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Aromatic iodinations

stoichiometric_steve - 1-12-2008 at 13:19

Synthesis of 3,5-diiodo-4-methoxyphenethylamine. Jatzkewitz, Horst; Noeske, Hans Dietrich. Univ. Tubingen, Germany. Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie (1951), 287 43-6. CODEN: HSZPAZ ISSN: 0018-4888. Journal language unavailable. CAN 49:4568 AN 1955:4568 CAPLUS

Abstract

The synthesis of 3,5-diiodo-4-methoxyphenethylamine (I) is described. I is used to study the effect of biogenic amines on the action of mescaline. To 14 g. tyramine-HCl in 23 cc. H2O and 46 cc. N NaOH, 11.8 g. iodine in alk. KI soln. (contg. 20 g. KI, 160 cc. H2O, and 46 cc. N NaOH) is added dropwise with stirring, maintaining const. alky. The soln. is filtered and acidified with excess H2SO3, giving 12 g. crude 3,5-diiodotyramine-HI (II), yellow leaves (from H2O) m. 232-4¡ (decompn.). II (12 g.) treated with the calcd. amt. of hot Na2CO3 soln. gives 6 g. free base (III), pale yellow, m. 188-90¡. III (2 g.) boiled 10 s. with 5 cc. Ac2O and dild. with H2O gives 1.75 g. N-acetyl-3,5-diiodotyramine (IV), colorless plates, m. 139-40¡. IV (6 g.) (crude) in THF is methylated with 60 cc. ethereal CH2N2 dild. with 40 cc. CHCl3, washed twice with 5% NaOH and H2O, dried and the solvent removed, giving 5.2 g. N-acetyl-3,5-diiodo-4-methoxyphenethylamine (V), needles, m. 138-40¡. V 3.8 g. is refluxed 5 h. with 19 cc. HCO2H, 14 cc. HCl, and 14 cc. H2O., evapd. in vacuo and dried with EtOH and C6H6, the residue extd. with three 15 cc.-portions of abs. C6H6 gives on evapn. of the solvent 3.4 g. crude I.HCl. The pure compd. m. 213-15¡. The salt dried in Et2O over anhyd. K2CO3, on removal of solvent and crystn. from petr. ether gives I, colorless leaflets, loses its crystal structure at 41-3¡, and m. 55-7¡.

- - - -

Now the question:

In the preparation of iodinated arylalkylamines, protection of the amine moiety is usually applied as to prevent formation of halo-amines. How come this does apparentl not happen in the above procedure?
Is anybody aware if iodine (I2 or I+) will react with arylalkylamides to produce iodoamides?

panziandi - 1-12-2008 at 19:04

I posted a paper on the use of I2 / CrO3 in the anhydrous system AcOH/Ac2O for iodination and di-iodination of arenes. UTFSE but the paper is uploaded, it may use examples of protected arylamines not too sure.

chemrox - 1-12-2008 at 20:37

Iodine is the least reactive of the halogens and the attacking species is something other than polarized I2. In the example given it may be ISO3 formed in situ.

Nicodem - 2-12-2008 at 02:34

Quote:

Originally posted by stoichiometric_steve
In the preparation of iodinated arylalkylamines, protection of the amine moiety is usually applied as to prevent formation of halo-amines. How come this does apparentl not happen in the above procedure?
Is anybody aware if iodine (I2 or I+) will react with arylalkylamides to produce iodoamides?

In your example of a iodination the nucleophile is a phenoxide which reacts relatively easily with all iodinating species in the reaction mixture (I2, I3- and R-NHI). The amine protection is necessary when the N-iodoamino group decomposes under the reaction conditions because unable to react any available nucleophile (for example, if you would want to iodinate O-methyltyramine, etc.).
In my opinion, in the presence of excess iodide: R-CH2-NHI + 2I- <=> R-CH2-NH2 + I3- is considerably faster than R-CH2-NHI => R-CH=NH2+ + I-

solo - 2-12-2008 at 02:49

Reference Information Quoted

The Direct Iodination of Arenes with Chromium (VI) Oxide as the Oxidant.
Lulinski, P. Skulski, L.
Bull. Chem. Soc. Jpn1997, 70, 1665-1669

https://sciencemadness.org/talk/viewthread.php?tid=11033&...

stoichiometric_steve - 2-12-2008 at 06:47

i'm not quite sure if an unprotected amine would survive CrO3, not to mention the environental/health risk with Cr based reagents.

chemrox - 2-12-2008 at 08:29

In any case the method cited did not use CrO3 or the acidic conditions that were part of that method. I didn't spot the tyramine + OH- => phenoxide which should have jumped out of the page. As I understand this the phenoxide reacts with any I species much faster than the amino group would. This makes sense. @Steve: what health risk? you wear gloves in the lab don't you?

[Edited on 2-12-2008 by chemrox]

harrydrez - 2-12-2008 at 08:33

Quote:

Originally posted by stoichiometric_steve
i'm not quite sure if an unprotected amine would survive CrO3, not to mention the environental/health risk with Cr based reagents.

Hex chrome is some nasty stuff, definitely reduce it to the trivalent state before disposing of it if nothing else.

DJF90 - 2-12-2008 at 08:38

I think he's more worried about working with it in the hexavalent oxidation state. Reduction before disposal is expected. Its not that bad, as with every other chemical in the lab so long as you wear gloves and glasses, and use common sense, your exposure to it should be minimal. Handle in a hood if you're really worried about it.

chemrox - 2-12-2008 at 08:44

Hex chrome is nasty stuff if dumped on the ground. I hope we're all above dumping our waste out the back door!

panziandi - 2-12-2008 at 08:53

CrO3 is quite a powerful oxidising agent and is a category 2 carcinogen (IIRC) and is dangerous for the environment.

I have performed iodinations using the I2/CrO3 system in acetic anhydride/acid solution with a small quantity of H2SO4 for iodination of several compounds. I have not tried it with compounds containing an amine group. If I was, I would protect the amine by forming the acetamide by treating with acetic anhydride. Then I would take that solution (without isolation of the derivative) and perform the iodination with I2/CrO3. The reaction is quite nice and most of the CrO3 is reduced to Cr3+. When isolating the product I would treat it first with a little metabisulphite or something similar to remove the excess Cr6+ then under basic conditions free-base the product and extract into a suitable solvent (likely diethyl ether). I think the danger of Cr6+ comes from inhalation or ingestion, or skin contact with CrO3 will result in painful burns. There will be no Cr6+ in your product I'm positive and anyhow, even if there was I'm sure you wouldn't be consuming it :p

vulture - 2-12-2008 at 12:06

Instead of using CrO3 you might consider using KIO3 or KIO4. No nasty Cr6+.

stoichiometric_steve - 2-12-2008 at 12:16

What i meant about the Cr(VI) was that i dont like to work with reagents that aren't too easy to dispose of. Other than that, i dont give a shit about teh chrome, sure i wear gloves n all

If acetylation provides enough protection from the reaction of Iodine with nitrogens, then i'm fine with iodination using I2/Ag(I) salts in MeOH.

chemrox - 2-12-2008 at 17:16

I got curious about the relative reactivities of the halogens and went to another PEA synthesis. Two in fact. Thanks to Dr. Shulgin I was able to compare 2,5-dimethoxy-4-iodo-PEA with 4-bromo-2,5-dimethoxy-PEA. In the first case I-Cl was used for the iodination and the amine was protected via the phthalimide. In the second case the amine wasn't protected and elemental Br2 was used for the halogenation. My chemistry isn't developed enough to explain these facts right off the bat and I would appreciate anyone who can weighing in on this.

stoichiometric_steve - 3-12-2008 at 02:15

Quote:

Originally posted by Nicodem
In my opinion, in the presence of excess iodide: R-CH2-NHI + 2I- <=> R-CH2-NH2 + I3- is considerably faster than R-CH2-NHI => R-CH=NH2+ + I-

isn't it quite the other way around? take 2,5-Dimethoxyphenethylamine for a prominent example. the lone electron pair appears much more reactive to me than a weakly polarized C-H bond on the phenyl ring.

Nicodem - 3-12-2008 at 02:59

2,5-Dimethoxyphenethylamine is not a phenoxide! The electrophile in such a substrate must atack the neutral Pi-system which is only weakly nucleophilic, regardless of the +M effect of the methoxy groups. Comparing the nucleophilicity of such a system with that of a phenoxide ion is like comparing apples and tomatoes. In a phenoxide ion the negative charge is delocalized in the Pi-system making it many, many magnitudes more nucleophilic as well as a bidentate nucleophile (there can be both, the O- or C-attack by the electrophile, but in the case of iodination the O-attack is reversible and thus irrelevant for the reaction outcome).

Just to show the difference in the nucleophilicity:
- the nucleophilicity index N of anisol (PhOMe) is -1.18 (ref)
- the nucleophilicity index N of the phenoxide should be from 10 to 17 (I could not found the exact empirical value, but it should be there about the same range as alkoxides, hydroxide and amines)
Note that this is a logarithmic empirical index and thus it indicates a difference in reactivity in the range of 109 to 1016. As a practical example, consider that with methyl bromide, the phenoxide ion reacts rapidly even at room temperature, while anisole does not even if heated.

chemrox - 3-12-2008 at 15:41

Since no one did, I'm going to pose an answer to my own question. In the case of bromination, it's a free radical reaction with Br. acting as the electrophile. In the iodination the elctrophile is I+ which would react with the lone pair on the amine. (I edited to add this) However it seems like this would make the quaternary ammonium salt that could be converted back to the amine with base so why the phthalimide?

[Edited on 3-12-2008 by chemrox]

smuv - 3-12-2008 at 16:07

Under acidic conditions of the bromination the amine is non-nucleophilic as R-NH4+. Even if the N-haloamine is transiently produced in the weakly acidic medium it likely simply serves as a source of Br+ in the bromination, which regenerates the amine again. In order for amines to do truly dirty thing with halogens basic conditions are necessary.

The bromination should not be a free radical process. If you brominated in acetic acid the likely brominating species is AcOBr

AcOH + Br2 <--> AcOBr + HBr

AcOBr is a good source of Br+, and for activated aromatics gets the job done.

[Edited on 12-3-2008 by smuv]

chemrox - 3-12-2008 at 16:41

ahh- IC yes he used acetic acid not Fe, thanks. But why the protecting group for the iodination?

[Edited on 3-12-2008 by chemrox]

Nicodem - 4-12-2008 at 00:56

Quote:

Originally posted by chemrox
ahh- IC yes he used acetic acid not Fe, thanks. But why the protecting group for the iodination?

This was already explained. N-Iodoamines decompose easily, particularly in acidic media where they get protonated to R-NH2I+. This is unlike bromo- and chloroamines which are much less sensitive to acids, but are sensitive toward bases (due to the easy E2 reaction yielding iminium halides). See the N-X bond strength enthalpies, p-orbitals overlap ease due to element period, and electronegativity difference between N and X = F, Cl, Br and I for understanding the polarisation of the bond; all factors from which the different properties originate in the first place.
To take this comparison further, compare the shock sensitivity for NI3, NBr3, NCl3 and NF3. Actually NI3 does not even exist as a discrete compound - as far as I know only its Lewis complex with NH3 can be isolated, at least for the time it takes to blow up.

Quote:

Originally posted by chemrox
In the case of bromination, it's a free radical reaction with Br. acting as the electrophile.

It is fanny how you managed to make a claim and then deny it in the same sentence.

Electrophilic aromatic substitutions are polar reactions. They do not involve any radical mechanism - that's why they are called "electrophilic". Attacks from radicals on aromatic systems rarely lead to substitution since this would require an radical addition/oxidation mechanism. For example, radical chlorination of benzene never gives chlorobenzene, it gives a mixture of some diastereomers of 1,2,3,4,5,6-hexachlorocyclohexane instead (this is the schoolbook example thought to undergraduates on what is the difference between polar and radical reactions on aromatics). On the other hand, addition of carboradicals on benzene in the presence of a suitable single electron oxidant like Mn(III), Ce(IV), Ag(II), etc., can lead to substitution reactions since the intermediate delocalized radical formed by the radical adding on the Pi-system gets oxidized to a carbocation by a SET mechanism and this "rearomatizes" by eliminating a proton.

[Edited on 4/12/2008 by Nicodem]

stoichiometric_steve - 4-12-2008 at 01:29

Quote:

Originally posted by NicodemN-Iodoamines decompose easily, particularly in acidic media where they get protonated to R-NH2I+.

I'm not sure how/if this is meant to explain the need for protection of the amine. If the iodoamine decomposes more easily, does it decompose to the iminium salt or -NH2 and I3-?

chemrox - 4-12-2008 at 21:17

"It is fanny how you managed to make a claim and then deny it in the same sentence.
Electrophilic aromatic substitutions are polar reactions. They do not involve any radical mechanism "

Yeah I caught that a little late.... I had two ideas going at the same time; polarized Br-Br and Br. which would only exist in the presence of an initiator like Fe. I envy your work environment. I work by myself and the only chemistry interraction I get is here.

Nicodem - 5-12-2008 at 00:34

Quote:

Originally posted by stoichiometric_steve

Quote:

Originally posted by NicodemN-Iodoamines decompose easily, particularly in acidic media where they get protonated to R-NH2I+.

With "decomposition" I meant decomposition and not regeneration. I do not know the mechanism of N-iodoamines decomposition, but I do know it is not a simple elimination like in the case of N-chloro- or N-bromoamines (the reason why these later two are unstable under basic conditions). N-Iodoamines appear to be more stable under mildly basic than acidic conditions (kind of logical given the polarisation of the N-I bond precludes the E2 pathway). Furthermore, in the experimental example you gave in the first post, the N-iodoamine is not in a favourable equilibrium since part of the already mentioned redox system:
R-NHI + 2I- + H2O <=> R-NH2 + I3- + OH-
Besides, the reaction is basic all the time; the iodinating electrophile I3- is consumed rapidly; and no heating is required. I would estimate that practically no decomposition due to the N-iodoamine occurs under such conditions.
But again, this is a iodination of a phenoxide with I3- which is something very different from iodination of anisoles and other less nucleophilic Pi-systems where any amino group must be protected (except for some rare exceptions - I think the I2/Ag2SO4 system can be used on unprotected amines, but I'm not sure - check the literature).

Quote:

Originally posted by chemrox
Yeah I caught that a little late.... I had two ideas going at the same time; polarized Br-Br and Br. which would only exist in the presence of an initiator like Fe. I envy your work environment. I work by myself and the only chemistry interraction I get is here.

I'm not certain of what you mean by "Br. which would only exist in the presence of an initiator like Fe", but I'm pretty sure you mixed up something. Maybe you meant that a bromine radical can not exist in the presence of a reducent like elemental iron. That would make more sense though I can't see the relevance here.
Anyway, if you rely on the information you get on this forum rather than reading scientific books and papers, you can be sure you will never learn much of anything reliable or comprehensive regarding chemistry.

stoichiometric_steve - 5-12-2008 at 01:53

Quote:

Originally posted by Nicodem

I think the I2/Ag2SO4 system can be used on unprotected amines, but I'm not sure - check the literature

I've been SciFinding high and low, and i couldn't dig up any useful information on that, so i came here to ask. This is apparently a not-too-well researched field of the art...

Barium - 5-12-2008 at 06:22

Tet. Lett., 1993, Vol. 34, No. 39, pp. 6223-6224
Iodination of various unprotected amines with iodine and silver sulfate

[Edited on 5-12-2008 by Barium]

solo - 5-12-2008 at 07:19

Reference Information

Iodination of various unprotected amines with iodine and silver sulfate
Wing-Wah Sy
Tet. Lett. 1993, Vol. 34, No. 39, pp. 6223-6224

Abstract
Iodination of methoxyamphetamines with iodine / silver sulfate at room temperature gives iodomethoxyamphetamines in good yield.

[Edited on 5-12-2008 by solo]

Attachment: Iodination of methoxyamphetamines with iodine and silver sulfate..pdf (129kB)
This file has been downloaded 1263 times

chemrox - 5-12-2008 at 09:50

Br. was Br radical which happens easily in the presence of elemental Fe. Also, I did not mean to imply that I get my scientific information here. I think you know from my posts in refs that I research the literature as often as I can. I was referring to the advantages in having frequent discussions with other chemists that you have and I only get here. I hope this clears up two misunderstandings. The best I can do to type a radical mark is a period (.).

UnintentionalChaos - 5-12-2008 at 10:25

I dislike posting useless naggy things, but wouldn't Br* be more appropriate chemrox? Your keyboard does have an asterisk key, doesn't it?

stoichiometric_steve - 5-12-2008 at 13:18

Quote:

Originally posted by solo
Reference Information

Iodination of various unprotected amines with iodine and silver sulfate
Wing-Wah Sy
Tet. Lett. 1993, Vol. 34, No. 39, pp. 6223-6224

That paper was of course the first one i consulted on this particular matter, although Tet. Lett. not being a peer reviewed journal, it happens to have a relevant number articles which are outright bullshit. And the amines in this article are all on a secondary carbon, not sure if this might put some steric hindrance to the N-iodination.

Nicodem - 6-12-2008 at 06:37

Quote:

Originally posted by chemrox
Br. was Br radical which happens easily in the presence of elemental Fe. Also, I did not mean to imply that I get my scientific information here.

I thought you just confused something. Just about every undergraduate schoolbook about organic chemistry describes the electrophilic bromination of benzene with Br2 using iron as precatalyst and explains why so. Iron reacts with Br2 to give FeBr3, an acid which catalyses the electrophilic bromination. You can not have a radical bromination in the presence of elemental iron because it is a reducent, thus reducing any potentially occurring Br* radical to bromide.

See:
http://mason.gmu.edu/~bbishop1/chem318/Chem318%20020607.pdf
http://www.scribd.com/doc/7757435/Aromatic-Rxns-for-Beginers
http://www.chem.ualberta.ca/~fenniri/CHM-263/Chapter15.pdf
http://en.wikipedia.org/wiki/Electrophilic_halogenation
http://www.chem.umd.edu/courses/fall05/chem231fribush/pdfs/C...
...and about hundreds of other random sites

Quote:

Originally posted by stoichiometric_steve
That paper was of course the first one i consulted on this particular matter, although Tet. Lett. not being a peer reviewed journal, it happens to have a relevant number articles which are outright bullshit. And the amines in this article are all on a secondary carbon, not sure if this might put some steric hindrance to the N-iodination.

Actually, Tetrahedron letters is a peer reviewed journal with a relatively high impact factor (not that this guarantees its quality). Even though it is true that a lot of bullshit nevertheless passes through (the reviewers are just the same researchers who publish there anyway), I would not claim this paper bullshit before trying that method. On the other hand, the only organic journal/series that publish checked procedures is Organic syntheses, so you might (and you should) as well consider all the rest as potential bullshit anyway.
The amine being on a secondary or primary carbon is more or less irrelevant stericaly. Actually, I would tend to believe the iodoamine on a secondary carbon would tend to decompose even faster than the one on a primary.

S.C. Wack - 1-8-2009 at 16:09

Comparison of Iodination of Methoxylated Benzaldehydes and Related Compounds using Iodine/Silver Nitrate and Iodine/Periodic Acid

I/AgNO3 works OK for certain aldehydes of interest here.

Attachment: synth_comm_37_3855_2007.pdf (74kB)
This file has been downloaded 2243 times

JohnWW - 1-8-2009 at 21:01

That iodination procedure sounds as if it would be an important step in the total synthesis of the thyroid hormone thyroxine and related compounds; see http://en.wikipedia.org/wiki/Thyroxine for its structure and properties. It is administered to patients suffering thyroid deficiency, who would otherwise become cretins. (These are the subnormal people who squeal to Rapidshare, alleging "breach of copyright" and demanding that uploads be deleted, in spite of not even being the authors).

Sandmeyer - 2-8-2009 at 08:48

Quote: Originally posted by stoichiometric_steve

Quote:

Originally posted by solo
Reference Information

Iodination of various unprotected amines with iodine and silver sulfate
Wing-Wah Sy
Tet. Lett. 1993, Vol. 34, No. 39, pp. 6223-6224

The method isn't bullsit. Some russian members have even used silver nitrate instead of sulfate and it has worked too.

ctrlphreak - 15-8-2009 at 10:22

I can safely say that NaOCl + KI iodination of Vanillin works nicely.

Formula409 - 5-9-2009 at 19:15

I don't think this method has been discussed previously. Found it a while back but lost the link:
http://www.erowid.org/archive/rhodium/chemistry/aromatic.iod...

Formula409.

stateofhack - 8-9-2009 at 06:46

Quote: Originally posted by Sandmeyer

Quote: Originally posted by stoichiometric_steve

Quote:

Originally posted by solo
Reference Information

Iodination of various unprotected amines with iodine and silver sulfate
Wing-Wah Sy
Tet. Lett. 1993, Vol. 34, No. 39, pp. 6223-6224

The method isn't bullsit. Some russian members have even used silver nitrate instead of sulfate and it has worked too.

Have anything about it?

Iodine-Iodic acid 5-minute-iodination proof-test

bipolar - 29-3-2019 at 15:31

Month ago I tested this easy iodination procedure with I₂-HIO₃ system from the paper given below, using vanillin as substrate.
It worked, but the yield is very bad.

Avinash T. Shinde, Sainath B. Zangade, Shivaji B. Chavan, Archana Y. Vibhute, Yogesh S. Nalwar, Yeshwant B. Vibhute
A Practical Iodination of Aromatic Compounds by Using Iodine and Iodic Acid
Synth. Commun., 2010, 40 (16), 3506-3513
DOI: 10.1080/00397910903457332

pdf attachted (I did UTFSE and didn't find this paper posted before)

Attachment: shinde2010.pdf (336kB)
This file has been downloaded 593 times

Authors claim good to excellent yields on all kinds of substrates and provide very easy procedure (only 5 minutes reaction time!)

Quote: Originally posted by PROCEDURE FROM THE PAPER

General Procedures for Iodination of Aromatic Amines, Hydroxy Aromatic Aldehydes, Hydroxy Acetophenones, and Phenols

Aromatic Compounds (50 mmol), iodine (20 mmol) dissolved in ethanol (20 ml) by warming, iodic acid (10 mmol) dissolved in water (1 ml) was added with shaking and refluxed on boiling water bath for 5 min. on cooling solid separated out. Obtained solid product was filtered and crystallized from ethanol.

Experiment:

Iodic acid solution was prepared by dissolving I₂O₅ (0.34 g, 1 mmol) in ~0.3 mL of hot water.

I₂O₅ + H₂O = 2HIO₃

In a RBF, equipped with a reflux condenser, was prepared solution of iodine (1 g, 4 mmol) in 95% EtOH (4 mL) by heating it to slight boiling.
Then this solution was chilled to ~RT° and there was added vanillin (1.52 g, 10 mmol). Obtained mixture was stirred for half a minute and there was added previously prepared iodic acid solution (exothermic reaction occures). Reaction flask was set in a boiling water bath and heating with stirring was applied for 5 minutes. After that, the reaction flask was cooled for 10 minutes on a cold water bath. Then, the reaction mixture was diluted with 5 mL of 95% EtOH, filtered and solids on the filter was thoroughly washed with EtOH (2 x 5 mL).
Product was recrystallized from 25 mL IPA, filtered, washed with 5 mL of fresh cold IPA and dried at 50°.
There was obtained 0.8 g (only 28.7% yield) of 5-iodovanilin as beige colored crystalline powder with very subtle smell (which indicates impurity since pure 5-iodovanillin doesn't have any smell). Mp. 178-180° (- slightly depressed even after recrystallization).

Authors of the paper give their yield for ethyl-vanillin as high as 75%. Unfortunately, there is no regular vanillin in the paper.

Then I repeated this procedure on the same scale, but heating was continued for 30 instead of 5 minutes (but also I used a little bit more of the solvent).
This time the yield was significantly less (0.6 g, 21.5% - and this is yield without recrystallization).

So, since increased reaction time has led to lower yield of the product, I can conlude that this reaction takes place at, indeed, very high rate (at least with this substrate).
Resulting 5-iodovanillin seems to be relatively stable in the reaction conditions (only ~7% yield loss after 25 min), so it seems that most of the initial vanillin simply doesn't have time to iodinate - side reactions are happening much faster.
Well, that's how I see it anyway.

Maybe this procedure will work as it should (with good yields as given in the paper) for some other, more 'inert' compounds, but I am kinda skeptical about that.

[Edited on 30-3-2019 by bipolar]