i want to find out the procedure for esterification of cyclen. i
specifically need the reaction procedure or any articles published
specifically on this topic.

 HINT: cyclen is a macrocyle of nitrogen 
 chemical name: 1,4,7,10-Tetraazacyclododecane
  cas number: 294-90-6

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Clarification of Question by amar548-ga on 07 Jul 2004 14:08 PDT

i mean to alkylate the cyclen on the nitrogens attached to it and then
esterify it.{i want to alkylate the cyclen with bromo isopentanoic
acid and then esterify it with an alcohol.}

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Clarification of Question by amar548-ga on 07 Jul 2004 20:41 PDT

i want to alkylate all the 4 nitrogens on the cyclen with the bromo
alkyl moieties with boc protected groups and then esterify it.so
please give me the method to alkylate all the 4 nitrogens.

errr... you want to make an ester from something that has no carboxylic acid?

Do you just want to acylate one or more of the nitrogens on cyclen? eg. Make amide?

or, would you like to add CO2 to one of the ring carbons, then make
the methyl ester?

pls clarify.  

cyclen, from my personal experience with others can be a tricky
molecule to functionalize.

do you want to make carbamate? (nh-ch2-ch2-)3-n-(c=o)-o-me

or, do you want to add OH to one of the ring carbons and acylate?

what kind of ester?  ethyl, methyl, 

oh...my head is hurting from all the possibilities!

mm...

methinks, this will be grumpy.  

here's why:

I gather you are going to use this stuff to attach onto some
macromolecule and you need a long tether. Using an alkyl halide like 5
bromo pentanoic acid is going to be hard because SN2 displacement of
primary bromides is freakin slow.  So slow that you'll likely get a
mixture of quaternary amine, dialkylated cyclen and basically a god
awful mess.

U can try making the iodo, like these doods:  Tetrahedron, 57(12), 2385-2390; 2001

 
as such these chinese guys said 'eff it' and boc'd 3 amines before
busting chops to get n-alkyl

Chinese Journal of Chemistry, 21(7), 910-916; 2003

So if you haven't tried the obvious, you might as well:

1 equivalent of pentenoate, 1 equivalent of bromide cook.  Esterify: a
little more than 3 equivalents of h2so4, methanol, cook-->ester.

If that doesn't work: 1 equiv cyclen, 1 equiv acetic or hcl gas, 1
equive pentenoate.  Now you got two equivalents of base to pull off
two acid protons, and one equivalent of base to make the HBr.. 
esterify same as i said b4.

Given that those two ideas are likely to go down in flames, here are
some options I would suggest:

If the tether doesn't matter, try other more activated bromides, benzyl, allyl, 

 If it does, you could try alpha bromo ester,( Bioorganic & Medicinal
Chemistry Letters, 10(18), 2133-2135; 2000) etc then all you gotta do
is saponify and decarboxylate.  Any of these ideas all will likely get
you product a heck of a lot faster than what you picked.

Also bromo acetonitrile would alkylate in good yield, dibal to get to
the aldehyde, Wittig, to get the ester, diimide to reduce the double
bond.  Inorganic Chemistry, 42(4), 1023-1030; 2003

do you want to alklylate all 4 nitrogens?  grr...
if so, you can forget about doing it with the 4 bromo ester, not gonna
happen without getting mostly quaternary amine methinks.

In that case, my bottom choices will be best.

ynthesis of 1,4,7,10-tetra-n-alkyl-1,4,7,10-tetraaza-cyclododecanes.  
  Fricke, Tom; Chrapava, Sarka; Konig, Burkhard.    Institut fur
Organische Chemie, Universitat Regensburg,  Regensburg,  Germany.   
Synthetic Communications  (2002),  32(23),  3595-3602.

Abstract

We report a concise method for the prepn. of
1,4,7,10-tetra-N-alkyl-1,4,7,10-tetraaza-cyclododecanes via
deprotonation to the fourfold lithium amide followed by alkylation
with alkyl bromides.  The procedure circumvents the problem of
ammonium salt formation and provides direct access to hydrophobic
1,4,7,10-tetraaza-cyclododecanes in moderate yield.  The so obtained
hydrophobic macrocycles were converted into the corresponding
zinc(II), copper(II), nickel(II) and cobalt(II) complexes, that may be
used as water stable Lewis-acids in catalysis and anion extn.

So lithiate with 4 eq of n-bu-lithium, chuck in bromide.  you can
either make the bromo esters first, use a ketal protected pentanal,
terminal olefin and ozone etc to get to the ester.

First things first.  I don't have any experience w/ cyclen, but i've
worked w/ cyclam derivatives.  Dr_bob is right, alkylating this ligand
could get messy, though, I'm sure, procedures exist (probably with low
yields).  You could try to deprotonate the amine with something like
LDA and use that in the reaction with an alkyl bromide.
   Another possibility, often forgotten, would be to put a metal ion
in the macrocycle first, then derivitize the resulting metal complex. 
In cyclam chemistry, this would often be the only way to get the meso
form of TMC (tetramethylcyclam) complexes, where methyl groups point
in the opposite direction.  Inserting a metal ion into TMC almost
always would give the complex with all 4 methyl groups pointing in the
same direction.
   I could look up specific references tomorrow.

acrh2-ga: LDA would not work, methinks because you're going to try and
make a tetra anion, which will probably be more basic than LDA.(a
single lithio-amide).  I this case, n-butyl lithium should work(same
way you make LDA).

Bear in mind he's wants to make an ester at the end of these long
groups, so the shortest number of steps..

terminal olefin would probably be the best, then just oxidatively
cleave with Ozone, sodium periodate etc.  One could get the methyl
ester by working up the ozonide with methanol.

Or sodium periodate, osmium...blah blah blah.... or since he's already
got the acid, he could probably just make the ester of that
first...and chuck that in.  I think SN2 would be faster than making
the amide...

Anyway....  i think he should just stop asking questions and put his
head in the hood and make some gloop.

I don't know why I said LDA.  It was late at night and silly.  And you
are right about actually doing the synthesis instead of disussing it. 
I have a weak gut feeling that it would be one of those preps where,
even with a procedure, it would be hard to get good yields.  People
often publish things and forget to mention some cruicial little
detail.
Dr_bob, have a question for you.  You seem to be well versed in
synthesis, and I'm just a kineticist.  I need to make a labeled
pivalaldehyde, (CD3)3C-CHO, to test something.  We bought the
appropriate acid, (CD3)3C-COOD, and the idea was to reduce it.  One of
the org. synthesis professors in the department suggested that much
better yields could be obtained by first redicing to neopentyl
alcohol, then oxidizing to the aldehyde.  I found the preps with near
quantitative yields: reduction w/ BH3.THF, then oxidation w/
CrO3Cl-pyH+.  I tried a normal pivalic acid and it does seem to go in
almost quanitative yields.  "My big problem" is the workup gives a
fairly dilute solution in 20% THF / 80% ether.  When I try to rotorvap
it, bubble it w/ Ar, or just leave it to evaporate in the hood,
neopentyl alcohol just disappears.  I'm pretty sure that it's because
it's very volatile.  I can see the crystals just crawl up the
flask/vial.  I get about 20% isolated yields.  And we paid something
like $700 for just a gram of the acid.  I think I may have to
fractionally distill but not sure how that would work, since the
melting point of this sucker is about 55C (bp ~ 113C).  I imagine that
the aldehyde would be even more pain (or less, since it's a liquid). 
Any thoughts?
Thanks in advance.

arch, mm... 

Getting the material away from the THF could be a bit of a problem.  I
would: a) not rotary evaporate  at high temperature.  and b) not to
dryness.  That reduction should be pretty clean anyway.

I think you can vacuum distill with a short path under reduced
pressure.  If you look in the aldrich catalog, probably they'll have a
bp and a pressure, that's a good place to set up.  Basically you'll
need a short path, (which will cost about as much as your starting
material), and a vacuum pump that can pull down to about 1 mM
Hg(probably don't need that much but, a little extra is always a good
thing). Plug in the vacuum and just flask to flask distill the
neopentyl alcohol as you would at STP. reduce the vacuum to whatever
it says in aldrich or say 10 mm.  You'll probably lose a little but it
won't be 30%.

Generally, using things like DIBAL and stopping reduction of the acid
at the aldehyde only works when you want the alcohol... Thus, most
people reduce to the alcohol and then oxidize back up.

Alternatively, you can try making the acid chloride and reducing with
tributyl tin hydride.  Journal of the American Chemical Society,
106(10), 2923-31; 1984

on second thought,,, i'd be willing to bet a donut that, the product
will be clean enought that you won't even have to distill it to carry
on to the next step.  Just do a good aqueous workup to get rid of the
bh3(otherwise boom could happen).  remove as much of the solvent as
you can and oxidize using 1 eq. pcc(pyridinium chlorochromate)/ch2cl2.
No reason to use the cr reagent you mentioned b4. Run the reaction
overnight, filter the whole big mess through a plug of silica, and
you'll probably have 95% pure aldehyde.  Just remove the solvent and
distill. Now you only got one distillation to do, not two.

Also on second thought, I find it hard to believe that something with
a MP of 55 goes away on your rotary, unless you've got a pretty high
vacuum, or your water bath temp is too high.  I've isolated and
distilled many compounds with bp's of 150-200 or so, without much
trouble. At some point you should notice that nothing dripping off the
condenser of your rotary(unless you have a water cooled condenser) in
which case, you should notice an abrupt decrease in the amount of
stuff dripping off. Stop evaporating then.

Leaving such bottles open to the air, can be problematic if they
sublime easily.  You may also try to crystalize the material at low
temperature.

If I get a chance I'll look in perrin and amarego and see if there is a procedure.