
Action of some non-cyclic halogen derivatives on Hexamethylenetetramine
                    by M.Delepine and M.Jaffeyx
                 Bull. Soc. Chim. (4), p.108, 1921

                       Translated by Icculus

  We have prepared a very large number of combinations of HMTA with 
halogen compounds, non-cyclique or cyclique, but the halogen function is 
always primary. We know that these combinations must be considered like  
quaternary salts of ammonia C6H12N4-RX, the group RX(=R'CH2X) attached 
to the base, which acts like a tertiary amine.
  Our foremost goal was to react the four isomers of iodobutan with HMTA 
to judge their different reactivities. Two are primary: CH3CH2CH2CH2I 
and (CH3)2CH2CH2I; one secondary: CH3CHICH2CH3 and the last tertiary: 
(CH3)3CI. The differences in reactivities of these compounds are 
attributable solely to the structure of these isomers. 
Here are the results of our observations. 
  
Iodo-n-butylate: C6H12N4-C4H9I
  This iodobutylate was prepared without difficulty by the method 
indicated by us.  One heats to reflux in a double boiler 1mol of HMTA 
dissolved in 12-15 times its weight in chloroform with 1 mol of the 
iodo-n-butane. The quaternary salt precipitates at the end and is a sign 
of its production. Collect after the temperture progresses; we verified 
that 12 hours is sufficient; it is necessary to distill some of the 
chloroform towards the end of the reaction to finish with a suitable 
speed; after 12 hours the yield is 90-92% of theory and is good enough 
that one need not be preoccupied with perfection by concentrating the 
mother liquors.
  The combination of the idoine with the base takes place equally well 
in the cold. It also takes place in cold alcohol; after 45 days, 7.5 
grams of base in 50ml of alcohol with 6.5 grams of the iodine formed 7.5 
grams of crystals as opposed to the 8.1 grams theorized. It takes place 
the same in cold water, on the condition of shaking time to time; if one 
heats it you only obtain a gummy mass that can't be crystallized.
  The noral iodobutylate of HMTA is a substance well crystallized in 
thin white leaves(in needles when doone in the cold), here are the 
characteristics for this combination: flavor is bitter, moderate 
colubility in water (5%), less in alcohol (0.5%) and less still in 
chloroform (0.08% and ether. Melting is observed ~140 C., but with 
yellowing and decomposition, this is only an indication. M.Deroux found 
a temperature much higher (198 C). The transformation to butylamine by 
decomposition with HCL in alchol is an easy test.

Bromo-butylate: C6H12N4-C4H9Br
  This subsatnce is obtained by replacing the iodine with bromine. It 
precipitates in colorless flakes, has a bitter flavor and melts at 95 C 
with decomposition. It combines with bromine.

Iodo-i-butane: C6H12N4-C6H9I
  The rections is much slower and less complete than with the normal 
iodine compound.  Theyield after 15 hours was only 27% and it is likely 
that longer heating wouldn't increase it, also the chloroform solution 
was yellow. Besides, the salt isn't pure; the bitter taste is clearly 
accompanied with an acidic flavor.  The quaternary  salts of HMTA are 
neutral. like HMTA itself, while the salts of HMTA are acidic.  We were 
able to measure the acidity of the ppt. and found that it contained 15% 
of the iodine salt of HMTA.

Action of Secondary and Tertiary Iodo-Butylates: CH3CHICH2CH3 and   
(CH3)3CI
  These iodines give only slowly a white salt, with a distince acidic 
taste, not bitter, when they are heated with HMTA in chloroform. The 
salt is composed almost exclusively of the iodohydrate of the base.
  These results show the large differences in the ability to join HMTA 
with halogen butanes. We wanted to see if these conclusions were 
generalisable.

Other Primary Iodines
  Among the other primary iodines we took two compounds : iodo-propane 
normal and iodo-octane. The first formed with excellent yields (80% 
after five hours, crystals melt @138 C with decomposition). The second 
reacted much slower; it formed a sour substance, slightly acidic, 
containig more idoine than expectd (40.7% instead of 33.4%), consistent 
with M. Deroux who obtained 44.3%
  In other words the combination is more difficult when the molecular 
weight is increased.

Secondary and tertiary Derivatives
  We addressed the iodo-isopropyl (CH3CHICH3) and the secondary isomer 
of iodo octene (C6H11CHICH3).
  The iodo isopropyl reacted, but more difficultly than the normal, and 
gave the combination C6H12N4-C3H7I; the reaction is visibly accompanied 
by the formation of secondary products that strongly color the solution  
after several hours.
  The iodine of octene formed only a small quantity of the idodhydrate 
of HMTA after many hours.
  
Tertiary Iodine of C8
  We examined the methyl-3-iodo-3-heptane: CH3CH2CI(CH3)C4H9. It formed 
paridly a large portion of the iodohydrate of HMTA.

  To sum up, aside from the iodo-isopropyl, the secondary and tertiary 
halogens don't form salts with HMTA.

References:
1. M. Delepine, Bull. Soc. Chim (3), p.353, 1895 

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Here's a ref talking about making phenethylamine from phenethylbromide. 
54% yield after three weeks. And we all has yet to see the Delepine 
reaction work with a secondary halide, such as bromo/iodosafrole...
This is also the article mentioned in "The Complete Book of Ecstacy", BTW.


                     The Preparation of Primary Amines
                    Galat & Elion, JACS 61, 3586 (1939)

The transformation of alkyl halides into primary amines by the formation of
a double compound with hexamethylenetetramine, followed by alcoholysis in
the presence of hydrogen chloride, affords a very convenient means for the
preparation of primary amines [1,2,3]. As this method has been practiced in
the past, the alkyl halide is added to a solution of hexamethylenetetramine
in chloroform, and the addition compound, after it has precipitated, is
filtered off. The alkyl iodides react with reasonable rapidity, but the
chlorides and bromides react much more slowly, and if they are to be used
as starting materials, they should be converted into the iodide by addition
of sodium iodide in acetone solution.

This procedure has now been simplified by operating in a single solvent,
alcohol, without isolation of the addition compound. The new procedure is
as follows.

To a solution of 1 mole of hexamethylenetetramine in eight to ten times its
weight of hot 95% alcohol slightly more than 1 mole of sodium iodide is
added. One mole of the alkyl chloride or bromide is then added and the
solution is allowed to stand until the precipitation is complete. The
period of precipitation will vary from a few minutes to several weeks
depending upon the substance. The longer the carbon chain the longer is the
time required for the precipitation. The mixture containing the precipitate
is saturated with hydrogen chloride gas, whereupon the precipitate dissolves
and ammonium chloride precipitates. When the latter has been filtered off
and the alcohol removed by distillation, the resultant impure hydrochloride
is converted into the pure amine by distillation with an excess of sodium
hydroxide.

The times of precipitation and the yields of several of the amines obtained
were as follows: methylamine, one week, 72%; ethylamine, eight days, 82.5%;
benzylamine, two hours, 82.5%; p-nitrobenzylamine, one day, 61%; phenethyl-
amine, three weeks, 54%. The products obtained were of high purity, having
melting points closely in accord with the values given in the literature.

(1)  Delépine, Compt. Rend 120, 501 (1895); 124, 292 (1897);
     Bull. soc. chim. [3] 17, 290 (1897); ibid. [4] 31, 108 (1922).
(2)  Mannich and Hahn, Ber., 44, 1542 (1911).
(3)  Foldi, Ber 58, 1830 (1920).


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I know everybody has heard of the Delepine, but here is a trick that makes 
it work better. See Chemistry and Industry (London) Dec 7, 1974, p.962. 

0.035 mol of hexamine, 0.035 mol of chloro or bromo compound and 0.035 mol 
of NaI are stirred in 400 ml of ethanol @ room temp for 24h. Crystals are 
filtered, waseh w/ cold EtOH and then refluexed for 2h in 300ml EtOH and 
conc. HCl (20ml). On cooling crystals preciptate. If not acetone can be 
added to the mixture to induce crystalization. 

The NaI speeds up the fromation of the quaternary salt with hexamine, since 
Cl and Br are much less ractive than I. 

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J. Am. Chem. Soc. 61, 3585 (1939)

(details the use of NaI to convert the chloride or bromide to the iodide in 
ethanol without isolation of the addition compound and subsequent formation 
of a comound with hexaime. Also mentions the formation of methylamine in 72% 
with this method. Was methyl chloride used as the alkyl halide? I think this 
could be a new (for the hive) route to methyalmie production!) 

Chemistry and Industry (London), 962 (1974) (mentioned in my earlier post) 

Arch. Pharm,282,p.100 (1944) (german article on the formation of hexamine 
salts with alkyl halides. Gives a 100% conversion (I think that is what it 
is saying) of piperonyl bromide to the primary amine) 

J. Biol. Chem., 20, p.682, (1915) 

Organic Reactions (ref. book), 8, p.197 (1954) 

Bull. Soc. chim. 	[3], 356 (1895)  
			[3], 293 (1897) 
			[4], 108 (1922) 

Ber., 44, p.1542 (1911) 

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