) was added in one portion followed by some additional water (50 mL). The mixture was shaken vigorously for 10 min, the precipitated product was collected using a large Buchner funnel. The solid cake was compressed on the frit, washed with ice-cold water (5x20mL), dried by suction and then on highvac.
Y=61.05g (94%) of a yellowish-white solid

1H(d6-DMSO, 400MHz): 8.439(s, 3H), 3.535(s, 9H), 3.376(s, 9H)

Note 1: The formylation is complete in 6 hours at 90C. KPF6 is probably a better source of hexafluorophosphate because unlike the sodium salt it does not hydrolyse readily, does not etch glass and is non-hygroscopic. Aqueous HPF6 can be also used. It is important to remove most DMF from the reaction mixture, this takes some time (I used a rotovap hooked to oil pump).

Note 2:  The product can be re-crystallised to analytical purity from MeCN + some antisolvent (THF) but the crude material is suitable for most purposes. 

Note 3: Bromoacetic acid can be replaced with bromoacetyl chloride or bromide – in such case the POCl3 amount can be reduced by one equivalent


  1. What is the Arnold salt used for?

    Comment by Chris — February 24, 2008 @ 6:07 pm

  2. It is a functional equivalent of triformylmethane (which can be made from it) and it is a very nicely-behaved solid. I am using it for heterocyclic chemistry.

    Comment by milkshake — February 24, 2008 @ 6:11 pm

  3. Is there another reason for making the PF6 salt other than precipitating it out from water?

    Comment by Ron — February 26, 2008 @ 5:36 am

  4. Not really. You can make bis-perchlorate (explosive) or bis-terafluoroborate (rather soluble, needs a re-crystallization in multiple crops for good yield) or bis-tribromide.

    Hexafluorophosphate is nicely-behaved and inexpensive to make. The only drawback I can think of is the high molecular weight.

    Comment by milkshake — February 26, 2008 @ 6:01 am

  5. with regard to mechanism…after initial Mannich and tautomerization to the vinylogous amide, a second Mannich is then followed by decarboxylation (intramolecular proton transfer perhaps?) At that point you still have the bromide at the central carbon which still needs to be reduced (formally). I can do another Mannich, but the reduction…what am I missing?

    Comment by synthon — March 1, 2008 @ 8:47 pm

  6. You are correct, some redox step must happen. There hasn’t been done any thorough mechanistic investigation but it is known that bromoacetic acid at 60C gives the regular product with the Vismeyer reagent, the iminium salt of bromomalondialdehyde. This iminium is not stable at 90C and further formylates reductively. How this happens I am not sure but dibromo-derivatives of malondiesters or malondinitrile are known to act as mild brominating agents: they transfer single bromine to other reactive methylene compounds. I suppose hererolysis of C-Br to anion and Br+ might be happening but I am not sure. (DMF itself is a reasonable reducing agent, I would not mix it with bromine).

    Comment by milkshake — March 1, 2008 @ 9:57 pm

  7. Perhaps there is some formic acid and HMPT generated?

    Comment by synthon — March 2, 2008 @ 10:54 am

  8. Colorful reaction! …. I prepared the perbromide analogue a few times as intermediate to TFM. I still have small scars in my arms thanks to bromoacetic acid 😛

    Comment by Luis — March 5, 2008 @ 5:27 pm

  9. Hi MS,

    1. Off topic again.. I would like to introduce CH2COOEt group in pyridine ring system. I got bromo pyridine with protected amino group (planning to protect the amino as trityl/any other bulk group)..Is it possible to use BrZnCH2COOEt reagent for this transformation? or please suggest me any synthetic equivalents of this group. It would be really helpful if you suugest any reagents which works in pyrdine bromo compounds…any organometallic reagents which are commericially available will be very conveninet..

    2. I would like to substiute bromo (protected amino) pyridines with imidazole. Please suggest me any amination method. also advise me a suitable protecting group for the amino group.. I am planning to try with 2-Bromo pyridine comopund initially..

    3. I would like to know the Pkas of this imidazole subtiuted pyridine compounds ..i really dont know whether pyridine nitrogen would act as nucleophile or the imidazole side chain..



    Comment by marto — April 26, 2009 @ 11:41 am

  10. 1-aryl substituted imidazole will be less basic than unsubst imidazole but that is all I know, you need to look in the literature for similar compounds. Beilstein/Crossfire has disociacion constants included as a search field/

    N-arylation of imidazoles: I would try uncatalyzed direct reaction first – heating the bromopyridine with excess of imidazole without a solvent, to high temperature, preferably in a microwave.
    There are copper-catalyzed imidazole arylations: JOC 74, 2200-2 (2009)
    Also there is a publication from Buchwald group, in Angew Chem 45 (39) 6523 – 6527 (2006). They have a curious pentamethyl substituted biaryl ligand that for the first time allowed Pd-catalyzed arylation on imidazoles. The ligand is available from Aldrich but it is rather expensive.

    For introducing carboxyethyl I would use malondiester: Org Lett 2005, 7(21) 4693-5 and then decarboxylate.
    Or you can use tBu acetate with a strong base: Org Lett 11(8), 1773-5 (2009)

    For protection of aminopyridines, you should look into Greene “Protective Groups” book because the choice will depend on your chemistry. If you are trying Boc I must warn you that aminopyridines do not react well with Boc2O under standard aqueous conditions (it produces lots of diaryl urea sideproduct) and they are best protected with Boc2O in the presence of a strong base like LiN(TMS)2 at low temperature.

    Comment by milkshake — April 26, 2009 @ 5:31 pm

  11. Your blogpost has been cited in a paper… (a first?):
    “Title: [not available]
    By: [Anonymous].
    [No title captured] Published: 2002

    Source of citation:
    O. V. Maltsev et al, Eur. J. Org. Chem. 2014, 7426.
    Synthesis of Soai Type 2-Arylpyrimidine-5-carbaldehydes through Desulfurative Cross-Coupling with Arylboronic Acids

    Comment by Look@s — December 17, 2014 @ 3:19 pm

    • I was surprised that you follow chemistry blogs, and that you would even put one into your paper as a citation. (I have seen our group’s publication list – and it is really good) Cheers!

      Comment by milkshake — December 18, 2014 @ 12:58 am

      • Hi Milkshake, I always like to read good synthetic procedures and had your blog in my literature RSS-feeds (when the Safari-browser still had an RSS-reader). Learning about Arnold’s salt here was one piece of the puzzle inspiring the “Soai” project (cf. also: Org. Lett. 2014, 16, 1282;; citing this post seemed like a way to acknowledge this. Best wishes!

        Comment by Look@s — December 21, 2014 @ 11:35 am

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