Sciencemadness Discussion Board

Synthesis of 3-(p-Hydroxyphenyl)-2-Butanone "raspberry ketone"

Klute - 25-12-2007 at 05:05

As a weekend distraction, I'm thinking of trying to synthesise this flavor at home.

HO-Ph-CH(CH3)-CO-CH3

(EDIT: apparently this is a isomer of the so-called "raspberry ketone". See the ohter posts. These two paths are obviously not revelant.)

Two paths came to my mind:

1°- Enolate synthesis: Forming the enolate of MEK with NaOMe, and reacting it with a protected p-halophenol. The phenol would react with the methoxide, and could/would form an ester. I'm not sure on what to use for a protection, maybe reacting the phenolate with BnX or forming another ether..
From the information available, using DMF as a solvant for the alkylation, and either FeSO4 or UV as catalyst. I'm not sure how well the reaction would proceed.

2°- Acetoacetic ester synth of the protected bromophenol, followed by alkylation with MeI of the formed ester with another equivalent of alkoxide at the benzylic carbon, followed by hydrolysis/decarboxylation.

Then of course deprotection of the formed ketone. Would the clivage of an ether with a Lewis acid damadge the ketone?

Any advice, ideas, suggestions? Any other ideas of pathways would be welcome.


[Edited on 27-12-2007 by Klute]

solo - 25-12-2007 at 06:32

Hydroxybenzaldehydes
Christian Maliverney1 and Michel Mulhauser1
Kirk‑Othmer Encyclopedia of Chemical Technology



Abstract
Among the hydroxybenzaldehydes, only mono-, di- and trihydroxybenzaldehydes are known. Salicylaldehyde (2-hydroxybenzaldehyde) and 4-hydroxybenzaldehyde represent more than 99% of the hydroxybenzaldehydes' market. The physical and chemical properties of hydroxybenzaldehydes are described. 2-Hydroxy and 4-hydroxybenzaldehydes react in a similar manner as phenol toward electrophiles. The aldehyde function can be reduced or oxidized to form a variety of compounds depending on the reagents and conditions used. Hydroxybenzaldehydes undergo the normal reactions of aromatic aldehydes.

Most industrial methods for the manufacture of hydroxybenzaldehydes are based on phenol, but other routes exist, starting from hydroxybenzoic acids, by reduction, or from cresols, by oxidation. Both p-hydroxybenzaldehyde and salicylaldehyde have a low to moderate acute oral toxicity, but salicylaldehyde is, in addition, corrosive toward skin and appreciably irritating to the eyes.

The hydroxybenzaldehydes are used primarily as chemical intermediates to a variety of products. The largest single use of salicylaldehyde is in the manufacture of coumarin. Both are used as intermediates in the synthesis of agrochemicals, pharmaceuticals, fragrances, and in electroplating. Condensation products of salicylaldehyde and diamines have important chelation properties, and have wide use in the stabilization of petroleum products, and in chemical processing, especially as oxidation catalysts. These and other applications to polymer chemistry are described.

Keywords: Hydroxybenzaldehydes; Agricultural chemicals; Disinfectants; Coumarin; Flavors; Fragrances; Salicyladehyde; Electroplating; Pharmaceutical intermediates

[Edited on 25-12-2007 by solo]

Attachment: Hydroxybenzaldehydes.pdf (160kB)
This file has been downloaded 2956 times


not_important - 25-12-2007 at 07:56

Bunce, R.A., and Reeves, H.D. 1989. Synth. Comm. 19:1109-1118.

Tateiwa, J.-I., Horiuchi, H., Hashimoto, K., Yamauchi, T., and Uemura, S. 1994. Cation-exchanged montmorillonite-catalyzed facile Friedel-crafts alkylation of hydroxy and methoxy aromatics with 4-hydroxybutan-2-one to produce raspberry ketone and some pharmaceutically active compounds. J. Org. Chem. 59:5901-5904.

Halogen isn't going to come off the phenol very easily. This sounds more like the palladium catalysed reactions, you might even be able to get MVK to couple with the halo-phenol, the reduce the alkene which should happen easily as it's a,b to the keto.



[Edited on 25-12-2007 by not_important]

leu - 25-12-2007 at 17:31

Description of GB2416770

Raspberry ketone (p-hydroxyphenyl-2-butanone) is a key flavour molecule with typical raspberry flavour characteristics and a low odour threshold. Raspberry ketone is one of the most expensive flavour components used in the food industry. Up to $20,000/kg may be paid for the natural compound.

Raspberry ketone can be found in raspberries and other fruits (such as peaches, grapes, apples and various berries), vegetables (e.g. rhubarb) and in the bark of tree (e.g. yew, maple and pine).

Raspberry ketone can be used in the aroma formulation of, for instance, strawberry, kiwi, cherry and other berries. However none of these fruits are used to obtain the raspberry ketone as the low content of raspberry ketone in these fruits makes the extraction and purification process unprofitable.

Raspberry ketone can be produced chemically via the condensation of p hydroxybenzaldehyde with acetone.

However, the chemical synthesis of compounds can often result in environmentally unfriendly production processes and in undesirable racemic mixture of the compound of interest (Vandamme and Soetaert 2002; J Chem Techno Biotechnol 77:1323-1332).

In raspberries, the synthesis of raspberry ketone is one part of the phenylpropanod pathway. This pathway has been described by Borejszaysocki and Hrazdina (1994). In the first step, coumaryl CoA (which Is present In many plant tissues) is condensed with one malonyl CoA into benzalacetone (p-hydroxyphenylbut 3-enc-2-one). The enzyme catalysing this step is called benzalacetone synthase (BAS). In the second step, the double bond in benzalacetone is reduced, resulting in raspberry ketone (p-hydroxyphenyl-2-butanone). The enzyme catalysing this step is called benzalacetone reductase (BAR), this enzyme requires the presence of NADPH. Benzalacetone synthase (BAS), EC 2.3.1.-., is a member of the polyketide synthase family.

Benzalacetone reductase condenses one acetone unit from malonyl CoA with one p-coumaric acid to form benzalacetone. Chalcone synthase (CHS), EC 2.3.1.74, is another member of the polyketide synthase family, which condenses three acetate units from malonyl CoA with one p-coumaric acid to form chalcone. Stilbene synthase (STS), EC 2.3.1.146, is another member of the polyketide synthase family, which condenses three acetate units from malonyl CoA with one p-coumaric acid to form stilbene (Zheng et al 2001). The polyketide synthase family is described in detail in Schroder 1999 (Comprehensive natural products chemistry vol 1: polyketides and other secondary metabolites includingfatty acids and their derivatives [U. Sankawa Ed] pp 749-771).

CHS is part of another part of the phenylpropanod pathway, which converts phenylalanine into naringenin chalcone and its derivatives (Weisshaar and Jenkins 1998; Hwang et al 2003). This part of the phenylpropanoid pathway involves the following enzymes: phenylalanne ammonia Iyase (PAL), cinnamate-4-hydroxylase (C4H), 4-coumarate:coenzyme A ligase (4CL) and chalcone synthase (CHS).

As a first step phenylalanine Is deamnated to yield cinnamic acid by the action of PAL. Cinnamic acid is hydroxylatcd by C4H to 4-coumaric acid. 4-coumaric acid is activated to 4-coumaryl-coenzymeA (CoA) by the action of 4CL. CHS catalyses the stepwise condensation of three acetate units from malonylCoA with 4-coumaryl CoA to yield nanngenin chalcone (which is a precursor for some flavonoids). Naringenin chalcone is converted to naringenin by chalcone isomerase (CHI) or naringemn chalcone spontaneously converts to naringenn.

Evidence for the relation between BAS and CHS is provided by BorejszaWysocki and Hrazdna (1994 and 1996). Borejsza-Wysocki and Hrazdina (1994) show that the timing of BAS activity parallels CHS activity. In addition, Borejsza-Wysock and Hrazdina (1996) show that CHS and BAS co-purify, and seem to react with the same antisera. However, CHS and BAS activity in the same enzyme preparation showed a different response to treatments with, for instance, 2-mercaptoethanol and ethylene glycol. Also, CHS activity and BAS activity showed different induction patterns upon treatment of raspberry cell cultures with yeast extract, suggesting that these enzymes are not one and the same molecule.

Soluble enzymes catalysing the reduction of a double bond using NADPH, for example benzalacetone

reductase (BAR), are classified by the International Union of Biochemistry and Molecular Biology as belonging to enzymatic class EC 1.3.1.X. For instance, an enzyme annotated as EC 1.3.1. 11 from Arthrobacter sp. was reported to remove a double bond from coumarate (Levi and Weinstein,

1964). However, no gene has been identified in connection to this enzymatic activity. Other enzymes In the enzymatic class EC 1.3.1.X are orotate reductase, 2-hexadecenal reductase,

cholestenone 5 alpha-reductase etc. for which genes are known. However, none of these enzymes was reported to have benzalacetone reductase (BAR) activity. It is known from literature that 4-hydroxybenzalacetone can be transformed to raspberry ketone by fungi or yeasts such as Pichia, Saccharomyces, Beauveria, Kloeckera, Aureobasidium, Cladosporium Geotrichum, Mucor and Candida spp. (Fuganti and Zucchi, 1998). However, no gene has been identified in connection to this enzymatic activity. Also, to our knowledge, no such activity has been reported for bacteria, neither gram negative nor gram positive.

Attempts to biosynthesise raspberry ketone have been described. Hugueny et al (1995, Boflavour 95

pp 269-273) teach a biotechnological method for producing raspberry ketone. This method comprises culturing a microorganism which has a secondary alcoholdehydrogenase (ADH), such as Candida boidinii, and adding the precursor betulosde to the culture medium. In this cellular environment the secondary ADH dehydrogenatates betuligenol into raspberry ketone.

Various studies have been carried out to determine the role of polyketide synthase genes in the production of flavonoids using E cold transformed with a raspberry CHS gene (see Zheng et al 2001; Kumar and Ellis 2003), a Glycyrrhiza echinata CHS gene (Hwang et al, 2003) or a Arabidopsis thaliana CHS gene (Watts et al 2004). However these studies teach the in vitro or in vivo synthesis of naringenin.

These studies do not teach the in vivo synthesis of benzalacetone or raspberry ketone.

Abe et al (2001) teach the cloning of rhubarb BAS, expression of the gene in E colt, purification of the recombinant BAS protein and the in vitro synthesis of benzalacetone. However this study does not teach the in vivo synthesis of benzalacetone or raspberry ketone.

SUMMARY OF THE INVENTION

According to a first aspect of the present invention, we provide a host cell comprising a chalcone synthase (CHS) polypeptide sequence and a 4coumarate:CoA 1igase (4CL) sequence in which one or both of the CHS polypeptide sequence and the 4CL sequence is heterologous to thc host cell.

Preferably, the CHS polypeptide sequence is derived from one of the following: raspberry, petunia, grape, Medicago sativa, Arabidopsis thaliana, Antirrhinum majus, Zea mais and Petroselinum crispum, preferably a raspberry CHS sequence. Preferably, the CHS sequence is selected from the group consisting of: accession number AF292367, accession number AF400567, accession number X04080, accession number X76892, accession number L02902, accession number AF112086, accession number X0371O, accession number X60204, accession number V01538, a sequence shown in SEQ ID NO: 2, and a sequence having at least 75% sequence homology thereto.

Preferably, the 4CL sequence is a tobacco 4CL sequence.

Preferably, the 4CL sequence is a sequence having an accession number U50846 or a sequence shown in SEQ ID NO: 3.

Preferably, the host cell is transformed with an expression vector encoding the chalcone synthase (CHS) polypeptide sequence and an expression vector encoding the 4-coumarate:CoA ligase (4CL) sequence, or an expression vector encoding both sequences.

Preferably, the host cell is a microbial host cell selected from the group consisting of F,scherichia spp, Saccharomyces spp, Pichia spp, Beauveria spp, Candida spp, Aspergillus spp, Bacillus spp, Pseudomonas spp, Hansenula spp, Klayveromyces spp, Schizosaccharomyces spp, Streptomyces spp, Lactococcus spp, Lactobacillus spp, Pediococcus spp, Kloeckera spp, Aureobasidium spp, and Streptococcus spp, preferably an E. colt, preferably strain BL21, or a Saccharomyces cerevisiae, preferably strain YPH 499, or a Bacillus subtilis host cell.

Preferably, a polypeptide expressed from the CHS polypeptide sequence has benzal acetone synthase (B AS) acti vity.

Preferably, the host cell is capable of producing benzalacetone when supplied with a precursor of benzalacetone, preferably p-coumaric acid or a source of p coumarc acid.

Preferably, the host cell has benzalacetone reductase (BAR) activity, preferably inherent benzalacetone reductase (BAR) activity.

Preferably, the host cell further comprises a benzalacetone reductase (BAR) sequence, preferably a heterologous BAR sequence, preferably shown as SEQ ID NO: 5.

Preferably, the host cell is capable of producing raspberry ketone when supplied with a precursor of raspberry ketone, preferably benzalacetone or a source of benzalacetone. Preferably, the host cell is capable of producing raspberry ketone when supplied with a precursor of raspberry ketone, preferably p-coumaric acid or a source of p-coumaric acid.

Preferably, the host cell further comprises a cinnamate-4-hydroxylase (C4H) sequence.

Preferably, the host cell Is capable of producing benzalacetone or raspberry ketone, or both, when supplied with cinnamic acid or a source of cinnamic acid.


:cool:

Reference Information

solo - 25-12-2007 at 18:00

Cation-exchanged montmorillonite-catalyzed facile Friedel-crafts alkylation of hydroxy and methoxy aromatics with 4-hydroxybutan-2-one to produce raspberry ketone and some pharmaceutically active compounds.
Tateiwa, J.-I., Horiuchi, H., Hashimoto, K., Yamauchi, T., and Uemura, S.
J. Org. Chem. 59:5901-5904., 1994


Abstract
The Friedel-Crafts alkylation of hydroxy and methoxy aromatics with 4-hydroxybutan-2-one (y- KB) in the presence of a cation-exchanged montmorillonite (Mn+-mont; Mn+ = Z++, N3+, Fe3+, and Zn2+) was investigated. Phenol was C-alkylated regiospecifically with y-KB in the presence of Z1A+-, A13+-, or Fe3+-mont to produce 4-(4-hydroxyphenyl)butan-2-one (raspberry ketone) in 31-35% GLC
yield. Anisole, 2-methoxynaphthalene, and 1-methoxynaphthalene were regiospecifically C- alkylated to produce 4-(4-methoxyphenyl)butan-2-one, 4-(2-methoxy-l-naphthyl)butan-2-one (phar- maceutically active), and 4-(4-methoxy-l-naphthyl)butan-2-one, respectively. N3+- and Fe3+-mont
were the most effective catalysts in these cases (13-58% isolated yield). y-KB could be used as an alkylating agent instead of the highly toxic 3-buten-2-one (MVK) which also polymerizes easily.

Attachment: Cation-Exchanged Montmorillonite-Catalyzed Facile Friedel-Crafts Alkylation of Hydroxy and Methoxy Aromatics with 4-Hydr (553kB)
This file has been downloaded 1776 times


Reference Information

solo - 25-12-2007 at 18:09

Amberlyst-15 Catalyzed Addition of Phenols to agr,b.beta-Unsaturated Ketones
Richard A. Bunce a; Henry D. Reeves
Synthetic Communications Volume 19, Issue 5 & 6 March 1989 , pages 1109 - 1117


Abstract
Amberlyst-15 has been used to catalyze regioselective additions of phenols to agr,b.beta-unsaturated ketones in yields of 20-90%. The reaction is superior to the analogous reaction employing concentrated sulfuric acid in affording greater yields and purer products with a minimum of laboratory operations.



[Edited on 25-12-2007 by solo]

Attachment: Amberlyst-15 Catalyzed Addition of Phenols to agr,b.beta-Unsaturated Ketones.pdf (417kB)
This file has been downloaded 2361 times


Klute - 26-12-2007 at 07:19

Thanks for all thoses articles!
I've just realized that there seems to be some confusion in the litterature on the exact nature of the so-called "raspberry ketone": in two of my org.chem books, and in some articles on the net, it is said to be the branched p-hydroxyphenylbutanone, the phenyl ring being attached to the third carbon of the chain, alpha to the carbonyl. See here: Smell Database
But in all the articles/patents you guys have kindly provided, it is said to be the straight-chained isomer.

To my eyes, the linear isomer 4-(para-hydroxyphenyl)butanone seems easier to synth, especially through the p-hydroxybenzaldehyde pathways.

A crossed aldol with acetone is easy and well documented, basic conditions would be more effective here I guess, the benzalacetone should be easy to isolate and purify, and I guess a CTH could reduce the double bond, or NaBH4 even if the carbonyl gets reduced, it could easily be re-oxydized.
US4414417 deals with a CTH using Rhodium and Iridium catalysts that yield the saturated ketone; this could be applied to other catalyst/donors.

The FC option seems equally interesting, but not possessing any b-hydroxybutanone, it doesn't seem readily obtained from MEK or other accesible reagents.

p-hydroxybenzaldehyde could be obtained through a Riemmer-Tiemann as mentionned in the review Solo provided, I remember ready about performing the reaction in alcoholic medium to preveil the para-formylation.
I have ~30g of phenol left, so this could be enough on a small scale, though I want to give the o-formylation a try using Mg(OCH3)2/paraformaldehyde a try again. Maybe a bayer-villiger oxydation on benzaldehyde could give workable yields of phenol. I don't want to melt any benzenesulfonic acid with NaOH :).

Well, I guess I'm going to keep busy for a while :) thanks for the help!

LSD25 - 1-1-2008 at 04:13

Klute,

I just found this whilst looking for zingerone (fuck knows why I was looking for that, but...)

http://www.apc.titech.ac.jp/~tikariya/mito/teaching/2005/tex...

Seems like a nice, simple route

I reckon I could even practice the yeast reduction on the zingerone - although that rhodium catalyst makes ones mouth water eh?

Reference Information

solo - 1-1-2008 at 08:21

Rheosmin (“Raspberry Ketone”) and Zingerone, and Their Preparation by
Crossed Aldol-Catalytic Hydrogenation Sequences

LEVERETT R. SMITH
THE C H EMICAL EDUCATOR VOL . 1 , N O . 3


Introduction
Preparations of the two closely-related natural products rheosmin (“raspberry ketone”, 4-(4'-hydroxyphenyl)- 2-butanone) and zingerone (4-(4'-hydroxy-3'-
methoxyphenyl)-2-butanone), are well-suited for the introductory organic laboratory. The crossed-aldol condensation of 4-hydroxybenzaldehyde with acetone gives an adduct (4-(4'-hydroxyphenyl)-3-buten-2-one), which is hydrogenated
cleanly over rhodium on alumina to form rheosmin. Condensation of vanillin with acetone gives 4-(4'-hydroxy-3'- methoxyphenyl)-3-buten-2-one, which is hydrogenated to zingerone. The article includes background information on the
target compounds and the synthetic methods used, along with experimental procedures and IR and NMR data on the compounds encountered.

[Edited on 1-1-2008 by solo]

Attachment: Rheosmin (“Raspberr Ketone”) and Zingerone,and Their Preparation.pdf (99kB)
This file has been downloaded 2543 times


Klute - 3-1-2008 at 15:39

Thanks alot for those two last papers, especially your Solo, just what I need.
I think i will ratehr try a NaBH4 reduction of the unsaturated ketone though, as I don't plan on aquiring any rhodium catalyst, and Pd/C would surely give the same result as NaBH4, or a mixture of the saturated alcohol and ketone. I might try it with some recylced catalyst at a small scale, as per Solo's document.

I will surely try making zingerone first, trying the aldol condensation and see how the reduction goes, I've encountered a few mishabs with the Mg(OMe)2 / (H2CO)n formylation, although the reaction seems to proceed well. Left the acidifyed mixture stir too long, resulting in a f**king polymeric sludge (excess paraformaldehdye). It's just a lot of work, along with the preparation and drying of the reagents. Does seem more interesting than the Riemmer Tiemann though.

pantone159 - 3-1-2008 at 19:12

Thanks also to solo for the last paper... Also thanks for pointing out 'The Chemical Educator', a journal that I wasn't aware of. Perhaps this is akin to the Journal of Chemical Education(?) which I like a lot.

Klute - Let us know how the NaBH4 reduction goes, that would be easier for me to try then the hydrogenation.

stoichiometric_steve - 4-1-2008 at 01:11

klute: Pd/C-CTH does generally NOT reduce carbonyl functions.

Klute - 4-1-2008 at 01:33

From the document Solo has just posted:
"Literature reports appear of palladium and Raney nickel giving significant over-hydrogenation to give alcohols as byproducts, in 15–20% yield, which complicates cleanup and isolation of pure ketone products [30,
36, 47].

30. Mannich, C.; Merz, K. W. Archiv d. Pharm. 1927, 265, 15.
36. Pabst, A.; Barron, D.; Adda, J.; Schreiber, P. Phytochemistry 1990, 29, 3853.
47. Banno, K.; Mukaiyama, T. Bull. Chem. Soc. Japan 1976, 49, 1453."

I might try a microscale experiment with recycled Pd/C, both by CTH and catalytic hydrogenation as per the article, if I have enough time. But if NaBH4 reduction works as cleanly and effeciently as I hope it will, and oxydation with either H2O2/Fe3+ or some HOCl source works nicely, it could come out cheaper/more practical than getting some Rh/Alumina, of which I won't have any immediate use elsewhere.

Klute - 6-1-2008 at 13:56

Thanks to Nicodem, who kindly retreived European Journal of Organic Chemistry 9,(2000) 1793-1797, dealing with the use of NaBH4/CoCl2 system in either MeOH or aq. medium for reduction of 4 unsaturated ketone, including benzylideneacetone, the unsubstitued derivative of the two unsaturated ketones mentionned further up, to afford either:
-the unsaturated alcohol by using straight NaBH4 in protic medium
-the saturated ketone by using NaBH4/CoCl2, giving 86% of 1-phenylbutan3-one when using a Sub/NABH4/CoCl2 ratio of 1/3.5/3
-the saturated alcohol, by doing a two-step one-pot procedure, first reducing the carbonyl then the double bond, or vice versa.

So this really is a key article for this synth, no need of catalytic hydrogenations, or multiple steps to obtain the ketone. Aldol, reduction, voilà. Mild conditions, easy workup.
I will try out the zingerone synthesis as soon as I get my vanillin, and then start working on get that para-hydroxybenzaldehyde... Any ideas apart from the Riemmer Tiemann, which isn't really para-selective, and would yield o mixture of o- and p-isomers?

BTW, NiCl2 can be used aswell with similar results. I will also report back on the Mg(OMe)2/(CH2O)n formylation once everything is done.

EDIT: I read the wrong colum in the tables, actually the best yield of the 1-phenylbutan-3-one is 86%, when using a solution of Sodium Dodecylsulfate..

[Edited on 7-1-2008 by Klute]

UnintentionalChaos - 6-1-2008 at 14:28

I don't know about purity, but to get some vanillin on the cheap, go buy the cheapest bottle of clear artificial vanilla extract that you can (essentially containing vanillin, ethanol, and water) and place it in a flask with air excluded (such as by a piece of aluminum foil with a small hole in it) and heat until ethanol stops boiling off (I did this a looooong time ago before I had much experience or a decent thermometer and remember that the solution suddenly changed boiling pattern when this happens..I was also checking the flammability of the vapors). You may have a second phase seperate. This is liquid vanillin or perhaps liquid vanillin with water dissolved in it (mp. vanillin 81-83C). Add water and heat to dissolve if this occurs. Chill the solution (which may be a pale amber color from oxidation/polymerization products. Using aluminum foil and allowing water/alcohol vapor to form a protective atmosphere minimizes this) Vanillin crystallizes out as long, thin, pale yellow/cream colored needles. I got 13g from an 8oz bottle ($7 US) I'm sure most here can improve on this method though.

[Edited on 1-6-08 by UnintentionalChaos]

Klute - 7-1-2008 at 08:48

UnintentionalChaos, thanks for the advice, but I think I will be getting my vanillin from a flavoring supplier, which offers it in >99% purity for a reasonable price. But I might give it a try with the flavorings at the local supermarket, as the minium is 500g, and I wouldn't know what to do with so much vanillin, even if using it for baking cakes and stuff :)

As I only screened quickly through the article yesterday, I mixed up some entries, and the fact that the only way of obtaining good yields of pure phenylbutanone is to use a 0.1mol.L solution of Sodium Dodecylsulfate (SDS), which I don't currently have at hand, as a reagent anyway. Apparently, Tetrabutylammonium Bromide can't be a good substitute as it doesn't form micellar emuslions, which apparently "protect" the ketone from reduction by BH4-; it's the formed H2 which is the true reducing agent, catalysed by the formed metal boride. I could try using benzylalkylammonium chlorides, in C10-C12, which would form micellar emuslions and might act similarily. It's starnge as they have a few entries were using MeOH and H2O as solvants give 77% et 51% yield respectively, but latter state that:

"The preparation of pure product 3c [1-PhButanone] was not possible in either MeOH or water, and only use of aqueous solutions of SDS afforded it in good yield (entry 10). It seems that this surfactant ‘‘protects’’ the micellar-bound substrate
from attack by the reactive anion BH4 –, the main reduction
pathway being, therefore, the one carried out by H2."

I guess the product is contaminated by saturated alcohol, and that the 2 must be hard to seperate. A light oxydation could convert any over-reduced material back to the ketone, but could also make more impurities, and give a complex mixture of products. Let's try it one pot.
So if the benzalkonium (pool supply) doesn't work out nicely, I was thinking about generating before-hand the metal boride with stoechimetric amounts of borohydride and the chloride, in the appropriate solvant, and then adding the substrate and performing a atmospheric catalytic hydrogenation. Wouldn't it basicly proceed the same way as in-situ formed H2? I think it is molecular hydrogen that is evolved and not nascent, but don't take my word on this. Can anyone can help me out here? This way, no need of using expensive Rhodium catalyst.

EDIT:I've been kindly given ~30g of reagent-grade vanillin, so I will be able to perform the aldol condensation this weekend.
I've decided on trying a simple atmospheric catalytic hydrogenation with preformed CoB catlyst (from CoCl2 and stoechiometric NaBH4), as I've realized I've only got a couple grams of CoCl2 and no NiCl2... We will see how it turns out. I'm still undecided concerning the amount of catalyst to use... Any advice would be welcome.

[Edited on 10-1-2008 by Klute]

Klute - 10-1-2008 at 04:54

Solo kindly retreived two more article on the catalytic hydrogenation of unsaturated ketones:

Colloidal nickel boride on rare earth oxides for hydrogenation of olefins
Yu-Lin Jiang, Xue-Yun Wei, Shou-Ping Tang and Liu-Bin Yuan
Catalysis Letters; 34, (1995) 19-22

This deals with the use of colloidal NiB catalyst, mixed with rare earth oxides in some cases, to afford a highly active catalyst, prepared from the metal salt, and alcoholic NaBH4 in presence of PEG. The hydrogenation of p-hydroxyphenylbut-3-en-2-one to Rheosmin "raspberry ketone" is covered. The preperation of the "simple" catalyt is straight forward. They claim a 96% isolated yield of rheosmin when using Ni2B, in 170min, and the hydrogen uptake rate and thus reaction is much quicker when the catalyst is made as described with PEG and Nd2O3.
Another particluary interesting thing is that they compared the activity of this catalyst with Pd/C, and claim a 96% isolated yield of Rheosmin in 160min! This is pretty contradictory with the Chem.Educ. article.
At first reflexion, I would rather trust the Chem. Educ. article, as the reactions were reviewed for use in academic labs by students, although it is not explicity claimed that the Pd/C hydrogenation was. But then again, when presenting a new catalyst, the authors of the Cat. Today would have highlighted the strong superiority of their catalyst towards product isolation if they had obtained bad yields when using Pd/C. Although dishonest, claiming higher yields with the object of their article would seem more logical than claiming high yields (although longer reaction times) with such a widely used catalyst. In any case, this inspires me at trying it.
The other good news is that with both catalyst atmospheric hydrogenation seems to give very good yields, so no need of pressurized hydrogen.


Selective hydrogenation of 4-(6-methoxy-2-naphtyl)-3-buten-2-one to Nabumetone®
Nicoletta Ravasio, Federica Zaccheria, Pietro Allegrini and Mauro Ercoli
Catalysis Today, Volume 121, Issues 1-2, 15 March 2007, Pages 2-5

This article describs the use of reuseable, easily prepared SiO2-supported Cu catalyst for hydrogenation of unsaturated ketones.
Highly-loaded catalyst promotes complete reduction to the saturated alcohol. But 8% Cu/SiO2 apparently gives good yields when reducing the titled compound, derivative of benzalacetone were the phenyl ring is replaced by a substitued naphtyl ring. Both compounds should behave similarily I guess.
No isolated yields are mentionned, only high selectivities, which can be unclear towards to true efficienty of the reaction. High selectivites but low conversions can be usefull for industrials when the substarte can easily be recycled.
Once again, >98% selectivites are mentionned for 5% Pd/C. It is also mentionned that adding ~5% K2CO3 to a Pd/C hydrogenation minimizes the formation of the saturated alcohol, which is a good find.
Even if the catalyst can easily be prepared before introduction of the substarte, the problem is that changes in the quality of the silica can cause drastic changes in the products, especially with aliphatic unsaturated ketones. Conjugated aromatic unsaturated ketones appear more resitant to this change in chemioselectivity. But as I personally make my silica gel from soduim silicate solution and HCl, the quality varies enormously, and I don't really have means of controlling porosity, surface/gram and other caracteristics that seem to play a important role here.
But the simplicity of the procedure still makes this a interesting experiment. Cu-based catalyst are said to be more selective to carbonyl reduction than double-bonds, and if reprocuble results can be obtained with home-made catalyst, this could have other applications for different compounds, and thus make cheap, available hydrogenation catalyts for the home chemist, compared to other mostly expensive ones.

I'm finding this subject more and more interesting. What started as a simple weekend-occupation subject is turning into my major center of interest actually. I'm very lucky that there some interesting litterature on the subject, and incredibly helpfull members here that provided these articles as I can't access any libraries at the moment. Again, thanks a million.

LSD25 - 12-1-2008 at 19:05

Solo,

Thanks for J.Chem Ed article - I'd seen the abstract to that before and have long wanted to read it....

Klute - 16-1-2008 at 13:15

Synthesis of 1-(4-hydroxy-3-methoxyphenyl)but-1-en-3-one by basic crossed-aldol condensation of vanillin and acetone.

Finally started this very easy reaction. I just scaled up 20x the L. R. SMITHChem. Educ. 1(3) "short" synthesis, and plan on leaving it 48h at room temp.

Synthesis

5g (33 mmol) of reagent-grade vanillin [Picture 1] were weighed, and dissolved in 20mL (~280 mmol) of technical acetone, giving a totally limpid solution, in a 100mL capped bottle containing a stir bar [picture 2].
2g (50 mmol) of technical NaOH were dissolved in 20mL dH2O (10% w/v, 2.5 mol/L), and the warm solution was cooled under a stream of cold water. Once at room temp, the solution was slowly poored into the acetone solution with steady stirring. This immediately caused the solution to turn yellow and warm up somewhat [picture 3]. The color gradually darkened, becoming dark orange after 5min, and the bottle cooled down gently [picture 4]. This will be stirred at RT for 48h, then worked up as per the article: addition of 100mL of 3M HCl, filteration and washing of the resulting solids, recrystallization with EtOH/H2O, and caracterisation of the product.
This unsaturated ketone will then be hydrogenated over 10% Pd/C to the corresponding ketone, 1-(4-hydroxy-3-methoxyphenyl)butan-3-one, or Zingerone. Hydrogenation over preformed Co2B might also be tried.

Picture 1





Picture 2





Picture 3






Picture 4





Sorry if the pics are big, I didn't find how to just post a "icon" to the large pictures for display on another window. If this causes too much problems for uploading this thread, I'll diminish the size...

EDIT:
12h later, the mixture is now dark cherry red. I will post a picture tomorow as I don't have the time right now.

[Edited on 17-1-2008 by Klute]

Klute - 18-1-2008 at 16:06

Synthesis of 1-(4-hydroxy-3-methoxyphenyl)but-1-en-3-one - Continued


After 48h stirring at RT [Picture 1], the dark red/black mixture was transfered to a 250mL beaker, and 100mL 10% HCl poored in with magnetic stirring. A black oil crashes out, giving a black heterogenous mixture [Picture 2]. After 2min stirring, a fine yellow solid started precipitating [Picture 3]. Black droplets were still present at the bottom.
After another 5min stirring , the suspension was filtered, care taken of decanting the heavy, dark granules present at the bottom of the beaker. The fine suspension gave a greenish crystalline powder [Picture 4], which was washed with a little water, dried with suction on the buchner, and transfered to a small beaker.
The dark crystalline granules were equally washed, filtered and dried [Picture 5]. They did not agglomerate, and were very easy to collect in a seperate beaker.

The two crops were recrystallized with hot 10mL EtOH, followed by gradual addition of 5-8mL water, and left to cool. The first crop gave a clear, greenish solution, the second gave a dark brown, but limpid solution. The first crop crystallized very quickly. It was filtered, briefly washed with water, and dried on the buchner [Picture 6], giving beautifull canary-yellow crystalline flakes [Picture 7] .
The second crop crysatllized much less, not enough water had been added. The formed crystals were filtered, the filtrate replaced in the beaker, and the cake sparingly washed with water and dried. The crystals formed, although larger than the first crop, were of a more darker yellow [Picture 8].
The two crops of crystals were left to dry in the dessicator, and finally weighed exactly 2.53g each!

The final weight was 5.06g (26.35 mmol), representing a yield of 79.86%. Not bad.


Picture 1


Picture 2


Picture 3


Picture 4


Picture 5


Picture 6


Picture 7


Picture 8



Hydrogenation will hopefully be performed next weekend.

tinydantzler - 20-1-2008 at 20:40

I was wondering if someone could help me out with something regarding this synthesis of zingerone.

I am currently in a beginner-ish orgo chem lab in college, and I need to propose a 3 step synthesis of a compound of some interest. As far as I can tell, the synthesis of zingerone from vanillin is only a 2 step (the vanillin and acetone with NaOH and the hydrogenation), and I'm having trouble coming up with a possible third step either at the beginning or end.

I mean, I can sort of see some compounds I could possibly synthesize vanillin out of, but they seem to be unimportant things that would not be readily purchasable.

I read that zingerone is produced by heating gingerol through a retro aldol reaction. Now, mind me if I say something stupefying as I do not have much practical lab experience, but would an aldol reaction of zingerone and what appears would be an aldehyde be at all feasible?

If anyone could help out, I'd really appreciate it. I have a backup plan if I cannot figure something out with zingerone, but this seems more interesting.

Klute - 21-1-2008 at 06:49

You could make the vanillin from eugenol, that's a common academic synthesis IIRC, using KMnO4. I'll have a look to see if I can't find a protocol at home. Or there some news ways of making vanillin from lignin.
Maybe you could reduce the unsaturated ketone all the way to the saturated alcohol (NaBH4/CoCl2 2 steps-one pot, see the article mentionned earlier in the thread, or better LiAlH4 if they let you handle that) and then oxydize to the saturated ketone.

You could try the rheosmin synthesis, making the p-hydroxybenzaldehyde, although I haven't found a practical way with the chems I can acces for now. It seems the Riemmer Tiemann formylation would essentially yield salicylaldehyde, with only small amouts of p-isomer.


Good luck, please keep us posted on what you decide on doing, and how it goes.

Nicodem - 21-1-2008 at 07:56

@Tinydantzler: Vanillin can also be done by formylating guiacol (2-methoxyphenol) - a cheap and readily available chemical. This can be done by the Reimer Tiemann reaction in the presence of cyclodextrin or tertiary amines (they change the regioselectivity of the reaction thus allowing for the para formylation). Other published methods include the condensation with glyoxalic acid in basic media following by the oxidation of the intermediate mandelic acid to vanillin (but these are two steps). One Japonese patent also describes the Vilsmeier-Haack formylation of guiacol using DMF/POCl3 at 120°C. This last is probably the most suitable for lab scale.

@Klute: Nice work. :)

Edit: Wrote glycolic acid instead of glyoxalic...

[Edited on 22/1/2008 by Nicodem]

LSD25 - 21-1-2008 at 09:36

Or you could oxidise the ketone to the cinnamic acid... Ferulic acid:

http://en.wikipedia.org/wiki/Ferulic_acid

Alternatively, I think Solo (here or elsewhere) came up with a 1-step procedure for benzaldehyde from phenylalanine - this might hold true for tyrosine (p-hydroxyphenylalanine) then you have the p-hydroxybenzaldehyde. From that rheosmin synthesis could be acheived in the remaining two steps.

If yields ain't important - the Strecker degradation of tyrosine with glyoxal or potassium peroxodisulfate:

http://www.cazv.cz/attachments/3-Adamiec.pdf

Will give crap yields of the benzaldehyde, but like I said, if yield ain't important. If however you use diazomethane some very interesting methyl ketones might result.

Klute - 21-1-2008 at 13:31

Nicodem: does that tertiary amine trick work in general, or is this only related to vanilin? I don't remember ready about this before, IIRC the Riemmer Tiemann review (haven't got the ref on hand, but it was made available here) doesn't mention it, but I haven't got the document at hand so can't confirm this. If you've got a ref or two, I'd be delighted to give them a look.

LSD25, smart idea from the tyrosine, but indeed seperating the vast amount of byproducts would be time-costly, and for minimal yields. But both products (tyrosine and S2O82-) are pretty available. I'll have a look for Solo's idea, or ask him directly if I can't find anything.

Nicodem - 22-1-2008 at 03:35

The reference about the influence of tertiary amines on the regioselectivity of the Reimer-Tiemann formylation of guiacol was already posted:
https://sciencemadness.org/talk/viewthread.php?tid=9596&...
The reference for the regioselectivity effect of cyclodextrin is also there (guiacol is one of the tested substrates).

Another reference says:
Quote:
Abstract:

Refluxing 2-methoxyphenol with CHCl3 in EtOH in the presence of NaOH and Et3N gave 76.5% vanillin.

Huaxue Shiji, 15 (1993) 184, 138.

dangator - 24-1-2008 at 23:16

A nice trick for conjugate reduction of the enone formed after the aldol condensation/dehydration is CuI/LAH. See Tet Let No. 50 4453-4456 or I can mail it to whomever needs it.

solo - 25-1-2008 at 02:56

The most recent issue of Tetrahedron Letters is Volume 49, Issue 7, Pages 1091-1282 (11 February 2008), so tell me how you propose to provide a reference that doesn't exist.......also why didn't you just upload it, whatever you have as a reference surely isn't the reference noted................solo

dangator - 25-1-2008 at 09:05

Lol @ internet tough guy.

Attachment: lahcui.PDF (163kB)
This file has been downloaded 1156 times


not_important - 26-1-2008 at 01:35

Volume 16, Issue 50, not Number 50. Volume 49, Issue 7 is the current one.

Also in JOC:

New and effective reagents for 1,4 reduction of .alpha.,.beta.-unsaturated ketones, LiAlH4-CuI and Its reactive species H2AlI
E. C. Ashby, J. J. Lin, and R. Kovar

Journal of Organic Chemistry
Vol. 41, No. 11: May 28, 1976
pp 1939 - 1943; DOI: 10.1021/jo00873a011

Reference Information

solo - 26-1-2008 at 03:59

New and effective reagents for 1,4 reduction of .alpha.,.beta.-unsaturated ketones, LiAlH4-CuI and Its reactive species H2AlI
E. C. Ashby, J. J. Lin, and R. Kovar
Journal of Organic Chemistry Vol. 41, No. 11: May 28, 1976, pp 1939 - 1943;

Attachment: New and effective reagents for 1,4 reduction of .alpha.,.beta.-unsaturated ketones, LiAlH4-CuI and Its reactive species (551kB)
This file has been downloaded 1749 times


Klute - 26-1-2008 at 04:47

LiALH4 is a bit of an overkill for such a reaction IMHO. If the reduction can be easily done with cheaper, safer reagents, such as NABH4 and H2/Catalysts, using expensive LiALH4 is a bit of waste. But of course that simply depends on your financial aids/work environement :) .
I'm sure there's lots more one can do with LiAlH4 that can't be done by other means. Oh well, just another article in another journal I guess.

BTW, the two recrysatllized crops had a sharp 127°C melting point (lit: 127–128.5 °C ) , so I think I can safely say it quite pur. The crystals have a lovely, light vanillin-like smell, a bit more fruity.

LSD25 - 2-2-2008 at 04:03

Klute,

Here is a Pd-CTH enantioselective reduction of a-methylcinnamic acid to the corresponding (S)-2-methyl-3-phenylpropanoic acid...

It proceeds at fairly low temps, seems remarkably simple (in fact seems awfully like, well apart from the time, the one I posted earlier - albeit it is CTH).

I'd dearly love to know how the l-tartaric acid promotes the claimed huge increase in ee's (98% ee or 99% of the (S))

PS Thanks Stoichemetric Steve for this site:o

Filemon - 2-2-2008 at 17:12

You may make it condensation with p-hydroxibenzaldehyde and acetone => p-hydroxibenzalacetone

You reduce p-hydroxibenzalacetone with Zn + AcOH.


http://www.orgsyn.org/orgsyn/pdfs/CV1P0077.pdf

http://www.orgsyn.org/orgsyn/pdfs/CV9P0186.pdf

carbonic - 5-3-2008 at 21:10

This is truly interesting and informative post! A nice change from all the posts on aminating questionable substances and so on...

I hear a lot about the thermogenic power of Raspberry ketone - just a little bit will make you warmer immediately, and it is very popular with the weightlifting guys these days.

So rhodium is out of the question for me, anyone can suggest a simple and gentle hydrogenation that is a little more OTC? pd/c is too strong? And nobody sells borohydride (even for fuel cell) anymore!

Klute - 6-3-2008 at 06:10

Yes, apparently Pd/C has been often employed for such reduction, although the problem is a certain amount of the saturated alcohol is also formed, and the ketone and alcohol are hard to effectively seperate. A carefull coluum chromatography could do the trick, or maybe a bisulfite if the adduct isn't too soluble...

I have still not proceeded to any hydrogenations, although I now have sevral unsaturated ketone at hand: straight phenyl, 3-MeO-4-OH; 2-MeO; 3,4-MeO, etc. Most of the unsaturated ketones have a light, pleasant smell.

Raney nickel is said to work for such reduction too. I'm surprised you can't find any NaBH4, it is relatively availble.

LSD25 - 6-3-2008 at 06:35

Is it possible to just use crushed-up automotive catalytic converters as is? They are supposed to contain 'some' rhodium, in addition to slightly larger quantities of both platinum and palladium. As they are designed to be catalysts per se, would they not be able to be utilised? IIRC the platinum group metals are supported on predominantly alumina, which shouldn't cause too much trouble... (although I am unsure if the cesium oxide content would be problematic).

Klute - 6-3-2008 at 08:07

Honestly, I can't say. The quality of the catalyst, impurities, catalyst poisons, support, ect all play a very important role, for example home-made Pd/C never has the same activity as commercial catalyst. It could be interesting to try, but I would use a "simplier" substarte, one where only 1 reduction product is possible, and easily seperated from the substrate for such experimentations. This reaction already seems delicate with commercial catalyst, the result of using such material wouldn't bring any reliable information IMHO.

carbonic - 6-3-2008 at 08:31

Used cat. converters are poisoned already by exhaust. So in addition to the catalyst being deactivated you are going to introduce all the heavy metals from 10yrs of gasoline.

Now my warning is done, so I will show you someone else recycling cat. converters. But he is simply using it to degrade CO as it was intended. However, it supports your recycling scheme.

http://mattson.creighton.edu/CO/index.html

not_important - 6-3-2008 at 09:24

Quote:
Originally posted by LSD25
Is it possible to just use crushed-up automotive catalytic converters as is? They are supposed to contain 'some' rhodium, in addition to slightly larger quantities of both platinum and palladium. ...


Some do have rhodium, some don't. But they are optimized for their job, high temperatures and IC engine exhaust. You'd likely have to strip the metals off the substrate and work that solution up to make a catalyst.

You might look into pentacyanocobaltate catalysts, which can be used to reduce double bonds in conjugated unsaturated but do not catalyse reduction of isolated C=C double bonds. While normally used on dienes and similar hydrocarbons, I dimly remember it being used with unsaturated ketones.

Fleaker - 6-3-2008 at 15:00

Very nice post Klute.

Many catalytic converters contain rhodium along with other amounts. I doubt that they would be poisoned, but they will definitely not be as effective as freshly prepared catalysts done conventionally with BH4- onto carbon or alumina.

LSD25, it's cerium oxide, not cesium mixed with the gamma alumina substrate.

LSD25 - 6-3-2008 at 17:25

ooops, did I really write cesium? I did mean cerium - I have been playing with 'em for three weeks now, the trouble is that my only source of sodium nitrite is out at present. This means I have to try and find a good basic resin, any ideas (I have been looking into the ones used for water deionization not the ones for softening they are acidic)

PS Are the exchange resins used in aquaria the same as the ones we want here, the ones that remove chlorine from aquarium water?

LSD25 - 5-6-2008 at 10:18

Sorry, I posted something which Solo had already posted (thought that sucker looked familiar).

BTW I recently encountered a silver oxide mediated decarboxylation-deamination of phenylalanine which reportedly gave mainly benzaldehyde (thus, it 'MIGHT' be useable to form the p-OH-benzaldehyde from tyrosine).

[Edited on 5-6-2008 by LSD25]

Klute - 15-6-2008 at 08:13

I've FINALLY decided on trying to reduce the double bond on the unsaturated zingerone ketone. :)
I thought it would be a good occasion to start working with atmospheric catalytic hydrogenations. I decided on starting with aregular hydrogenation over recycled Pd/C, and see what gives, before trying out cheaper catalyst, so than I coul dcompare yields, hydrogen uptake rates, ratio ketone:alcohol, etc

I tried a setup using a chromatography column as H2 reservoir, but apparently it didn't work well as the pressure must diminsih too much after a little absorption to let the recation going.
I also did a stupid mistake, adding K2CO3 to a phenol w<hile I didn't want the phenoalte...

Synthesis of Zingerone 4-(4-hydroxy-3-methoxyphenyl)butan-2-one by atmospheric catalytic hydrogenation over Pd/C

Ref: Us patent N° 5,847,225





The following setup was assembled:
A 100mL schlenk was connected via a gas outlet adaptator and plastic tubing to a 350mL chromatography column mounted with a schlenk tap. The bottom of the column was immersed in a beaker containing 500mL water, the column's tap fully opened.
A hydrogen generator was assembled: a 250mL 4-neck RBF with a stir bar was mounted with a 70mL addition funnel, itself mounted with a gas outlet adaptator connected to some tubing.

The column:


The complete setup:


40mg of recycled Pd/C from a previous CTH reduction was charged into the schlenk, along with 10mL AcOEt.

The setup was then charged with hydrogen in the following way:

A very weak vacuum was connected to the schlenk's side arm. The schlenk tap was opened, aswell as the tap on top of the column. The water started rising into the column. Once it was near the top, the tap on top of the column was closed, followed by the schlenk's side arm. The vacuum tubing was disconnected, and the argon tubing tubing attached after purging the side arm a few times (attach the tubing, leave some pressure to build up, briefly discconect the tubing to evacuate the argon/air pressure, etc etc to chase any air from the side arm), then the schlenk tap was opened, followed by the column. The water level fell, and a flow of argon was left to bubble through the setup for a few minutes.

The addition funnel was charged with 20mL 37% H2SO4, and 0.5g of zinc dust was slurried into the RBF with a little dH2O.
The schenk and column were once again evacuated until water level was near the top of the column, acid dripped onto the zinc, and a flow of H2 was left to purge the generator for a min. The closed schlenk side arm was then purged with H2 as previously, the tap opened, and the column opened. The column was filled with H2, and a flow of H2 bubbled through the setup until evolution of H2 slowed down. The column was sealed, filled with H2, and stirring continued for 10min [Note1].

Catalyst during saturation:



The H2 tubing was disconnected, the schlenk briefly evacuated (column still closed), and flushed with argon [Note2]. The schlenk's top was disconnected, and under a flow of argon, 0.39g (2.82 mmol, 0.25eq) of K2CO3 were added [Note3] , followed by a solution of 2.15g (11.20mmol) of 4-(4-hydroxy-3-methoxyphenyl)but-3-en-2-one in 20mL AcOEt [Note4]. The erlen containing the yellow solution was rinsed with 5mL AcOEt.

The unsaturated ketone:


The obtained reaction medium:



the schlenk was closed, evacuated, back filled with argon, evacuated, back filled with H2 (adding more zinc dust to the H2 setup) twice, then the schlenk arm was closed, the column opened, and vigorous stirring started. H2 uptake was immediate, but slow. Slight warming was noticed.





After 30min, the reaction medium had turned to a suspension of guacamole-green solid along with the catalyst: the phenolate. Ihad completly forgotten there was a phenol group in the molecule, and that K2CO3 would form the phenolate... Even if this wasn't obviously a problem for the reduction, the solid could cover the catalyst enough to limit H2 uptake, considering the weak loading. So 0.3mL (~5.5mmol) GAA were added (opening the schlenk after performing all the operations described previously), along with a spatula (~1g) of dry AcONa. The green solid dissolved immediatly, leaving a faintly emeraude-green solution and a few orange carbonate particules.


The phenolate:


After adding the acid:



It was noticed that the water level never went above a certain point, even after recharging the column with H2, more absorption occured, but each time the level stopped at the same level (pretty low) [Note5].
It was decided to change the setup (not more than 30mL H2 absorbed over 3h) to a conventional inverted cylinder.

The flask was evacuated, aswell as the column, and back filled with argon. The column was disconnected, schlenk closed, and under a flow of argon the gas tap was attached on the top of the schlenk. A tubing was attached from the top of this tap, and placed in the cylinder, which was inverted under the surface of the water in the beaker. The setup was evacuated to rise empty the column from it's air, just under the tubing, and back filled with argon, doing this twice.

Setup with inverted cylinder:



More zinc was added to the H2 generator, and the setup purged with H2 before filling the column. The schlenk side arm was then closed, and vigorous stirring started. H2 uptake started immediatly, monitering the rate: 1mL/min.

After 20min, it seemed the H2 uptake has ceased. a White inorganic solid had precipitated, and seemed to cover the catalyst....

The inorganic precipitate on the catatalyst (very quick decantation):




The setup was opened (following the directions given previously, and 20mL MeOH containing 1 mL dH2O added. This completely dissolved the solids, but H2 uptake still didn't continue. A spatula tip of potassium formate was then added: there was a slight gas evolution (column closed, side arm opened) for a few minutes, that died off quickly. The column was then opened again after flushing the schlenkwith H2, and H2 uptake started immediatly, quickier than before (2mL/min), and calmed down to 1mL/min over 15min [Note6].

Inorganic dissolved:



The absorption rate then gradually diminished (1mL/2-3min), but didn't stop. The hydrogenation was stopped overnight (sealed column, stopped stirring), and restarted in the morning. The green color had lightened up considerably, and TLC (Eluant: 10:1 DCM:AcOEt) indicated a good amount of saturated ketone was formed, along with a little alcohol [Note7].

Reation medium in the morning:



125mL H2 had been absorbed since the cylinder setup was assembled. I considered that roughly 40mL had been absorbed with the column, so there isn't much left before reaction is finished, but I prefer following the reaction with TLC.

H2 absorption:



Each sample is taken after stopping the stirring and leaving the catalyst enough time to settle, and 0.2mL of the green solution are taken, placed in a vial, and acidified with a drop of GAA. The first sample taken (1H afetr beginning of hydrogenation with the column) stayed green afetr acidification, and only the unsat ketone was detectable by TLC. The sample taken 1h after switching to the inverted cylinder setup cleared up^entirely after acidification, and showed 3 spots (see Note 7). Further samples show that the unsat ketone spots is diminishing, the sat ketone getting larger, and the alcohol staying roughly the same.


TLC samples after acidification:



After a total of 24H hydrogenation, TLC indicated all the unsaturated ketone was consumed, and only a minimal amount of alcohol was present.
After leaving the catalyst decant, it was obvious the solution was completly clear.



The solution was vacuum filtered over 2 filters, the caatlyst washed with 2x5mL AcOEt and 5mL MeOH, and the clear filtrate transfered to a seperating funnel. 50mL of brine was added, and the funnel gently shaken. The very slightly yellow organic was seperated, and the aq. extarcted with 2x10mL AcOEt.




The combined organics were washed with 50mL brine, and dried 20min over Na2SO4. The solevnt was then removed under avcuum at 40°C, to afford a clear pale yellow oil with a very pleasant smell. :)



The oil was placed in the fridge, covered with a little pet ether, to try and induce cristn, without succes

The crude product will be purified by column chromatography, or by bisulfite adduct formation. Details to come when done.



Notes:

Note 1: The was done to fill the column with hydrogen (250mL required to complete reaction), and to pre-saturate the catalyst with H2.

Note 2: Each time the setup was opened, it was evacuated and flushed with argon to chase any H2, to avoid any fire hazard.

Note 3: the base was added to hinder reduction to the alcohol. Unfortunaly, an acetate should have been used to not form the phenolate.

Note 4: Slight warming was required to acheive complete dissolution.

Note 5: The pressure needs to diminish considerably for the water leevl to rise up more than this level I suppose. maybe at a certain pressure the equilibrium constant diminishes enough to stop the reaction. Prhaps the water leevl rising was simply du to leakes, although the joints were greased and double checked, I decided to follow conventional directions (inverted cylinder), as these were sure to work.

Note 6: apparently formate can reactivate Pd/C catalyst efficiently. this measn saturating Pd/C before a CTH is useless, but adding a little formate before a catalytic hydrogenation could substitue to conventional H2 saturation (no need to open the setup with H2-saturated catalyst: less fire hazard)

Note 7: a few eluants were tried and this variation afforded perfect seperation: from bottom to top: the alcohol as a thin rim, the unsaturated ketone (compared to pur sample), and then the saturated ketone. Rfs to come shortly.

Comments

Well, the selectivity of Pd/C is very encouraging, contamination with the amcohol is only minor by TLC, but nevertheless enough to prevent cristn. On the other hand, the recation is much too long. Is it the low loading? The fact that's it's a recycled catalyst? I haven't tried any used catalyst for other recations up to now, maybe the regeneration method isn't that efficient... I will see with another reaction.

I still plan on trying out other catalysts. I'm particularily interested by the Cu/SiO2, as it can be easily and cheaply made at home. On the other hand, the authors of the patent use fumed silica, which I don't have. I will surely try chromatography silica (60-200 mesh, acros) and home-made silica (less porous, but of varying quality).

I still have 2.15g of dehydrozingerone to play with, and enough vanilline to make some more (considering how easy it is..), but I would like to obtain some 4-hydroxybenzaldehyde. I definitively can't find some at a decent price, and am out of phenol. I'm afraid I will not be able to buy some until a little time,a s I've been spending too much lately :) and have other projects to attend to (TEMPO derivatives, etc).

If anyone find a relatively cheap source of 4-hydroxybenzaldheyde, please contact me! :) I would be delighted to obtain ~50gr at a reasonable price.. I'm sure we could work out a compassion :)

[Edited on 16-6-2008 by Klute]

Nicodem - 16-6-2008 at 01:27

Great contribution! :P
(Though I have to admit I have not read it all since I don't have much time at the moment)

Quote:
Originally posted by Klute
The crude product will be purified by column chromatography, or by bisulfite adduct formation. Details to come when done.

Just a quick advice before you waste time with a chromatographic column. 4-Arylbutan-2-ones do form bisulfite adducts, but in my experience they do so terribly slow and quite inefficiently. Use a threefold excess of NaHSO3 (or more) in aq. ethanol and let it stir for several hours at 40-60°C.

LSD25 - 16-6-2008 at 03:22

As to the p-hydroxyphenol - anise/fennel essential oil ain't expensive and here's the route:

http://wmw.justice.gov/dea/programs/forensicsci/microgram/jo... (the link don't work, good)

Quote:
Anisaldehyde (4-Methoxybenzaldehyde [2])
A freshly prepared and stirred solution of 30 mL concentrated sulfuric acid in 150 mL water was allowed to cool down to 30° C, and anise oil (9.8 g) was added. A total of 25 g sodium bichromate was then added, at such a rate that the reaction temperature remained between 35-40° C. The reaction mixture was extracted four times with toluene (75 mL each), and the combined organic phases were washed twice with 5 % NaOH (100 mL each), and once with water (100 mL). The organic phase was evaporated to about 20 mL, and anisaldehyde was then isolated as its bisulfite adduct. The yellow precipitate was washed with an EtOH/ether (1:1) mixture until the precipitate's color turned white (that is, similar to the bisulfite adduct generated from commercially available anisaldehyde). Setting the anisaldehyde free resulted in 4.9 g of a yellow oil with a pleasant odor. The mass spectrum was in agreement with an authentic sample. Anisaldehyde was the main product (95 % by GC/MS), but several minor impurities (not further identified in this report) were noted.


Still needs demethylating, but comparatively quick and easy

Klute - 16-6-2008 at 07:04

Thank you for your comments, both of you.

Nicodem, thank dfor the advice regarding the bisulfite adduct, especially I would have though it woulo dhave reacted pretty well being a methyl ketone but... I guess I'll just do a quick column: I am one the rare chemists at work that actually LIKES doing columns :D

Alice, that synth looks pretty nice, but I don't have any dichromates and am not particularily found of using them. But the degradation of tyrosine with TCCA (IIRC?) that you proposed looks very interesting. If I can find some tyrosine locally, I wil give it a try.
At one moment I will have to get some more phenol, as I'm out of salicylaldehyde (had problems forming the N-ethyldiethylenetriamine ligand), so I will try the Riemmer-Tiemann with triethylamine..

LSD25 - 17-6-2008 at 06:30

Klute, I am on fucking drugs I swear - I meant to write p-methoxybenzaldheyde (anisaldehyde) not p-methoxyphenol

I also meant to say fucking nice job:D

PS Wouldn't the permanganate oxidation of anethole give the same result?

http://www.erowid.org/archive/rhodium/pdf/isosafrole2piperon...

http://designer-drugs.com/pte/12.162.180.114/dcd/chemistry/b...

The tyrosine variant uses Silver oxide as the oxidant which is going to make it too expensive.

PPS I also added something which Solo only just got today, the demethylation of substituted porphyrins with anilinium chloride, used in preference to the more usual pyridine.HCl, HBr, etc.

[Edited on 17-6-2008 by LSD25]

Attachment: Demethylation.AniliniumChloride.pdf (210kB)
This file has been downloaded 1256 times


Klute - 17-6-2008 at 17:33

After purification on a short column, using 50:50 AcOEt:Pet Ether, 1.61g (8.30 mmol) of practically colorless zingerone was obtained, giving a 74.11% yield from the unsaturated ketone, and 59.18% from vanillin.

The oil is practically pur by TLC, only a very faint spot of the alcohol from the last fraction, but nevertheless is very hard to cristallize; it is very slowly starting to cristallize in the freezer, with 2 nucleation points, very slowly propagating (over several hours). They look like mold growing in the oil :)


The compound has a very pleasant, slightly pungeant though faint smell of ginger. Hurray! :)

Hopefully Cu/SiO2 will be more selective than Pd/C, and there will be no need of seperating the ketone from the alcohol, and it will possibly cristallize more readily.

EDIt: I forgot to add the Rf's:

Eluant: 10:1 DCM:AcOEt

Saturated ketone: 0.65
Unsaturated ketone: 0.56
Alcohol: 0.45

[Edited on 18-6-2008 by Klute]

Klute - 23-9-2008 at 10:32

An update:

After considering the Orgsyn prep Filemon indicated, and the notes in OrgSyn preparation of benzylacetophenone, I decided to try reducing the unsaturated ketones with Zn dust: the procedure seemed ridiculousy simple, and sued very easily accesable reagents. This would really make the method of choice for preparation of phenolic phenylbutanones...

I gathered a few old Ber. refs on the reduction of bezalacetone and benzalacetophenone to their saturated ketones, and with the unvaluable help of Woelen at translating german, managed to figure out the sparse details furnished... basicly, the zinc dust was added to the unsaturated ketone in GAA, the mixture heated to reflux for 3-4H, the solids filtered off, GAA diluted with water,a nd products extarcted with ether.

Now, the Zn reduction of a,b-unsaturated ketones is said to produce varying amounts of a dimer, and higher polymers, which are only slightly soluble in ether. This is with the non-phenolic unsaturated ketones...


I performed a few reductions of 4-(4'-hydroxyphenyl)but-3-en-2-one, here are my notes and some pics:



Preparation of 4-(4'-hydroxyphenyl)but-3-en-2-one



(no pictures, but basicly very similar to dehydrozingerone)

5,0 g (40.94 mmol) of p-hydroxybenzaldehyde are dissolved in 20mL (272.04 mmol) freshly distilled acetone inside a colorless 100mL bottle, giving a dark orange solution, with a very small amount of some fine amber solids in suspension.
2,0g (50 mmol) of NaOH are dissolved in 20mL dH2O (10% w/w; 2.5N), and the cooled solution is slowly added to the stirred aldehyde solution. At first, a beige voluminous solid is formed, but it quickly dissolves to give a very light yellow limpid solution, gradually darkening to a deep orange.
The solution turns dark orange/brown over 1H, and is left to stand for 24H, with occasional stirring. A dark red solid appears after two hours, giving a dense cristallin slurry.

The mixture was then added to 100mL of 10% HCl in a 250mL beaker, with good stirring. White fumes are evolved, and the dark orange/brown mixture warms up. the beaker is cooled in a ice water bath with vigorous stirring, and the oily material crystallizes as a dark brown solid after a couple of minutes. The suspension is stirred for another 10min at 5°C, then vacuum filtered over a glass frit. The brown mass is washed with a little amount of ice-cold water, giving a dark brown filtrate and light green cristillin solid. The solid is dried by suction for 20min, and dried in a CaCl2 dessicator over night.

the solids are added to a 100mL erlenmeyer, and covered with 25mL toluene. The toluene is heated to ~80°C on a hotplate, and AcOEt added dropwise until total dissolution of the solids (2-3mL required). An equal volume of toluene is added, and the dark green mixture is left to cool slowly. The next morning, beautifull yellow prisms are obtained. The crystals are vacuum filtered, washed with cold toluene:AcOEt 10:1, and pet ether, and dried by suction.

After 24h drying in a desicator, the crystals weighed 4.9g (30.21 mmol), 73.79%, and pur by TLC (single spot, eluant 3:1 AcOEt:Pet ether).

By evaporating part of the mother liquors and adding pet ether, some more orange solids are obtained. They are recrysatllized by toluene/AcOEt to offer 1.13g (6.97 mmol) of TLC pur yellow crystals, bringing the yield to 90.81%.





Notes:
-The first few times I left the reaction proceed for 48H, but it seems the yields are even better with 24h reaction time as they are less impurites.
-Dissolving the crude solid in a solvent, and washing with cold brine (the unsaturated ketone is sparingly soluble in H2O) could be a more efficient approach.
-The recrystallization system is really adequate, I had trouble finding a good solvent system as the product kept on oiling out of solution with EtOH/H2O, AcOEt/Pet ether, etc. Having the crude product as clean as possible gives better results.
-the product has a very slight, pleasant smell, much lighter than dehydrozingerone (which gives 80-90% yields by following this procedure using 5.0g vanillin, all other reagents in same quantities)





Synthesis of 4-(4'-hydroxyphenyl)butan-2-one (Rheosmin)






1.62g (10.00 mmol) of the unsaturated ketone previously prepared were crushed to a fine powder and dissolved in 30mL GAA in a 100mL 3-neck 14/19 RBF, equipped with a CaCl2-guarded condenser, a thermometer and amgnetic stirring.








1.32g (20.00 mmol) of zinc dust were weighed out, and added in small portions to the stirred solution over 30min, at room temp. There was no exothermic reaction of noticeable bubbling, and the yellow solution took a greenish tint before enough zinc was added to give a light grey suspension.





20min after addition:




The mixture was then heated to 50-60°C in an oil bath, gentle H2 evolution started, and the green/yellow color disappeared in 10min.

40min after addition (leaving the zinc decant before taking picture):


1H:


2H:



after 2h reaction time, the flask was cooled, and the unreacted zinc was filtered on a glass frit. the zinc was thoroughly washed with 2x10mL GAA.






The slightly yellow, cloudy filtrate was then added to 150mL ice-cold water, in a beaker immersed in a ice bath. The mixture immediatly turned pink, and some ice was added.



Unfortunaly, a viscous semi-solid was obtained, but smelling very strongly of raspberries. Solid NaCl was added to precipitate even more of this viscous paste.





The paste was dissolved in a small volume of MeOH, NaCl filtered off, and solvent evaporated. Pet ether boils on the obtained viscous liquid didn't yeild any cristillin product. The slightly pink aqueous mixture was extarcted with AcOEt and the solvent evaporated afetr been washed with brine, togive a viscous, raspberry-smelling paste. Attempts to cristallize this with various solvents and conditiosn were all fruitless.. A column chroamtography could be done, but th eobjective is to find a easy reduction with acceable reagents giving a pur enough product..

TLC (3:1 AcOEt:Pet ether) indicated saturated ketone (major stain), a little unsat ketone, and two other spots (dimers).

Comments:

I performed a first reduction using 4x zinc, but directly extracting the diluted AcOH solution. After washings, drying and removal of the solvent, as viscous dark purple goo was obtained, which smelled very strongly (and nicely) of raspberries. There again, it was impossible to obtain any cristilline material from this substance ( mp pur rheosmin= 80°C).

The pink colour is a very curious thing: when collecting samples during the reaction, the pipet used to withdraw the supernatant turned pinkish after a few minute sexposiiton to air. On the TLC plates, the saturated ketone stain turns dark pink whne exposed to UV! (and not before!) It gets darker and darker when exposed several times... Quinonic material? Adding trace amounts of reductant makes the colour disappear, and when in solution in AcOEt, it turns light red/orange....


I'm afraid the reaction conditions are not suited to phenolic unsaturated ketones, which must polymerise/dimerise much more easily than benzylacetones and acetophenones... But the material does smell very nice!

So I'm going to work on other reductions, Cu/SiO2 seems to be the most promising, as CoCl2/NaBH4 requires 5x weight of the unsat ketone in CoCl2....

It's really a pity as this seme dto be the ideal reduction: very cheap Zn dust, easy reaction conditions and workup, etc Just too good to be true.. i might try leaving the recation perform at room temp for 12h and see what happens.. Maybe dimerisation can be reduced enough to obtain a cristallizeable product...

Also, this reduction could be applied to the ethers of phenolic unsaturated ketones: methylzingerone is said to smell of ginger too, p-methoxyphenylbutanone is used in perfumery (not sure how it can smell though).
On the latest discoveries in the so-called Cassinone, 3,4-methylenedioxyphenylbutanone, a natural compound which is said to smell of blackcurrant, and is used commecially. I think piperonal is fairly regulated in my country, so I will surely go via the benzyl halide and acetoacetate anion for this one... That I will make in small quantities considering the lengthy preparation of the precursor.


Many thanks to Woelen for help with translations, and all the very kind people at the ref forums that helped me out with bibliographic research on this subject...

Info on the Cu/SiO2 reduction will be summerized here, or a link to the Cu/SiO2 thread will be placed here.

Anyone with further suggestions on a easy, efficient reduction is very welcome to comment further..


[Edited on 23-9-2008 by Klute]

Klute - 5-10-2008 at 10:20

Good news!


I have tried out the atm hydrogenation of dehydrorheosmin over Pd/C, using 25% mol/mol AcONa as an additive, in AcOEt, and after 14H all the unsaturated ketone was reduced to the saturate dketone, without any traces of the alcohol!

I'm unsure if it is this substrate that is much more ressitant to reduction of the carbonyl, or if using sodium acetate is very effective as suppressing 1,2-hydrogenation, but the reduction was text book perfect: regular H2 absorption, and theoritical amount consumed.

Using 1:1 AcOEt:Pet ether as an eluant proved to give a superior seperation than with the eluant used during the Zn reduction. I am unsure of which side-products are formed during the reduction, but I'm pretty sure Zn/AcOH can't be used as a preparative procedure for phenolic butanones..

Sorry, still no photos I haven't got the camera issu dealt with yet..

Workup was simple: filtration of the catalyst and suspended AcONa, washing on the colorless filtrate, followed by drying and removal of the solvent..

The isolated product smells much nicer than the Zn reduction product! Much more subtle, "natural" aroma.

I can't wait to try the NiB hydrogeantion on the substrate. Even if it is clear than Pd/C is an ideal catalyst for such hydrogeantion, it si quite expensive and not always accesable. A cheap, easily made catalyst would really be usefull to many.

Nicodem - 5-10-2008 at 23:30

Quote:
Originally posted by Klute
I'm unsure if it is this substrate that is much more ressitant to reduction of the carbonyl, or if using sodium acetate is very effective as suppressing 1,2-hydrogenation, but the reduction was text book perfect: regular H2 absorption, and theoritical amount consumed.

The aliphatic ketone carbonyl is not reducible using Pd-C (at least not at the usual conditions), with or without additives such as you used. In conjugated ketones it is normal that only the double bond gets reduced. Conjugated double bonds, particularly such conjugated with electron withdrawing groups like in your case, are considerably slower to reduce than isolated double bonds. Actually, isolated double bonds reduce in matter of minutes using couple of mol% 5% Pd-C at 1 atm. Moderately electron rich double bonds conjugated with the benzene ring (aka styrenes) also reduce quite fast.

Thanks for sharing your experience with Cu/SiO2 catalyst. I'm looking forward to read about your experiments using nickel boride based catalysts.

Klute - 6-10-2008 at 02:07

Well, when reducing dehydrozingerone, at least 5% saturated alcohol was formed using Pd/C and K2CO3 (which I neutralized after). The Chem Educ. article on Rheosmin also mention this. It seems dehydrorheosmin is much less prone to this.

One of the NiB article claimed 99% selectivity using Pd/C, which i doubt at first, but has now confirmed. They say NiB give sthe same selectivity, but with a much higher absorption rate, and reduction of the double-bond is doen in a matte rof minutes. Can't wait to get this started.

not_important - 6-10-2008 at 02:43

That ref I gave over in the Cassione, using MVK in a Heck reaction, used Pd/TiO2 for both the Heck and the reduction of the C=C double bond, further suggesting that Pd is useful although perhaps not optimal time-wise for this class of reduction. I wonder if Pd/TiO2 would prove easier to reactivate than Pd/C.

Klute - 8-10-2008 at 12:36

Ok, I just HAD to find a camera to take pictures of theses and show them to you guys... I have fallen in love of my Rheosmin and have been showinbg it to evryone I cross :)








96.6% Yield by H2/ Pd/C hydrogenation (actually I realized absorption was finished after 4h, as the theorical volume was 150mL! I guess the other 100mL were lost from small leaks or something. The absorption rate had greatly diminished afetr 150mL mark...

Ideal TLC eluant: 50:50 AcOEt: Pet ether. Will get Rf if someone wants them (saturated ketone higher than the unsaturated one, no traces of alcohol or other by-products!)

Let's hope NiB can do as good! I feel like making dozen grams of the stuff, my room smells beautifull :) Pretty strangely, the nice crystals smell much less than the crude powder, before recrystallization.

Klute - 6-2-2009 at 03:44

I've stumbled on a pretty interesting article, detailing the use of NiB supported on silica gel to selectivily reduce cyclopentadiene to cyclopentene...

NiB/SiO2 is prepared by impregneting NaBH4 on silica gel, then adding this silica to a solution of NiCl2, forming amorphous NiB on the support. Good selectivities are reported for the reduction of cyclopentadiene, and I assume the NiB posses the same reactivity as collodial NiB towards unsaturated ketones, and would then offer a good alternative to collodial borides and their tedious workup..

EDIT: attached article


Selective hydrogenation of cyclopentadiene to cyclopentene
Wang et al.
Applied Catalysis A; 163, 101-109 (1997)

Abstract
An amorphous NiB/SiO2 catalyst, with a large specific surface area, was prepared by a reductive-impregnation method. The
selective hydrogenation of cyclopentadiene to cyclopentene was carried out in a continuous flow fix-bed reactor at
atmospheric pressure and with 10 g g cat -I h -l of cyclopentadiene feed. The catalyst showed high selectivity and stability.
Cyclopentene was obtained in 96--100% yield at complete conversion of cyclopentadiene at temperatures ranging from 80°C
to 200°C and no significant decrease of the activity was observed during the reaction period of 500 h. The catalyst sample was
characterized by ICP, XRD, DSC, SEM, XPS, BET and 02 adsorption. XRD measurement revealed that the amorphous state
was kept after catalytic reaction. Differential kinetic study showed that the hydrogenation proceeded according to a Rideal-
Eley mechanism.

Keywords:
Supported amorphous alloy; Nickel-boron alloy; Cyclopentadiene hydrogenation; Catalytic activity; Differential
kinetics

[Edited on 6-2-2009 by Klute]

Attachment: NiB_SiO2.pdf (590kB)
This file has been downloaded 1700 times


stateofhack - 6-2-2009 at 06:59

Yes i am !

panziandi - 6-2-2009 at 12:19

Klute you have some amazingly pretty crystals there! Nice work and great yield!

Klute - 6-2-2009 at 12:30

Thank you :)

They really are part of my favourites! Both the smell and the apparence!

kmno4 - 30-4-2009 at 14:40

Recently I have got few grams of 10% Pd/alumina, so I have tried hydrogenation of benzylideneacetone. Unfortunately, suspension of catalyst (0,3g) in 30g unsaturated ketone+50 cm3 of toluene does not want to "eat" hydrogen (under almost atmospheric pressure and 30-40 C). I also tried ethyl acetate instead of toluene - results the same.
This Pd/alumina is a little old - is it possible that it needs to be activated somehow ? I mean H2 stream nad ~300 C....
I do not know, I am not familiar with hydrogenations on Pd :(

Paddywhacker - 30-4-2009 at 23:12

Klute has reported in this thread that formate can liven up an old catalyst. Can't say about the solvent, but I would stick to GAA for starters.

Barium - 1-5-2009 at 07:12

The activity of the catalyst depends on how the metal has been deposited on the carrier. There are three types of deposition and the one suited for low pressure reactions is the eggshell type. The fact that alumina is the carrier makes it likely that you have an industrial catalyst which requires higher pressures, although there are eggshell types of catalysts using alumina as carrier.

kmno4 - 3-5-2009 at 07:35

All I know is on the label: Koch-Light, 8874h Pd 10% on alumina, for lab use only.
I did reactivation in slow H2 stream at 320 C and hydrogenation takes place, but is very slow. I will try to increase overpressure from 100 to 200 mm of H2O.
ps. product smells nicer and nicer, strawberry-like and reminds me benzylmethyl ketone.

Klute - 4-5-2009 at 00:14

I would try using CTH conditions, I requested a few articles on the subject lately, apparently ammonium formate gives excellent resultd for the selective reduction of the conjugated double bond, without producing any (or very little) alcohol. You could try adding some formate to a suspension of your catalyst and see if any gas is evolved, then try the reduction under CTH conditions in methanol. Good luck! Please let us know how it goes!

Sydenhams chorea - 22-8-2009 at 12:51

Why not give sodium dithionite a try for the reduction of the double bond?

It works for isatylideneacetone, it might as well for your substrate. The procedure is so straightforward that it can't hurt giving it a try.



Tet. Lett. 49, 21 p 4741-4758 (1993)




Attachment: isatylideneacetones.pdf (1.8MB)
This file has been downloaded 1037 times

Klute - 23-8-2009 at 13:35

Interesting, never thought of that. Could be worth a try!

Sleipnir - 11-9-2009 at 00:38

Maybe you could try a catalytic reduction with an iron catalyst:

catalytic amounts of [Fe(CN)5NH3]3- reducte in an excess of NH2OH oelfines without affecting carbonyl functionalities and aromatic rings

[Fe(CN)5NH3]3- can be prepared from [Fe(CN)5NO]2- (Nitroprusside-anion) with can be prepared from [Fe(CN)6]4-

seen at: http://pubs.acs.org/doi/abs/10.1021/jo800302v

Klute - 12-9-2009 at 10:43

Interesting alternative, but the preparation of the catalyst requires cyanide, which I do not have, and isn't specialy oTC.. But surely other ligands could work aswell..
I have started to interest myself to homogeneous catalysis, using avaible transition metals, like Cu, Fe, Ni, etc. Not alot of ligands are easily made at home, but there could be some viable paths.. I guess reduction-wise , Nickel complexes are the best candidates. If I could find a cheap source of ruthenium, I could try using some of teh catalysts I worked on recently, very active in CTH conditions..

Jor - 12-9-2009 at 11:40

No, it does not require cyanide. Potassium ferrocyanide , K4Fe(CN)6.3H2O is very cheaply available from chemicals suppliers, is not suspious, and is not toxic. The cyanide is only slowly released when heating with a strong acid.

IIRC, the nitroprusside can be prepared by treating the ferrocyanide with nitric acid, but I don't know the exact procedure. Be warned, the nitroprusside is very toxic, at least it is when injected.

Sleipnir - 12-9-2009 at 12:17

other lingand no problem.... ;)

http://pubs.acs.org/doi/abs/10.1021/om050625b

but i think this one might be carcinogen and it need's (silght) overpressure... would prefer the [Fe(CN)5NH3]3- which possibly is not toxic at all since the toxic effekt of the [Fe(CN)5NO]2- is induced by the elimination of NO

I've tryed to make [Fe(CN)5NH3]3- some time ago (wanted to use it on dehydrozingerone) but instead of obtaining nice red crystals i obtained a brown slurry, if someone made this already i would be thankfully for some hints ^^

UnintentionalChaos - 14-9-2009 at 06:36

Quote: Originally posted by Sydenhams chorea  
Why not give sodium dithionite a try for the reduction of the double bond?

It works for isatylideneacetone, it might as well for your substrate. The procedure is so straightforward that it can't hurt giving it a try.



Tet. Lett. 49, 21 p 4741-4758 (1993)


Interesting. However, that double bond is doubly alpha to carbonyls, and hence highly activated. Perhaps thiourea dioxide would be worth a test here.

EDIT: What am I thinking. Thiourea dioxide would reduce the ketone.

[Edited on 9-14-09 by UnintentionalChaos]

UnintentionalChaos - 22-9-2009 at 23:03

Here's a little something for anyone interested. I ran the condensation of Vanillin with acetone (24h at room temperature), and recrystallized my product from 50:30 water:isopropanol. I then brought it over to school for use as a Michael acceptor in undergrad research. Here's a 400MHz proton NMR for you guys. Looks pretty good for all over the counter chemicals, huh? :P

The peak at 1.6ppm is water, but after running a blank of CDCl3 through the NMR, it's contamination of the chloroform, not the sample.

2.35ppm is the methyl ketone.

3.9ppm is the methoxy group

5.9ppm is the phenol hydrogen

The "triplet" with integration of 2 at 7.1ppm is the overlap of the singlet from the hydrogen in the 2-position on the ring with what I suspect is the 6 position hydrogen's doublet.

Unrelated, but has anyone seen what this stuff costs from Aldrich?

http://www.sigmaaldrich.com/catalog/ProductDetail.do?lang=en...

:o

[Edited on 9-23-09 by UnintentionalChaos]

vanillylNMR.jpg - 20kB

Klute - 23-9-2009 at 02:52

Nice! Thanks for sharing! It's a rather clean spectra you've got there! Looks like the reaction is pretty selective and no impurirites remain after a single recrystallization..

Do you intend on reducing it to the butanone? A spectra of the butanone would be great too!

UnintentionalChaos - 23-9-2009 at 04:57

Quote: Originally posted by Klute  
Nice! Thanks for sharing! It's a rather clean spectra you've got there! Looks like the reaction is pretty selective and no impurirites remain after a single recrystallization..

Do you intend on reducing it to the butanone? A spectra of the butanone would be great too!


I also have a carbon spectra for this one if you'd like and I forgot to mention that I took a m.p. with a thiele tube and got 126-128C.

Possibly over winter break when I'm at home, but not with this material. More than likely, it'll be O-methylated to shield the phenol, since we think the reaction we're studying proceeds by a radical mechanism and phenols are radical traps. I won't know until I try though.

I will hopefully prepare some of the 4-hydroxyphenyl variant and reduce it to rheosmin, which I can get spectra for.

somebird - 23-1-2016 at 18:47

Thanks for Klute's thread, i learn a lot from here. And the pink colour must be the combination phenol and zn2+ . Maybe add EDTA solution can eliminate it.

CuReUS - 30-6-2016 at 05:21

on the 2nd page of this thread,klute tried to reduce the enone using Zn/AcOH, but failed since he could not separate the products-
Quote:
The slightly pink aqueous mixture was extarcted with AcOEt and the solvent evaporated afetr been washed with brine, togive a viscous, raspberry-smelling paste. Attempts to cristallize this with various solvents and conditiosn were all fruitless.
http://www.sciencemadness.org/talk/viewthread.php?tid=9706&a...
I thought about this and remembered a method someone had told a long time back in one of my posts.That method used Zn/HCOOH and had an easy way to remove the Zn- formate formed. http://www.sciencemadness.org/talk/viewthread.php?tid=34833#...
could this method give a cleaner product ?

Dennis A - 2-6-2018 at 01:08

Many years ago i tried the acid catalyzed Adol on 4-Methyl-Benzaldehyde with MEK/Butanone hoping to obtain 4-Methyl-BMK intermediate having extremely limited equipment on hand and being very inexperienced at the time was no doubt the reasons for my failures however in light of this i just could never manage to find out where the problem arose from

Reagents were always of high purity the reaction after full addition was left with strong stirring for periods between 18-24 hours as i had work among other things the red-ish reaction mixture was observed every time

Using 37% HCL acid in place of HCL gas as generating gases in that location was a definite no no and would have led to almost certain demise of ones self did others others encounter problems when using acid instead of gas ? Maybes it was the particular substrate although i find it very unlikely i seam to fine more base catalyzed Adols than acid catalyzed on Anisaldehyde/4-MeO-Benzaldehyde for example

http://www.xula.edu/chemistry/documents/orgleclab/Aldol_note...

I am old and rusty please forgive am i wrong to assume that the base catalyzed adol reaction of Benzaldehyde with Mek/Butanone would produce a intermediate that could be subjected to a reaction that i,m forgetful to name to produce propiophenone ?

EDIT - Thanks in advance just trying to clear up some loose ends maybe i,l give it another shot soon its one of the few reactions i never got to work i never forgot about it the feeling of being defeated haunts me

Regards

Dennis

[Edited on 2-6-2018 by Dennis A]

[Edited on 2-6-2018 by Dennis A]