Org Prep Daily

November 2, 2009

Easy Iodination of Alkynes

Filed under: krest17, procedures — milkshake @ 8:23 pm

iodination1

The question was: how to perform this reaction in a clean way (no column purifications, no distillations), cheap (if possible, no Ag salts or any other expensive metals), easy (if possible, no Ar and no Schlenk flasks, open air, solvents from bottles), scalable (well, this combines first three I guess), general (yes, I needed a library of these compounds with different functional groups and had no desire to develop different procedures for each of them separately).
Quick look in SciFinder showed two procedures as mostly used and welcomed by scientists; (a) using silver nitrate and NIS (posted on this website some time ago by Chris Douglas  (b) deprotonation with nBuLi in THF or Ether under Ar followed by quench with I2. Obviously, they could not meet my criteria. First approach required using of Ag salts and not so cheap and stable NIS, second one needed anhydrous conditions, cooling, flammable nBuLi and yes – Schlenk flasks and Schlenk line. It is not like I could not do it and I do have Schlenk line under my hood, but… sometimes 10-15 min more in SciFinder can save a lot of pain in the neck.
So, I found procedure from Scott E. Denmark (Tetrahedron 2004, 60, 9695) for the desired iodination in MeOH/H2O using KOH as a base and I2 to deliver I+. Although, this procedure was used only for omega-OH acetylenes, which could be the trick, I decided to give a shot. Reaction worked as a magic – easy, open flask, no cooling or heating, all reactants are cheap and could be found in any lab, water from tap and methanol from bottle. Yields are generally over 80% and no column needed. Below are some selected substrates I did.

iodination2

Here is the magic procedure:

To a solution of alkyne (50 mmol) in MeOH (50 mL) was slowly added an aqueous solution of KOH (2.5 equiv) in water (10-12 mL) at rt. (I tried recommended 0°C and did not find any difference). After 10 min I2 (1.5 equiv.) was slowly added within 3-5 min at rt (I tried recommended 1.1 equiv. but could not reach full conversion). The mixture was diluted with H2O and extracted with pentane. The combined organic layers were concentrated and filtered through 3-5 cm plug of silica gel. Silica gel was washed with pentane till disappearance of spot of product on TLC. Pentane was evaporated and … that’s it. For all substrates I did so far purity of product was >95% by NMR and GC.

Thank you for reading.

40 Comments »

  1. any interesting experiences with 1-iodoalkynes? Diiodoacetylene was seriously considered as a suffocating chemical warfare agent but was abandoned because of poor stability and shock sensitivity.

    Also, I worked next to a postdoc who needed lots of 1-iodopropyne and he complained that the stuff was highly irritating, and it also had a tendency to suddenly violently decompose in a burst of smoke – once it happened in my presence when he spilled few drops from a pipette. (He was the kind of guy who was not afraid of pounding 100g chunks of barium rod with a sledgehammer to make Ba metal foil, but 1-iodopropyne made him nervous…)

    Comment by milkshake — November 2, 2009 @ 8:41 pm

    • 1-Iodoalkynes are just starting materials for me, and yes, time to time for whatever reason they decompose. Normally I use them the same day and trying not to keep them. But nC6H13CCI is in my fridge for several weeks already – so far, so good. Second step is kind of fun also – maybe I will post it next week.

      Comment by krest17 — November 2, 2009 @ 8:53 pm

    • i’ve heard about the shock sensitivity of iodoacetylenes…are some more stable than others?

      Comment by psi*psi — November 3, 2009 @ 2:02 am

      • I never worked with them but given that C triple C bond part is highly endothermic in itself, I guess it can be a function of the molecular weight like with azides – a small MW alkylazide is bad news. (Compressed acetylene gas for welding comes diluted with acetone so as to not blow up inside the tank). Maybe iodoacetylenes have lower barrier for going into pieces than acetylenes themselves.

        Comment by milkshake — November 3, 2009 @ 2:11 am

      • Well, nothing happened so far, thanks God. Anyway, if one of them finally explode you will here it first ;-)

        Comment by krest17 — November 3, 2009 @ 2:41 am

  2. This is actually a common theme where I hang my hat. The standard way we add alkyne anion to electrophillic things is the make the Na salt with 50% NaOH (dirt cheap) and feed in the ketone, I2, alkyl halide… what ever. Works really well, especially if you have a tank of acetylene around. Adding sodium acetylide to a ketone followed by reduction is the cheap and easy (and high yielding) way to circumvent the purchase of expensive vinyl grignard.

    Comment by organikchemist — November 2, 2009 @ 8:46 pm

  3. Sharpless recently came out with a paper where he synthesizes a number of iodoalkynes using, CuI and a really easy-to-make iodinating agent. Chromatography-free, of course

    http://www3.interscience.wiley.com/journal/122603818/abstract

    Comment by SN — November 2, 2009 @ 9:19 pm

    • Very good procedure, but you need to use CuI (5 mol%) and iodination agent you still need to prepare (even if it is very easy).

      Comment by krest17 — November 2, 2009 @ 9:42 pm

  4. Stupid question: what do people use iodoalkynes for? It’s not the formation of vinyl iodides, I’m guessing.

    Comment by Chemjobber — November 2, 2009 @ 9:22 pm

    • Yep, right guess :-) It is for vinyl iodides.

      Comment by krest17 — November 2, 2009 @ 9:42 pm

    • And definitely not for making iodotriazoles ;)

      Comment by LiqC — November 2, 2009 @ 11:03 pm

      • That’s for sure

        Comment by krest17 — November 2, 2009 @ 11:04 pm

  5. That prep works beautifully for propargyl alcohol as well. Just pop the reagents in, wait till
    the color of iodine disappears and voila.

    Comment by Just a thought — November 3, 2009 @ 2:17 pm

  6. How’d you monitor this reaction? Is there a worthy difference btw the acetylene and iodide?

    Comment by HB — November 3, 2009 @ 3:07 pm

    • I did it by GC/GCMS. Have no idea about TLC – but I will try.

      Comment by krest17 — November 3, 2009 @ 3:53 pm

  7. somewhat tangential, but did anyone see this paper that just came out? Looked cute. I wonder if calcium carbide can be a useful alternative to acetylene in most cases.

    Comment by excimer — November 4, 2009 @ 1:59 am

    • Excimer I owe you a big hug – just this afternoon we were discussing with my boss the hassle of ordering acetylene tank and regulator for an experiment that uses acetylene gas, and how to get rid of the acetone stabilizer in it…

      How could I have forgotten about those smelly chunks of calcium carbide that I used for pyromaniac experiments as a kid? And my dad still carries around a quarter-inch piece of glass lodged in the skull under the skin behind his left ear from dynamite fishing that went wrong – as kids they were actually using glass jam jars with water and calcium carbide.

      Comment by milkshake — November 4, 2009 @ 2:31 am

      • Eh-he-heh, we also did glass bombs with carbide, that’s was fuuun. Likely nobody was injured.

        Comment by krest17 — November 4, 2009 @ 9:15 am

      • Idea is not hew of course, here is nice paper from 1900 “laboratory method for the continuous and uniform generation of acetylene, and for its purification” DOI: 10.1021/ja02040a009. Hope you will find it useful.

        Comment by krest17 — November 4, 2009 @ 9:52 am

      • This one from 1918 is cool as well. They claim generation of dichloro-acetylene in situ. DOI: 10.1021/ja02235a009

        Comment by krest17 — November 4, 2009 @ 10:33 am

  8. Any way to turn those beautiful sp iodides into trans-vinyl iodides? I’ve use diimide reductions to form the cis-vinyl iodides but I couldn’t find a way to get the trans (hence the Takai reaction).

    Comment by JPB — November 4, 2009 @ 10:04 am

    • I did library of trans-vinyl diodes and bromides in one step directly from acetylenes with in situ generated Cp2ZrHCl (Lipshutz procedure TL 1990) followed by quench with I2 or NBS. Works perfect, over 99% E and normally over 80% isolated yield.

      Comment by krest17 — November 4, 2009 @ 10:29 am

      • Cp2ZrHCl? Use the Schwartz!

        Comment by excimer — November 4, 2009 @ 12:18 pm

      • Ok, buddy, Schwartz :-). I just wanted to say that there is no need to buy it, you can easily prepare it in situ (it really works great) and use directly.

        Comment by krest17 — November 4, 2009 @ 1:09 pm

      • I was going for the Spaceballs reference. Foreigners…

        According to many sources (all heresay, I’ve never dealt with the stuff), making Cp2ZrHCl in situ apparently works better than using the commercially-available stuff since the Schwartz is very sensitive to ambient conditions.

        Comment by excimer — November 5, 2009 @ 6:51 pm

      • 100% agree with you and literature – I checked it on my own ass ;-(

        Comment by krest17 — November 5, 2009 @ 7:16 pm

  9. I also tried those Denmark conditions few months ago. What is interesting is that initially i had a lot of trouble in reproducing those reactions (even though I was making the homolog of the compound reported in that paper). I was desperate and then decided to borrow different I2 (granulated) from a neighbouring lab and it worked perfectly :)
    I still don’t understand and can’t explain why the hell it was not working with our own I2 (even though it was an OK quality)

    Comment by TA — November 5, 2009 @ 7:27 am

    • perhaps it was too pure. I would check for traces of Cu.
      This would be easy enough to verify – take that I2 that worked, do atmospheric-pressure sublimation and try again if the re-sublimated stuff works as well – and maybe avoid using a metal spatula as to exclude metal impurities. (I2 reacts with metals rather fast – thats why methyl iodide comes stabilized with Cu powder – so it is possible it got contaminated with trace quantity of Cu during handling and packaging by the manufacturer.)

      Comment by milkshake — November 5, 2009 @ 8:17 am

  10. But, krest, I am extremely surprised you didn’t require the addition of a thermometer to this reaction, to monitor internal temperature! :D

    Comment by HPCC — November 10, 2009 @ 11:43 am

    • Happy to hear from you. No, no thermometer this time, no need, although as you know, I love to have it inside :-) Where are you now, write me.

      Comment by krest17 — November 10, 2009 @ 5:50 pm

      • A long-immersion thermometer can be great for all those places that a gerbil cannot reach. (Just make sure not to break it.)

        With regards to HPCC: if you go to “comments” in the menu on the left , and click on the IP address under his comment, that will give you all comments sent from that IP (together with all e-mail addresses and aliases that he used in the past – that should give you the actual name, either directly or with some googling). Then copy the IP and use ARIN WHOIS or RIPE or APNIC to find which company/location is he posting from. I am stalking people here like this all the time – how do ya think I found that you were a Knochel/KCN disciple…

        Comment by milkshake — November 10, 2009 @ 6:10 pm

  11. I tried this reaction a few times, it was relatively meager, and then I found this rather simpler prep….
    Oshima et al., Tetrahedron, 1999, 55, 9469.

    The group uses morpholine (although they misspell it as morphorine) as the base, and solid iodine, all of which are stirred with the substrate in benzene and allowed to stir at 60 C for 2hr. Worked like a charm, and in quantitative yield.

    Although I am still baffled at the ease of deprotanation in regards to aqueous pKas.

    Best of luck

    Comment by Raincoat — November 10, 2010 @ 2:09 pm

  12. Hi MS,

    Bit off topic..

    I need to couple 1-Propyne with aryl iodoides. Is there any synthon for this (high boiling / Protected derivative) transformation?.

    If you have any experince, it would be really helpful.

    Thanks

    Marto

    Comment by marto — February 1, 2011 @ 2:27 pm

    • I would use a balloon and perform Sonogashira similarly to hydrogenation at atmospheric pressure (with vacuum/argon/vacuum/propyne purge). This Sonogashira with aryl iodide should work at room temperature.
      Pure propyne is expensive but a good economical alternative should be the technical mix of propyne and allene (“Methylacetylene-propadiene MPS gas”) that is used as a explosion-safe welding fuel alternative to acetylene. Presence of allene should not interfere with conventional Sonogashira – I would just use large excess of the gas mix, maybe even as a sparge.

      Comment by milkshake — February 1, 2011 @ 3:27 pm

  13. Thanks very much for the suggestions.

    Marto

    Comment by marto — February 1, 2011 @ 11:56 pm

  14. Any chance you can remember the reaction time needed for phenylacetylene? Following it by TLC is difficult (as the compounds are quite volatile) and I don’t think these compounds would fly on the open access MS we have here.

    Comment by Dan — February 17, 2012 @ 11:46 am

    • I have not done this one reaction by myself, it is a procedure from Krest that he asked me to post. (He has been a co-admin but maybe lost interest at some point). If you want I can find his contact info, he has an industry job now.

      Comment by milkshake — February 17, 2012 @ 11:59 am

  15. Originally I had tried the iodination in methanol using NIS (as per Journal of Organometallic Chemistry 619 (2001) 49–61) but the workup was complicated by some solid precipitate (likely succinimide, but it didnt disappear no matter how many times I washed with brine). I abandoned this in search of a more simple procedure, which is when I remembered this post. Phenylacetylene was dissolved in methanol, the appropriate quantity (2.5eq.) 50% aq. KOH solution added (darkening of the solution), followed by the iodine, portionwise. The colour seemed to be discharged until a good amount was added, at which point the reaction mixture became dark with the colour of iodine. Left for 1hr. The reaction was worked up by taking into ethyl acetate, washing with brine, then thiosulfate, and finally brine again, and the solvent removed on the buchi. The brown oil remaining was left on the high vac to remove any starting material and/or solvent and a quantitative crude yield was obtained. The material was used as such for my next reaction.

    Comment by Dan — February 27, 2012 @ 1:00 pm


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