Author Topic: Acetone Enolate Question  (Read 3467 times)

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Bwiti

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Acetone Enolate Question
« on: May 27, 2002, 01:44:00 PM »
I was reading Drone #342's enolate phenylacetone FAQ when an idea popped into my head. Rather than reacting bromobenzene with acetone enolate, could substituted/halogenated benzenes such as bromo-benzodioxole be used? Peace! 8)

Love my country, fear my government.

Rhodium

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The reactivity of 5-bromobenzodioxole would be ...
« Reply #1 on: May 27, 2002, 10:15:00 PM »
The reactivity of 5-bromobenzodioxole would be lower due to the electron-donating properties of the oxygens, but providing that the reaction is valid, it would theoretically work to some extent.

Bwiti

  • Guest
"but providing that the reaction is valid" Cool, ...
« Reply #2 on: May 28, 2002, 10:34:00 AM »
"but providing that the reaction is valid"

  Cool, thanks! When you speak of the reaction's validity, are you referring generally to the successful reaction of chloro, iodo, and bromobenzene; Is the FAQ on your site a sure thing? Or, is it just the validity of the use of halogenated substituted benzenes that you're not sure of? Thanks and peace! 8)  

Love my country, fear my government.

Rhodium

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Somebody! Do it NOW!
« Reply #3 on: May 28, 2002, 02:35:00 PM »
In Drone's FAQ he has combined several tried and true enolate reactions:

Pinacolone Enolate + Bromobenzene + DMSO + FeSO4
Acetone Enolate + Iodobenzene + DMSO + UV Irradiation
Pinacolone Enolate + Iodobenzene + DMSO
Acetone Enolate + Bromobenzene + Anhydrous ammonia + FeSO4

...to hopefully assume that:

Acetone Enolate + Bromobenzene + DMSO + FeSO4

is something that will produce P2P in high yields. That remains to be discovered, as well as the reaction details - noone knows what the suitable reaction times is yet (although in the first ref they say the reaction with iodobenzene took one hour together with pinacolone enolate (which is more substituted and therefore a more stable/reactive enolate than that of acetone), and that together with bromobenzene reacted six times slower).

Also, the conditions needed for the production of acetone enolate has not been determined using OTC chemicals. In the refs they use KOtBu/Acetone, we don't know yet if easily made Mg(OEt)2 works, or NaOiPr. Iodobenzene is very expensive and involved to make, so we must hope for bromobenzene to be reactive enough to make the method attractive. And we definitely must test the method on unsubstituted bromobenzene before moving on to bromobenzodioxole.

I sound very sceptical, perhaps unnecessarily so, but I don't like to run around telling people that something definitely works until it has been proven in practice. The theory is just fine, I just wonder why noone has even tried it out - Drone posted this four years ago!

Bwiti

  • Guest
What's Holding Bees Back?
« Reply #4 on: May 28, 2002, 04:41:00 PM »
"And we definitely must test the method on unsubstituted bromobenzene before moving on to bromobenzodioxole."

  That sounds like a much more sensible approach! I tend to jump too far ahead as far as applying crank chemistry to trippy amphetamines, and this behavior has gotten me burned before. Yeah, it's kind of crazy that the FAQ was posted 4 years ago and nothing new has popped-up; think it's because that at least in the U.S. bromobenzene's watched for obvious reasons. Shit, it's not like the stuff's listed, but I'd still be nervous about buying it. I've tried making it with bromine/benzene/iron, which didn't work, so I guess that pyridine is needed, or maybe iodine? I'm getting a picture flashing in my head that says "UTFSE". 8)  


Love my country, fear my government.

jim

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References for enolate formation
« Reply #5 on: June 04, 2002, 05:35:00 AM »
Here is something that I put together a long time ago....


From "Advances in Solution Chemistry", Edited by I. Bertin, yr 1981,
Library of Congress # QD540 I57 1980; article title "Reactions and
 Behaviour of Organic Anoins in Two-Phase Systems", paragraph 4,
 page 311

"...  The low acidity of many CH acids requires, as a rule, only strong
bases: NaH, NaNH2, t-BuOK, etc., in strickly anhydrous organic
solvents, can be employed for the generation of carbonions.  The use of
 sodium hydroxide for the generation of carbonions is rather limited
because of the equilibrium

->C-H  +  NaOH  <==>  ->C(-)-Na(+)  +  H2O

is shifted to the left due to the high acidity of water, and also
because of its high hydrolytic activity.  Both these limitations are
 eliminated when sodium hydroxide is employed in the form of a
concentrated aqueous solution and the generation and reactions of the
carbonions are carried out in two-phase systems in the presence of TAA
 salts or other sources of lipophliic cations [5].  Here the acid-base
 equilibrium proceeds at the interface, producing carbonions in low
concentration in the inactive form of sodium derivetives anchored at
the phase boundary in a kind of absorbed state.  Subsequently these
carbonions are continously transferred into the organic phase as the
 TAA derivetives, where they enter into the required reactions,
 thus shifting the acid base equilibrium to the right. 

[Diagram]

This hyperbasic effect as well as the fact that the reacting compounds
 contact with aqueous alkali only at the interface are the most
 characteristic features of the catalytic two-phase generation of
carbonions.  These conditions are efficently applicable for a vareity
 of reactions of carbonions derived from CH acids of pKa value up to
22.

Such important processes as alkylation of arylacetonitriles,
 cyclopentadiene hydrocarbons, aldehydes and ketones, esters, sulfones
etc., condensation of carbonions with aldehydes or ketones, the
Knoevenagel, Darzens, Micheal and related reactions as well as many
reactions involving sulfonium and phosphonium ylides have been
sucessfully carried out under these conditions.

...

Although hetrogeneity of the catalytic two-phase system prevents
alkaline hydrolysis of the reacting compounds, there are many cases in
 which aqueous sodium hydroxide cannot be used as a base.  We have
found that instead of NaOH, anhydrous sodium or potassium carbonates
can be used for the generation of anions, even from rather weak CH
acids.  In these cases the systems contains organic reactants in
liquid phase, the catalyst (TAA salt or crown ether) dissolved in a
non-polar solvent and anhydrous alkali carbonate in the solid phase.
 Here the acid base equilibrium occurs on the surface of the solid,
subsequently the carbonions are transformed from this absorbed state
 into the organic phase in the form of TAA salts.  The carbonates are
relatively mild bases so they can be used at relatively high tempatures
 without decompostion of the starting materials and products. 

This simple solid liquid system can be efficently applied in many
 important reations involving carbonions and other organic anoins.  It
 is particularly useful for the alkylation of ethylmalonate,
 cyanoacetate, and acetylacetate
 [10] e.g.

CH2(COOEt)2  +  C4H9Br --{Q(+)X(-)/Na2CO3}--> C4H9CH(COOEt)2

...

Even such weak CH acids as phenylalkylacetonitriles can be deprotonated
 and acylated under these conditions [10]. 
"

[10]- J. Org. Chem. 43:4682 (1978)

============================================

From "Pure and Applied Chemistry", Vol 43, yr 1975, page 439-462,
article title "Two-Phase Reactions in the Chemistry of Carbonions and
Halocarbenes- A Useful Tool in Organic Synthesis", by M. Makosza

"Abstract

Amoung numerous base-solvent systems usually applied for the generation
 of carbanoins the two-phase system in which concentrated aqueous
sodium hydroxide solution in the presense of quaternary ammonium
compounds acts as the proton acceptor seems particularly useful. Under
these conditions, C-H acids up to 22 pKa value can be converted into
carbanions which exist in the organic phase as ion pairs with the
quaternary ammonium cation.  Though the concentration of the carbanoins
 is very low, and does not exceed that of the catalyst, numerous
reactions have been successfully performed under these conditions. 
Thus, alkylation of various C-H acids, such as arylacetonitriles, some
 esters, ketones, aldehydes, cyclopentadiene hydrocarbons, etc.
proceeds in this way with higher selectivity and yield compared to the
 tradional conditions.  The two-phase system is of particular advantage
 for the generation of trihalomethylanions and dihalocarbenes
thereafter, as it allows us to carry out all the reactions typical for
 these species in the simplest and most effective manner.  It is
moreover mostly convenient for the reactions of some carbanions with
aromatic nitrocompounds (substitution of halogen and nitro group or
electron-transfer) which otherwise give rather poor results.  And the
latest so far recognized application of this system in carbanions
chemistry is the reaction of halocarbanions and ylides leading to
oxiranes, cyclopropanes and alkenes. 

The author's point of view is that the first common step of all these
reactions, namely proton abstraction with the formation of a carbanion
quaternary ammonium cation ion pair, occurs at the phase boundary.

The ion pair thus formed penetrates inside the organic phase where all
the subsequent steps (reactions of carbanions with various
electrophiles, formation and reactions of halocarbanions etc.) take
place."

page 455
"LIMITAIONS

The numerous examples of the successful application of two-pahse
catalytic and ion-pair extractive methods in the reaction of carbanions
 and halocarbenes illustrate the great versatillity of these methods
in organic synthesis.  There are of course severe limations in these
methods.  The most important on results from the fact that only
relativity strong C-H acids can be anionized in the presence of
aqueous sodium hydroxide.  So far it seems the upper pKa limit is
around 22, since the alkylation of fluorene still occurs whereas that
of acetonitrile does not under these conditions.  The second limitation
 is due to the instablity of some C-H acids in the presence of aqueous
 alkali (e.g. hydrolysis of ester of other functional groups). 
This limitation can often be overcome by the use of more stable t-butyl
 esters, less concentration aqueous sodium hydroxide solutions, larger
amounts (up to equimolar) of quaternary ammoinium compounds etc.  The
compounds reacting with carbanions or halocarbenes should also be
stable in the presence of aqueous alkali.  This limitation is, however,
 often overestimated since many alkali-sensitive compounds have been
successfully used in these reactions.  Another significant limitation
of the catalytic procedure is that the products must not be stronger
C-H acids than the strating compounds, otherwise the former produce
relatively unreactive ion-pairs with the quaternary ammonium cations
and the reaction is arrested.  In these cases and in the cases of
relatively strong C-H acids, the application of ion-pair extraction
procedures is usually advantagous as compared to the catalytic or
tradional homogeneous ones.  The requirement that poorly solvated
inorganic anions (e'g' I(-)) should not be formed in the catalytic
process has not confirmed in some cases.  Of course it does not limit
the 'ion-pair' extractive procedure."

page 443
"Esters and other carbonyl compounds

...  The two-phase system with TEBA catalyst seems to be the most
convenient for the alkylation ofbenzylic ketones like desoxybenzoine
and phenylacetone [30].  The ion-pair extraction procedure has also
been very convenient for the alkylation of these ketones [21].  ..."

[21]- Tetraherdon Letters, 473 (1972)

[30]- Tetrahedron Letters, 1351 (1971);  Roczn. Chem. 45, 1027, 2097
(1971);  Roczn. Chem. 47, 77 (1973).

page 456-460
"MECHANISM

...

Many observations are, however, better explained by the supposition
that the first step of the carbanionic reactions- the abstraction of
proton and the formation of ion-pair in the two-phase system- occurs
on the phase boundary.  The ion-pair migrates subsequently into the
organic phase where all further reactons with the liberation of the
catalyst take place.  These two alternative mechanisms are visualized
as follows:
[not verbatum, but format changed, where " -> " indicates 3 bonds, Q
is the quaternary, X is the electrophile]

->C-H(org) + Q(+)X(-)(org) + NaOH(aq) <==>  ->C(-)Q(+)(org) + NaCl(aq)

->C(-)Q(+)(org) + R-X --> Q(+)X(-) + ->C-R

or...

Q(+)X(-)(org) + NaOH(aq) <==> Q(+)OH(-)(org) + NaCL(aq)

->C-H(org) + Q(+)OH(-)(org) <==> ->C(-)Q(+)(org) + H2O(org-->aq)

C(-)Q(+)(org) + R-X --> Q(+)X(-)(org) + ->C-R(org)

===========================================

From " The Journal of Organic Chemistry", Vol 43, No 3, yr 1978,
page 4682, article title "Sodium and Potassium Carbonates: Efficent
Strong Bases in Solid-Liquid Two-Phase systems[1]"

"Summary:  Anhydrous potassium and sodium carbonates in the presence of
 catalysts-tetraalkylammonium salts or crown ethers were found to be
efficent strong bases for generation and reaction of a variety of
carbanions.

Sir:  A recent paper by White [2], in which the alkylation of diethyl
 malonate, ethyl cyanoacetate, and some other compounds in the presence
 of potassium carbonate in DMF was reported, prompts us to to publish a
 preliminary communication describing some of our results concerning
the application of alkali metal carbonates as efficent strong bases.

Amoung the wide variety of basic agents employed for the generation of
carbanions, concentrated aqueous sodium hydroxide in the presence of
tetraalkylammonium salts or crown ethers is of particular interest [3].
Such reactions take place in a liquid-liquid two-phase system in which
 both phases, aqueous sodium hydroxide and organic reactants (neat or
in organic solvent) are mutally immiscible.  ...

Despite many advantages, the CTP [Catalytic Phase Transfer] system has
some limitations, one of them being the hydrolytic activity of
concentrated aqueous alkali.  Although, due to the mutal immisciblity
of the phases, hydrolysis of starting materials and/or products
interfers much less than one would expect; carboethoxy and
carbomethoxy groups are hydrolyzed in this system to a considerable
extent.  ...

We have found that many reactions proceeding via carbanions can be
efficently carried out useing anhydrous sodium or potassium carbonates
 as bases.  In these cases the reaction proceed in liquid-solid
two-phase systems.  ...  In this system reactions are catalyzed by
tetraammonium salts or crown ethers.  The catalysts are unable to
transfer carbonate anions ( CO3(2-) ) into the organic phase [4], thus
solid-liquid phase transfer phenomena are probably not involved here.
It is more plausible that the first step, namely proton abstraction,
takes place on the surface of the solid carbonate.  ...  Since ahydrous
 alkalicarbonates from fine powders with well devolped surfaces and
show no tendency to form lumps, the speed of stirring is is not of
crucial importance.  When K2CO3 or Na2CO3 are used as bases the
reaction should be carried out at higher tempatures than if aqueous
NaOH is used in the CTP system.  This normally does not cause any
difficulties, since the carbonates are rather mild bases. 

Up to now the following reactions have been found to proceed efficently
 in the presence of alkali carbonates. 

...

3.  Alkylation and nitroalkylaton of diphenylacetaldehyde.

Ph2-CHCHO  +  RX --{ K2CO3/crown }--> Ph2-C=CHOR

Exclusively O-alkyated derivetives are formed in high yeilds.

...

9.  Williamson ether synthesis.

C4H9Br  +  C4H9OH --{ K2CO3/18-crown-6 }-->  C4H9OC4H9

...

[1]- Paper 86 in the series Reactions or Organic Anions, Part 85;
 A. Jonczyk, Z. Ochal, and M. Makosza, Synthesis, in press.

[2]-  D. A. White, Synth. Commun., 7, 559 (1977), and refernces sited
therein.  One should mention a paper by R. M. Boden [Synthesis, 784
(1975)] describing the use of potassium carbonate for the generation
of phosphonium ylides and subsequently the Wittig condensation. 

[3]- Pure and Applied Chemistry, 43, 439, (1975);  W. P. Weber and G.
W. Gokel, "Phase Transfer Catalysis in Organic Synthesis", Springer
 Verlag, West Berlin, 1977.

[4]-  We have found that CO3(-2) anions (determined as total
alkalinity) are not transferred into acetonitrile on [<- a missprint I
believe, rather "or"] benzene solution from solid phase of K2CO3 either
by 18-crown-6 or by tetrabutylammonium bromide."

=========================================================

From "Tetrahedron Letters", No 18, pp 1351-1352, yr 1971, article title
"REACTIONS OF ORGANIC ANIONS.  XXVI. x/CATALYTIC ALKYLATION OF KETONES
IN AQUEOUS MEDIUM", by A. Jonczyk, B. Serafin, and M. Makosza

"... we found recently that ketones can be readily transformed into
[alpha]-alkylated products when reacted with alkyl halides in the
presence of 50% aqueous NaOH and catalytic amounts of triethylbenzyl-
ammonium chloride /TEBA/.  The catalytic effect of the latter on the
reaction yield was particularly strong in the case of weakly active
alkylating agents.  Thus, phenylacetone and Bu-Br in 50% NaOH gave
about 5% of 3-phenylheptanone /I, R=C4H9/, whereas in the presence of
TEBA the yield increased to 90%. 

Best results were obtained  in the case of ketones with an aromatic
substituent at the [alpha]-CH2 group; phenylacetone and deoxybenzion
yielded monoalkyl derivetives /I/xx/; with active alkylating agents,
e.g. benzyl or alkyl chloride, used in excess, [alpha], [alpha]-
disubstitution /II/ occured.  ...

I___Ph-(CH)R-COCH3

II__ Ph-(CRR)-COCH3

...

...  Catalytic alkylation of other ketones, e.g. acetophenone, cyclo-
hexanone and acetone, yielded mixtures of mono-, di- and O-alkylated
products, monoalkyl derivetives being usually preponderant.

The new method provides a convenient route for the synthesis of
[alpha]-substituted ketones.  It eliminates inflammable solvents and
unstable condensing agents /NaNH, tert- alkoxide, Ph3CNa, BuMgBr/ used
in the procedures described eariler /3/.  The yields are in many cases
 superior to those reported in literature."

x/ = Part XXv. M Makosza and M Jawdosiuk, Chem. Comm., 648 /1970/

xx/ = Examples given for phenylacetone

/3/ = Bull. Soc. Chim., 31, 1073, /1922/;  Chem. Rev., 12, 43 /1933/;
 20, 413 /1937/; Bull. Soc. Chim. France, 1040 /19656/;  Record Chem.
Progr., 24, 43 /1963/;  ibid., 28, 99 /1967/;  Modern Synthetic
Reactions, p 184, yr 1965; Bull. Soc. Chim. France, 160 /1969/.
 
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