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As expressed in the title, I am trying to figure out how to form a lactone from 5-amino-decanoic acid. The thing that comes to my mind as a start is the attachment of the amino group ($\ce{NH2}$) to the carboxyl carbon and then immediately break the double bond of this carbon with oxygen … But the process gets more likely to form a lactame, where my exercise is asking a Lactone. Can anyone help?

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  • $\begingroup$ It would be easier if the Oxygen in COOH would attach to the Carbon bonded with NH2, but that carbon is also bonded with the other Carbons on the decane chain, so it is not likely to be attached as much as the Carbon of COOH, which has a big delta plus due to the Oxygens, and the NH2 has a couple of unpaired electrons to use.. But still this is more likely to give a Lactam rather than a Lactone $\endgroup$ – Giorgio Vitanza Jun 6 '16 at 12:04
  • $\begingroup$ Yes that's what I think as well, but that's what the exercise is asking.. $\endgroup$ – Giorgio Vitanza Jun 6 '16 at 13:15
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I doubt your book is asking you to convert this molecule into a lactone. This would be very hard to do. It could, however, be easily converted into a lactam. 5 and 6 membered lactams are formed by simple dehydration. For your γ-lactam, this can be achieved by heating the amino carboxylic acid, forming the thermodynamically favourable, stable 6-membered lactam. Similarly, lactones can be be interconverted by adjusting the pH.

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IF you really wanted to convert the amine into a lactone, it would involve some pretty uncommon reagents. This blog post mentions that pyrylium salts can be used to make a primary amine into a leaving group, which would, presumably, allow you to substitute a hydroxyl group, thereby giving you access to the lactone. http://curlyarrow.blogspot.hu/2009/09/how-to-turn-amine-into-leaving-group.html

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  • $\begingroup$ I believe there was an error of printing as I perfectly agree with you. So I'll just take your answer and write a Lactam, which is the only normal product there.. $\endgroup$ – Giorgio Vitanza Jun 6 '16 at 17:38
  • $\begingroup$ Good point @Curt. F. I guess my fingers remember the word 'dehydrogenation' too well these days :P. $\endgroup$ – gannex Jun 6 '16 at 20:41
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After my initial comment I reconsidered and thought it through a lot. You can technically by not-so-common reactions turn your 5-aminodecanoic acid into a lactone if:

  1. You convert the amine into a leaving group — diazo jumps to mind (add $\ce{HNO2}$) but a triple alkylation would work, too.

  2. You then make sure that the carboxylic acid is nucleophilic enough to attack the ex-amine carbon in an $\mathrm{S_N2}$ manner (i.e. add a base) while making sure that:

    1. No $\mathrm{E2}$ elimination will occur
    2. There are no other nucleophiles around that could attack.
  3. If, unluckily, your amine eliminated, you will need to attack the double bond with a suitable leaving group. I don’t think a carboxylate is strong enough to attack double bonds to form a lactone.

  4. You look the thing you just did up in SciFinder and if it doesn’t exist, you publish it just because wow and why. Don’t aim for Angewandte or JACS, though, unless you did something really cool. ;)

A second option would be diverting after step 1 adding a hydroxide nucleophile so that you generate 5-hydroxydecanoic acid, which you can then transform into the lactone by about a million methods (Yamaguchi, Mitsunobu, Steglich just to name three).

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    $\begingroup$ With the alkene you can do an iodolactonisation then remove the iodine with e.g. Bu3SnH/AIBN although I guess you would probably get significant amounts of 5-ring product, don't know of any way to get selectivity with this kind of acyclic compound. Even the elimination would probably give you a mixture of isomeric alkenes $\endgroup$ – orthocresol Jun 6 '16 at 22:00
  • $\begingroup$ what about the triphenylpyrylium salt method? You can use triphenylpyrylium trifluoroacetate to form the ROCOCF3 ester corresponding to the primary amine, and then you can hydrolyze that to yield the alcohol, followed by lactone cyclization. It says here that this reaction is more 'clean and efficient' than diazotization: reag.paperplane.io/00002962.htm $\endgroup$ – gannex Jun 6 '16 at 22:14
  • $\begingroup$ @gannex Looks cool, but I don’t personally trust ‘clean and efficient’ mechanisms any more after having done too much total synthesis ;) $\endgroup$ – Jan Jun 6 '16 at 22:16
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    $\begingroup$ I wouldn't blame you. I think it looks like a nifty reaction though (on paper that is). $\endgroup$ – gannex Jun 6 '16 at 22:23
  • $\begingroup$ Yes but it only gives the amminoacid, and it asks to build a lactone out of it, so I believe it meant lactam instead, although it was useful to see such reactions through this question. Thank you very much sir! Perhaps trying photons as a catalyst might do the work, but I ain't trying very soon haha $\endgroup$ – Giorgio Vitanza Jun 7 '16 at 10:29

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