Porphyrin Synthesis

April 1st, 2007

In a three-necked, 1000-mL round-bottomed flask were placed 4-nitrobenzaldehyde (1.51 g, 10 mmol), 3,5-di-tert-butylbenzaldehyde (6.66 g, 31 mmol), and tetraphenylphosphonium chloride (75 mg, 0.2 mmol). The solids were dissolved in 400 mL of still-dried methylene chloride and the flask was sealed with rubber septa. Argon was bubbled through the solution for five minutes and pyrrole (3.0 mL, 43 mmol) was injected by syringe. The flask was covered with foil and boron trifluoride-diethyl etherate (0.6 mL, 5 mmol) was injected to begin the reaction. After 1 hour, DDQ (8 g, 35 mmol) was added as a solid to the dark brown-purple solution and the mixture was stirred overnight. The porphyrin products were isolated by flash chromatography on silica gel with 1:1 hexanes:methylene chloride as the eluant. The fast-running porphyrins were separated from each other on a second silica gel column with 80:50:1 hexanes:methylene chloride:triethylamine as the eluant. Unsubstituted tetra-3,5-di-tert-butylphenylporphyrin (Rf=0.57, 0.431 g, 0.4 mmol, 4 %) and the desired monosubstituted porphyrin product (Rf=0.13, 1.51 g, 1.5 mmol, 15 %) were produced in reasonable yields.

Note: I can’t find the exact reference at the moment, but it was almost certainly based on a procedure by J.S. Lindsey. I think it was a Tet. Lett. paper on how the yields for this reaction improve when salts are added (hence the addition of tetraphenylphosphonium chloride).

Previous Comments

  1. milkshake Says:
    April 1st, 2007 at 4:13 am I won’t tease you about the 15% yield because I worked in Prague right next to a porphyrin lab, my classmates were doing a thesis there and they showed me that after a big scale purification the porphyrins usualy leave a shiny metallic-like coating on the flask – rich in color and slim on weight. (Another lab on the same hallway was doing calixarenes – the same tar oligomer problem without the nice colors). But I wonder: what is the PPh4+ doing there? Do you need some phase-transfer catalyst, or what?
  2. Paul Says:
    April 1st, 2007 at 4:28 am Believe me, 15% was the best yield that I *ever* got. I was usually happy with 8% for these monosubstituted compounds. The other thing that was a pain in the ass was the reaction mixture was so mucky (with tons of DDQ byproduct plus linear condensation products that never cyclized) that you had to run two columns to get the stuff clean.I’ve seen people add Zn2+ (w/propionic acid as the solvent) to help aid the cyclization, but Lindsey showed that most organic soluble salts (using CH2Cl2) will improve yield. I’m not sure if they ever figured out what was happening, and I haven’t looked at the porphyrin literature in quite some time.
  3. Chemgeek Says:
    April 1st, 2007 at 10:55 pm As a former porphyrin chemist, I can relate to the excitement of a 15% yield for this type of reaction. There are just too many possibilities. I can also relate to the two or three column purification. Good God, that sucked. However, being able to follow compounds on the column using UV light was a bit satisfying.
  4. eugene Says:
    April 2nd, 2007 at 12:35 am The porphyrin lab that we teach to our undergrads gets higher yields, but it must be an optimized system. I still fear that lab though. The purple color gets everywhere no matter how much you warn them…
  5. Paul Says:
    April 2nd, 2007 at 12:54 am My guess is that you are having them make something that is symmetrical, probably tetraphenylporphine (TPP) or ZnTPP. In the above procedure, statistics alone deal a heavy blow to the yield. Anyway, you don’t want the undergrads messing around with liters of methylene chloride (TPPs are woefully insoluble, which is why you add those t-butyl groups) and grams of DDQ. You probably want them using the procedure that calls for heating in propionic acid, where the O2 that’s around is good enough to serve as the oxidant.
  6. excimer Says:
    April 2nd, 2007 at 1:48 am phthalocyanines are prettier… and about as much a pain in the ass to purify, but still prettier. I know where my loyalties lie.
  7. kiwi Says:
    April 2nd, 2007 at 7:04 am still remember that TPP prep from undergrad. the fact you get anything other than polymer (let alone purple organic crystals) still amazes me

12 Responses to “Porphyrin Synthesis”

  1. alexmdq Says:

    Hi, hope you are still there :)
    I am getting into porphyrin synthesis and almost no product using the Lindsay method. Even the very basic TPP. I distillated everything and still have problems. Is there any weel-known but not reported problem with that synthesis.
    Propionic acid synthesis works well, so the reagents seems to be OK.


  2. alexmdq Says:

    a post just for notifying

  3. Paul Says:

    Hi alexmdq,

    The Lindsay method is pretty standard, although yields for all porphyrin syntheses are notoriously bad. On the flip side, you are making something pretty big from small starting materials.

    I am not sure what is going wrong for you, but do you notice a color change upon addition of the BF3? Did you purge with N2 or Ar? Are you using CH2Cl2 as your solvent? It is good that you are distilling everything, which I assume includes the pyrrole and aldehyde, because they will go bad if allowed to sit out.

  4. alexmdq Says:

    Hi Paul, thanks for your answer.
    I have read several papers from Lindsay and other people using other
    strategies and I have problems only with Lindsay. I know that paper,
    and some other papers from him describes catalysis and co-catalysis
    with salts (tetraphenylphosphonium chloride) and alcohols (ethanol).
    So I think the dichloromethane quality is the key for that reaction.
    Too much purified seems to be actually worse.
    I am distillating my solvent from K2CO3 like Lindsay and, in a
    separate experiment, from CaH2. No results with any. My original
    solvent is ACS quality and it is not stabilized at the bottle. Do you
    remember what kind of dichloromethane did you use and how did you
    purified it? My guess is that the reaction works with some kind of
    impurity in the solvent, that K2CO3 (a weak dryer) does not purify.
    Maybe you know this cite Tetrahedron 60 (2004) 1863–1868. I tried and
    no reaction. I tried with several acids in that paper, and no
    reaction. Same pyrrole and benzaldehyde works in propionic
    acid and are distillated right before reaction. That
    is why I think my problem is in the solvent I use.
    By the way, trifluoroacetic is distillated with the anhydride present,
    BF3:Et2O is added neat.
    Protecting fron light means complete darkness like in actinometry?
    I did notice color changes after acid addition.
    Is there any way to identify the porphyrinogen formation NOT by oxidation?
    Maybe the problem is in the oxidation and porphyrinogen is there…
    Regards, and thanks again!

  5. Paul Says:

    We used a CaH2 still for our CH2Cl2.

    Weird. I can’t think of anything you missed. Maybe you should try a run with plain/unsubstituted pyrrole and benzaldehyde to see if it works for you? I never did anything to observe the porphyrinogen intermediate. I imagine monitoring the rxn mixture by UV will be a mess (and not very helpful).

    Good luck!

  6. alexmdq Says:

    I forgot! When I add tetraphenylphosphonium chloride and alcohol (ethanol) the reaction works better, but only 10% yield, not 25% not 50% like Lindsay says. No yield with TFA or BF3 alone.

  7. alexmdq Says:

    Yes, it is weird. I am doing TPP as training.
    Well, I keep trying. If I ever found whats going on.. I post it here and send it to publish.

  8. alexmdq Says:

    Hi Paul, I tried several things and I have about 30% yield now. Trifluoroacetic acid + BF3 works better. 0.1M in ethanol as cocatalizer works better. But, most of all, I had to add triethylamine to neutralize the solution (not to quench the TFA!). Even doing the oxidation with chloramine first, with the addition of TEA, I have a big purple spot in the TLC. It seems the TTP was there all the time, but not soluble. So I have no signal in the TLC.

    Hope this help someone else, thanks for the support.

  9. Paul Says:

    Did your columns before look really green? We noticed that when we added acids to our porphyrins our columns would often have a slow-running, streaked green band that appeared at the expense of the purple bands that are typically eluted first using CH2Cl2 on silica. For problem reactions, we would put 1% TEA in the solvent used to run the column.

  10. alexmdq Says:

    I have seen the green band in the silica TLC sometimes. I used to meet with greenish mixtures (black with greenish blend) after oxidation but I have not focused on how to reproduce that. In those cases, the purple spot in the TLC was very weak and there was lots of tar and solids in the solution (perhaps adding TEA to those solutions would have solved the problem!). I see the reaction turn dark brown after TEA, and now I have even saturation of TPP in the TLC (it crystallizes in the spot, and the center turns shiny violet)

    I usually pass the reaction mixture through a flash small Florisil column with CH2Cl2 and it is magical (about 1 gram each 100 mg of theoretical TPP). Dark stuff keeps at the column and purple TPP goes through like in a filter. What I have seen is that the green compound seems to run faster than TPP, but once it paints the Florisil phase it runs slower. Then, TPP wins. Perhaps the remaining acid runs the green spot faster until it dissapear in the column and leaves it at their normal speed with CCl2H2.

    After Florisil, I add an equal volume of hexane and seed it on a silica column (about 2 g each 100 mg theoretical TPP) with CCl2H2/hexane 50% and run the column increasing CH2Cl2.

    Last weird thing, if I heat the water in the rotavap over 60ºC , the purple solution turns yellow-brown and the solid is no more TPP. Last time, I bubbled air to evaporate the solution in cold. It was the only way to finish with a violet powder.

  11. Special Guest Lecturer Says:

    The green stuff is protonated porphyrin. Hit it with more base.

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