DraconicAcid
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FC Alkylation
So....
One of my labs at work is the t-butylation of biphenyl with t-butyl chloride in the presence of FeCl3 in dichloromethane. It's a nice reaction, works
well, doesn't take more time than their lab period (unless they are being confused or disorganized).
Now, i have a fair bit of leftover t-butyl chloride left to play around with, so I thought I'd try alkylating a couple of other aromatic things.
From what I can find, aldehydes aren't likely to be worth trying to alkylate; from the links I've found online, anisaldehyde is more likely to
electrophilicly add to an aromatic ring than to have an alkyl group added to them. (R-CHO + HAr ---> R-CH(OH)-Ar (in presence of AlCl3)).
Can anyone advise what other functional groups are incompatible with FC-alkylation? I know about the activating/deactivating groups, but I'm checking
for groups that will completely kill the reaction for other reasons.
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zed
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Draconic Acid, all 400 million members here have taken a vote, and we want you to try Indole.
Alkylation with Allyl Chloride would be better, but we will accept what you offer.
Naphthalene sounds good too. Might produce an impressive ratio of the 3 Isomer.
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myr
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Anything that makes a carbocation in those conditions, so benzylic alcohols and alkene side-chains will cause problems.
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DraconicAcid
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Quote: Originally posted by zed  | | Draconic Acid, all 400 million members here have taken a vote, and we want you to try Indole. |
Thanks, but I prefer to avoid things with an intense fecal odour.
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myr
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I browsed through a reference of mine [Perfume And Flavor Chemicals: (Aroma Chemicals), 2 vol. set] and I found a few compounds which would be much
more pleasant to smell than indole (although bulky substitution on the 3 position, like benzyl, seems to reduce the shit-notes of indole smells per
the above book)
One interesting target would be 3-methyl phenol or the corresponding methyl ether: these have a characteristic wood/leather aroma: "cuir de russie,"
and 1,4-diMeo 2-tBu benzene (as well as 1,3-diMeo 4-tBu benzene) apparently has a pleasant "warm, mossy-nut, root-like odor." All the tBu-phenol
compounds listed in the book share a common wood/tar element, but changing the substitution pattern does change the character. Tert-butylation of
nerolin probably will smell interesting.
If it can be made after some protection of the aldehyde, 3-tBu anisaldehyde sounds interesting enough: "powerful woody-floral aroma with considerable
tenacity." Ditto for tBu-benzaldehyde.
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DraconicAcid
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| Quote: Originally posted by myr | I browsed through a reference of mine [Perfume And Flavor Chemicals: (Aroma Chemicals), 2 vol. set] and I found a few compounds which would be much
more pleasant to smell than indole (although bulky substitution on the 3 position, like benzyl, seems to reduce the shit-notes of indole smells per
the above book)
One interesting target would be 3-methyl phenol or the corresponding methyl ether: these have a characteristic wood/leather aroma: "cuir de russie,"
and 1,4-diMeo 2-tBu benzene (as well as 1,3-diMeo 4-tBu benzene) apparently has a pleasant "warm, mossy-nut, root-like odor." All the tBu-phenol
compounds listed in the book share a common wood/tar element, but changing the substitution pattern does change the character. Tert-butylation of
nerolin probably will smell interesting.
If it can be made after some protection of the aldehyde, 3-tBu anisaldehyde sounds interesting enough: "powerful woody-floral aroma with considerable
tenacity." Ditto for tBu-benzaldehyde. |
Nice!
I remember making the di-t-butyl derivative of p-dimethoxybenzene as an undergrad (1st year organic chem), but since that was more than thirty years
ago, I don't remember much about the synthesis. I do have ethylene glycol, so protection of the aldehyde is a possibility; there's also the chance
that FeCl3 will catalyze the FC reaction without being Lewis-acidic enough to hit the aldehyde.
Are esters stable in FC reactions? I do have methyl salicylate that I can try..... (ETA: I found a reference to acylation of methyl salicylate
using anhydrous ZnCl2 and hexanoyl chloride in DCM, so yes, it will probably work.)
[Edited on 7-3-2021 by DraconicAcid]
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zed
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Umm. I'm thinking no ethylene glycol. Too much like water. Kills the FC. Well, usually. Usta be the FC was run with AlCl3. AlCl3, doesn't like
water. Also has a penchant for cleaving Ethers. FeCl3 huh? Sounds interesting!
Some folks are running an FC type Alkylation by Alcohols or Carboxylic Acids, in the presence of PPA.
Esters? Potential Alkylators. Might depend on conditions.
So, in some manifestations, alcohols and aldehydes ARE the alkylating agents.
And Dammit, Indole does not smell like poop! Nor does 2-Methyl-Indole! Nor 2-Phenyl-Indole, nor Tetra-Hydrocarbozole. Pure Indole has a pleasant
floral odor. Though I have never warmed it up, to fully "develop" its odor. Skatole is probably poop-ish.
I do have some Indole Butyric Acid on hand, and it is kind of Pungent. But, I'm thinking "Butyric" not Indole. Butyric Acid cannot be described as
"Rose-Like".
[Edited on 7-3-2021 by zed]
[Edited on 7-3-2021 by zed]
[Edited on 7-3-2021 by zed]
[Edited on 7-3-2021 by zed]
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DraconicAcid
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AlCl3 is the classic catalyst, yes, but iron(III) chloride is milder (and iron salts are the classic catalysts for halogenation- just add a bit of
iron into your aromatic compound before you start adding the bromine or chlorine, and you get nicely anhydrous iron(III) halide to catalyze your
reaction without having to open a jar of the salt and wondering if it's still anhydrous).
I'm not considering the ethylene glycol as a solvent, just to react with the aldehyde to make the whatsisname...a cyclic acetal. That may be more
robust towards the FC catalyst.
Acid-catalyzed FC alkylation or acylation with alcohols, carboxylic acids or anhydrides....these reactions are on my radar, but I'm mostly looking for
a way to use up my excess t-butyl chloride.
Indole may not smell fecal, despite common conception of it, but that may be in the same way that absolutely pure carbon disulphide has a mild,
pleasant fragrance. I've worked with mildly impure CS2 and don't want to again.
ETA: pdf added for the lab that we do. I don't actually remember where I first downloaded it, but we do it on a one-fifth scale. We use the product
as melting point unknowns in other experiments, but we still have a lot left.
[Edited on 7-3-2021 by DraconicAcid]
Attachment: FC-Alkylation.pdf (869kB)
This file has been downloaded 219 times
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zed
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Ummm. Also, can you link us to experimental details? I think many of us would like to see more. Sounds interesting.
Using T-Butyl because of its stability? Reactivity? Is the procedure broadly applicable to other Alkylating agents? Or, is this a special case?
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DraconicAcid
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T-Butyl is used because it's easy to make, reacts well without rearranging, and is big enough that it only goes para to the other substituent on the
ring. Non-tertiary alkyl halides may require the more reactive aluminum chloride (which may not work in DCM), and may add in multiple positions.
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zed
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I'm thinking you might be able to Alkylate Anisole. And, I was serious about Naphthalene. Cheap, Available, likes to be nitrated at the 3-Position.
And, maybe this trait will hold true for Alkylation. Could have an interesting odor, and a ten to one tendency to be attacked at number 3, would give
you a nice yield.
Or, maybe not. Don't know if steric hindrance would be a problem. Naphthalene might like to react at number 3, but T-Butyl might have too big a
butt.
Thank you for the procedure. I'll study it.
[Edited on 7-3-2021 by zed]
[Edited on 7-3-2021 by zed]
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DraconicAcid
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I don't have anisole, but do have naphthalene, 2-naphthol, and 2-butoxynaphthalene (which apparently smells like raspberries, but I can't small a
damned thing from it. 2-Ethoxynaphthalene smells wonderfully like lemon drops, though).
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zed
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Umm. Perhaps the correct term would be Ortho-Position. Of which Naphthaline has 4.
I call it the 3-Position, because it becomes that position, when Naphthalene is oxidized to Phthalic Anhydride.
3-Nitro-Phthalic Anhydride, being an important intermediate in several synthesis. Org. Syn. has several procedures.
Could use that T-ButylChloride in the Williamson Ether Synthesis. But, I wouldn't want to keep that product around. I'm thinking Major Peroxide
Problems. If Di-isopropyl is really bad, what might Di-T-butyl be like?
I also selected Indole because the 3-position is very reactive. Much more so than most aromatic rings.
Might turn out to be the Poopiest smelling material ever synthesized. Which would be a great discovery, in its own way. Though I'm thinking, most
likely you don't have any Indole to play with.
I read through that experiment. Nice! Got more? That's good stuff.
[Edited on 8-3-2021 by zed]
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DraconicAcid
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You can't use t-butyl chloride in a Williamson ether synthesis- the alkoxide or phenoxide would likely cause elimination instead of substitution. I
did find a prep for t-butylating phenols with t-butyl chloride and zinc dust, though (which I might try on methyl salicylate, for a funky new ester).
t-Butyl ethers don't form peroxides, as they don't have hydrogen on the carbon next to the oxygen.
Attachment: 030823400103167192.pdf (28kB)
This file has been downloaded 259 times
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draculic acid69
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Is biphenyl the bright red impurity in the Na benzoate+NaOH to benzene rxn?
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DraconicAcid
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No, biphenyl is white as a solid, colourless in solution.
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zed
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When I revisited my Alma Mater, years ago... I was shocked. The Chem Storeroom Shelves were bare.
The decades long accumulation of useful reagents, had been nullified. Gone, gone, gone.
I'm glad you have at least some reagents to work with.
It's really hard to play, when there is a shortage of toys.
Melting point experiment? The one where you use melting point depression, to estimate the molecular weight of an unknown?
Seems like I remember such an experiment. Sounds like a fun class.
[Edited on 8-3-2021 by zed]
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myr
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Have you made the t-butylated naphthol or salicylate compounds? I'm really curious what they smelled like (if they smelled like anything at all)
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DraconicAcid
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No, I haven't. I did try alkylating acetanilide, but that simply didn't react.
zed: the melting point experiment I mentioned was just a first lab for organic students, where they identify a compound by mp and mixed melting
points.
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