help with mechanisms

oh wow, I was just overlooking the chloride shifting over a carbon! derp. I knew the ring strain was what drove the reaction but didn't know exactly how to approach the first step. Interestingly enough, after building this reaction using a molecular model kit it made a lot more sense in 3d, especially for the double bond reformation. Thanks for the help!

edit: hope this picture works

[Edited on 8/13/2010 by cheeseandbaloney]

If you enjoy pondering or working through organic mechanisms I would suggest buying "The Art of Writing Reasonable Organic Reaction Mechanisms" by Robert Grossman. This is essentially the standard for mechanistic formality.

The ring expansion you've described is probably not as simple as DDTea described. If you were to draw a mechanism showing the C-Cl sigma bond breaking, populating the sigma* antibonding orbital of the cyclopropyl C-C bond and opening the ring this would not be correct - strictly speaking. In heterolytic mechanisms (moving electron pairs only - not radicals) bond cleavage - think SN2 type 'backside attack' mechanism - results from adding electron density to the antibonding orbital at the atom undergoing the bond forming/breaking event. Frontier orbitals would not predict good overlap for this process to take place. Also, keep in mind that the ring expansion you described might take place under various conditions, and each might utilize a unique mechanism.

Cyclopropanes undergo a rich diversity of reactions, many of which can be best rationalized by homolytic mechanisms. Solvolysis or thermolysis of 6,6-dichlorobicyclo[3.1.0]hexane is probably a radical mechanism, as evidenced by deuterium labeling experiments that show incorporation of deuterium at carbons 1 and 5 of the starting bicycle. The base induced ring expansion is probably best explained by an ionic mechanism (see below), but do not think of this as a 'chloride migration', because the chloride is probably not delivered intramolecularly.

Quote: Originally posted by Arrhenius

If you enjoy pondering or working through organic mechanisms I would suggest buying "The Art of Writing Reasonable Organic Reaction Mechanisms" by Robert Grossman. This is essentially the standard for mechanistic formality.

Arrhenius: nice call about the orbital geometry, I didn't think about that.


I'm trying to wrap my head around how this would affect the mechanism, but I can't quite see it: it's worth bearing in mind that in cyclopropane-type systems, the electron density is not concentrated between the atoms as one would expect from a normal sigma bond. There is a lot more pi character at play, so the electron density is concentrated outside of the ring, with the bonding orbitals arranged to form a hexagon rather than a triangle (i.e., imagine the nodes tangent to each vertex of the triangle). If you wanted to explain the type of orbitals in terms of valence-bond theory, you'd have to call them sp4 orbitals, which makes people uncomfortable This is confirmed by X-Ray Diffraction.

Here's another proposed mechanism: suppose the bond between the shared carbons breaks, moving to the bridging carbon and displacing a chloride. The result is a six-membered ring carbocation intermediate with charge delocalization. The expelled chloride ion can now bind to either of the two originally shared carbons. This would lead to a racemic product.


DJF90--interesting that you mention "Designing Organic Syntheses; the disconnection approach." I worked with a professor briefly a few years back who studied at Oxford. The two books he told me to look into as soon as possible were that one as well as "The Art of Writing Reasonable Organic Reaction Mechanisms." I never did buy them, though, as my interests shifted away from synthesis.

My turn to recommend a book: Anslyn & Dougherty's "Modern Physical Organic Chemistry." It's probably the best textbook I've ever come across. It's pricey for the amateur, but if you're serious about Organic Chemistry, it's well worth the money. There's more information in that book than you may ever need in your life.

Oh, and Arrhenius--what software did you use to draw your diagram?

[Edited on 8-13-10 by DDTea]

There is no simple answer as to when a sigma bond will be broken. Certainly we can think that when a bond breaking event leads to a more stable product, this 'downhill' process is likely to take place. Conversely, we can put energy into a system (heat usually) to drive the reaction 'uphill' on a reaction coordinate. Typically it is extremely difficult to break a sigma bond that is not weakened or strained in some way that will drive its breaking. In your example above, relief of the ring strain associated with a cyclopropane is the driving force. In an SN2 reaction the weak bond to the leaving group is broken to form a stronger bond (but not always stronger). For instance, the Finkelstein reaction forms a weaker bond, but the driving force in this reaction is entropy not enthalpy! This is the case in several other common reactions. The Fischer esterification typically is very poorly favored enthalpically, but clearly can be driven to completion by entropically removing the water by azeotropic distillation or by using a large amount of sulfuric acid to desiccate the reaction.

Other reactions include pericyclic reactions, sigmatropic reactions, metathesis, transition metal catalyzed reactions, photochemical reactions. The list is long. You will probably not become so talented at mechanisms that you will be able to avoid having to learn the enormous number of reactions that are possible. It's easiest to solve mechanistic problems when they look familiar to a reaction you know - at least to have a better idea of when bond formation/cleavage is likely to be allowed.

Here as some relatively simple mechanism problems:

Interesting posts Arrhenius!

Ideally, organic chemistry should be absolutely analytical, but it would mean that we are able to grasp the infinity. It is empirical, I guess for the same reason that we can not calculate pi. Experiment and extrapolation is the only means the organic chemists (humans) currrently have - in contrast to "God" (and possibly R. B. Woodward ).

At first - I am the last one who will propose any mechanisms just out of my head.
"While I agree with DJF90, mechanisms are only our best guess given the information at hand, I would argue that a very strong understanding of mechanism is absolutely crucial if you wish to be an advanced organic chemist."
I cannot agree with it. Guessing means and gives nothing. Reactions go (or not) without our guessing.
Only studying many experimental results can give you right to propose any mechanisms. Of course, some reactions are easy to explain, some are not.
"Very strong understanding of mechanism" is not the same as "very strong ability for writing nicely looking combination of arrows and lines". I have always felt respect for chemical reactions. The more I learn, the deeper respect I feel

Back to the point.
Uncatalysed, thermal ring expansion of mentioned gem-dichlorocyclopropane derivative goes most probably via concerted, disrotatory, electrocyclic ring opening at the
C-C bond and a concomitant ionization of a carbon-halogen bond.
Five-membered ring is itself strained and such isomerisation goes in temperature below 200 C (with 100% yield). In contrast, 6- and 7-membered rings are stable upon reflux above 200 C.

These wisdoms come from review article (one of many about cyclopropanes):
http://dx.doi.org/10.1021/cr0100087
and from literature cited there.

Quote: Originally posted by kmno4

"Very strong understanding of mechanism" is not the same as "very strong ability for writing nicely looking combination of arrows and lines". I have always felt respect for chemical reactions. The more I learn, the deeper respect I feel

Perhaps I chose my words poorly. Many reactions are very well established by experimental methods. I don't know how familiar you are with labelling studies, kinetic isotope effects, ultrafast spectroscopy, etc. but people work extremely hard to come close to proving mechanisms, and my hat's off to them (not my cup of tea!). I'll try to dig up some truly astonishing mechanisms - ones that are necessary to rationalize the result of a reaction. As for rationalizing how to make a reaction go, I think the Swern Oxidation is an excellent example. I'm sorry, but one wouldn't come up with the correct series of reagent additions to make that reaction go. I'm near certain that the mechanism preceded that reaction.

DJF90 IIRC there was 3eq of base and ~1eq MsCl. Enjoy! Let me know if you get stuck, or if anyone wants the answers. I think there's one excellent answer, and one somewhat acceptable answer for the last one (DJF90's). And yes, I second that - 5 & 6 member rings are not strained.

Ring strain:
3: -27kcal/mol
4: -26kcal/mol
5: 6kcal/mol
6: 0kcal/mol

[Edited on 15-8-2010 by Arrhenius]

Here KMnO4, this one's for you:



Not a really astonishing one, but I think you all can solve this one.

Quote: Originally posted by Arrhenius

Many reactions are very well established by experimental methods. I don't know how familiar you are with labelling studies, kinetic isotope effects, ultrafast spectroscopy, etc. but people work extremely hard to come close to proving mechanisms, and my hat's off to them (not my cup of tea!).

Here are my answers. In #4, the oxidopyrillium species is a well known in dipolar cycloaddition chemistry, hence I've drawn a concerted mechanism. The HOMO-LUMO pairing of the dipole and dipolarophile are such that it gives the 'conjugate addition' product.

Nicodem: It would technically fall under an aza Cope, not Claisen Regardless: Mundal et al "Triflimide-catalysed sigmatropic rearrangement of N-allylhydrazones as an example of a traceless bond construction" Nature Chemistry 2, 294–297 (2010)

Here's the supp. info.

Unfortunately I don't access to this article. I believe there are several related papers.
And thank you for being the first to back my opinion that mechanisms are useful. You make a good point though.

Quote: Originally posted by Arrhenius

It would technically fall under an aza Cope, not Claisen

Quote: Originally posted by Nicodem

For example, I still do not get it why in this particular case calling it an aza-Cope would be more appropriate than aza-Claisen, but I guess the authors had their own opinion on this. Perhaps because Claisen rearrangements are an undergroup of Cope rearrangements? But then they use a catalyst that can only catalyse Claisen but not Cope rearrangements (protonation of the heteroatom and the heteroatom is a Claisen's peculiarity).

Quote: Originally posted by Arrhenius

.... DDTea: Program is Chemdraw. I suggest you download ACD Labs' Chemsketch - free for 'student' version. .......

It's best to explain in pictures, following picture explains why I would call it aza-Cope and not aza-Claisen (sorry for the bad graphics, it is time to sleep):






I mentioned the presence of a carbonyl in product 1,5-diene as what distinguishes the aza-Claisen from aza-Cope, but hydrolysis of imine to a carbonyl is a separate step and not part of the pericyclic reaction. It follows that Claisen proceeds via O-allyl-enol species while aza-Claisen via analogous N-allyl-enamine species and so, logically, the reaction Arrhenius mentiones can not be considered as aza-Claisen since it does not proceed through a nitrogen analogue of allyl vinyl ether (Claisen), his example fits aza-Cope rearrangement more... All in my opinion of course...


[Edited on 17-8-2010 by Sandmeyer]

No, no, Sandmeyer. That is not what I had in mind. I was comparing the pericyclic step of the transformation directly to the Claisen rearrangement in a strictly isosteric fashion (N-Boc instead of O and C=N instead of C=C). See the first equation below.

The paper is now kindly made available in the Wanted references thread by Solo. The authors are of the opinion that the protonation occurs before Boc removal on the basis that equivalent non-Boc hydrazones give poorer conversion (see the relevant part of the article on the right). Seems plausible, however this also means comparing the sigmatropic rearrangement to Claisen's can not be correct, because this type of rearrangement can only be catalysed by the protonation of the other nitrogen (the one initially Boc protected). The catalytic effect of the acid by protonation of the "imine's" nitrogen (which is the only protonable one prior to Boc removal), indicates the electron flow is most likely the opposite to the one in the Claisen-type of rearrangements (see the third equation bellow). So it can not be a Claisen, but it does not have that much to do with a Cope either, because Cope does not involve protonation or heteroatoms in that position. Anyway, the authors avoid messing up with such details and do not compare the pericyclic component of this one-pot tandem transformation neither with the Cope nor the Claisen rearrangement, or any other named reaction, but consider it as a [3,3]-sigmatropic rearrangement of its own type. So, perhaps it was Arrhenius' idea to call it a Cope-like rearrangement? Or perhaps they call it that way in one of the two preceding papers that I did not yet check. Or maybe it was Stevens who 30 years ago reported the sigmatropic rearrangement of allylhydrazones who compared it to Cope. Better not call it names anyway.

My advice is try to move beyond Functional Group Interconversions (FGIs). It takes a sharp memory to write mechanisms for functional group dancing. However, it takes considerable skill to rationalize rearrangements, especially sigmatropy, etc. That being said, there are certain FGIs with stereochemical outcome that absolutely demand your understanding the mechanism. Also, given the abundance of transition metal chemistry in organic synthesis, I would suggest you take a look into these mechanisms. I would also recommend you consider purchasing one of KC Nicolaou's books "Classics in Total Synthesis" - I have the first edition and it's pretty good. The strategy employed in these highlighted total syntheses is typically quite fantastic. Anyone up to try working through a few more problems?

I've tried to hit on a few practical reasons that make mechanisms and associated transition states important 1.) Rationalizing FGI outcome 2.) Multi-step mechanisms 3.) organometallic mechanisms 4.) highly strategic bond formation (see anything by E.J. Corey & co. among others).

Quote: Originally posted by Nicodem

No, no, Sandmeyer. That is not what I had in mind. I was comparing the pericyclic step of the transformation directly to the Claisen rearrangement in a strictly isosteric fashion (N-Boc instead of O and C=N instead of C=C). See the first equation below.

Quote: Originally posted by Nicodem

The catalytic effect of the acid by protonation of the "imine's" nitrogen (which is the only protonable one prior to Boc removal), indicates the electron flow is most likely the opposite to the one in the Claisen-type of rearrangements (see the third equation bellow). So it can not be a Claisen, but it does not have that much to do with a Cope either, because Cope does not involve protonation or heteroatoms in that position.

Well, that's not the case, aza-Cope is catalyzed by protonation of imine nitrogen, logically, since the LUMO energy of iminium species is further lowered compared to that of the corresponding imine. We all agree that Cope and Claisen rearrangements are [3,3]-sigmatropic rearrangements, however, the reaction Arrhenius refers to can not rationally be considered a Claisen rearrangement since benzaldehyde can not enolize/enaminaze, I don't think this is such a far out idea, I think it is quite basic and obvious but for some reason you are avoiding it. You did compare the direction of the electron flow in the Arrhenius example with that of Claisen rearrangement, but more importantly you didn't mention that the electron flow in the Arrhenius example is fully consistent with that of aza-Cope rearrangement, i.e C=N carbon - LUMO, alkene - HOMO.

Quote: Originally posted by Sandmeyer

I see, however, it is an incorrect way of reasoning; 1.) since the first equation is messed up, logically LUMO should reside on the C=N carbon, 2.) since Arrhanius explicitly provided benzaldehyde as example of carbonyl component and not 2-phenylacetaldehyde (enol ether of). As we know, benzaldehyde has no alpha hydrogens, consequently it can not be used as a direct carbonyl precursor for Claisen rearrangement of any kind, only for Cope -- as I've depicted above.

I only compared it to Claisen because that is what it appeared like before I had the article in hands. I soon gave up on that comparison, but truly can not call that an aza-Cope rearrangement either, though I agree that that the electron flow is consistent. How about not calling it anything but a [3,3]-sigmatropic rearrangements? The names of named reactions are often used confusingly in the literature. There is an inflation of names and an inflation of their use. You think the use of the name aza-Cope is consistent? Check this:

3-Aza-Cope Rearrangement of Quaternary N-Allyl Enammonium Salts. Stereospecific 1,3 Allyl Migration from Nitrogen to Carbon on a Tricyclic Template

Is that an aza-Cope or an aza-Claisen? To tell you the truth, now that you got me so confused, I can't be sure any more (even though a few days ago I would say Claisen before even blinking with an eye). So, what you call aza-Cope would be 2-aza-Cope and what I would call aza-Claisen would be 3-aza-Cope. But that mean it could be the opposite as well! Some might call your aza-Cope an 2-aza-Claisen. Yet, how about HOMO & LUMO roles, and the flow of electrons? I think that until IUPAC defines the proper use of heteroatomic prefixes in named reactions, one should avoid their use and stick to naming mechanisms utmost (but only when enough evidence is obtained).

[Edited on 20/8/2010 by Nicodem]

So, regardless of the electron flow, structural peculiarities, etc., we can call the example at hands either as 2,3-diaza-Cope or 2,3-diaza-Claisen rearrangement. It makes no difference even if we see a difference. I just hate (stupidly) named reactions!

Quote: Originally posted by Nicodem

Ah yes. The flow of electrons is likely wrong in the first equation. I always have troubles with deciding which Pi-system interacts with its LUMO and which one with its HOMO. That orbital stuff was never appropriately thought to me (unfortunately we had very old professors). I never trust much my intuition on this and whenever I run on similar problem I go asking a friend to calculate energies with Gaussian (even though I have serious troubles trusting computational chemistry, but obviously it is more accurate than my intuition). I guess this is one of those things I was trying to explain in one previous post, that one should learn these things while young. It is too late trying to do so later when you work in the lab and have children at home.

No need for Gaussian, to figure out the direction of electron flow in this problem it is enough to know that enamines are nucleophilic on beta carbon while N-Boc hydrazones, in analogy to imines and contrast to enamines, are electrophilic.

EDIT: The review Nicodem refers to, and that settled the matter of naming the reaction, seems like an interesting read, can someone please post it, thanks!


[Edited on 22-8-2010 by Sandmeyer]

Quote: Originally posted by Sandmeyer

No need for Gaussian, to figure out the direction of electron flow in this problem it is enough to know that enamines are nucleophilic on beta carbon while N-Boc hydrazones, in analogy to imines and contrast to enamines, are electrophilic.

Quote: Originally posted by Nicodem

I could not answer easily without resorting to Gaussian or Schrödinger-Jaguar. And even then, interpreting the results leaves much too much uncertainties.

Hey, another quick mechanistic question! Was flipping through some of the chapters in one of my orgo books ferking around with some of the problems. Came across what seemed like an easy one, but was an answer I didn't expect. What would you fellow chemists consider the major product of this reaction?

The major products would be cyclohexanone and methyl iodide. Mechanistically, the vinyl ether is protonated on *carbon* with formation of an oxocarbenium ion, then iodide attacks at the methyl carbon of the methyl vinyl ether. Hydrogen iodide mediate cleavage of aryl methyl ethers should proceed through the same mechanism. I do believe it can cleave other ethers, but this is definitely a brutally harsh reagent. Trimethylsilyl iodide (TMSI) is often employed to cleave ethers, especially methyl ethers, as a gentler alternative.

Cheers & keep reading!





[Edited on 13-10-2010 by Arrhenius]

Quote: Originally posted by cheeseandbaloney

yo Arrhenius! Why does the iodide specifically attack the methyl group and not the carbonyl carbon? edit: wait, does it haff to do with the stability of products, or enthalpy?

Quote: Originally posted by Ebao-lu

What is the mechanism of this kind demethylation?

Quote: Originally posted by Ebao-lu

Btw, Nicodem and Arrhenius, the rearrangement you are talking about could be also semi-homolytic, like in Fisher's indole synthesis and Hoffman-Loeffler reaction. That means, any arrows should be avoided in the mechanism, because arrow is an electron pair, not a single electron.

Quote: Originally posted by Ebao-lu

Quote: I never heard about articles claiming it involves a homolytic cleavage of bonds here is one http://www.springerlink.com/content/x0h4047554788212/fulltex... I have also seen most articles that claimed an arrow-drawn mechanism of fisher indole synthesis, that is maybe due to simplicity Indeed, i think there is no _ideal_ synchronous sigmatropic rearrangement. Some are bit heterolytic(even having extremely short living ion intermediates and such), some bit homolytic.. depending on what is more beneficial.

Thanks, i prefer using Einstein's razor! (or Einstein's interpretation of Occam's razor, not sure) that says "Make everything as simple as possible, but not simpler."
I think i used it ->. There was no sophistication in my D-A explanation, it was just simplification. Most terms i used are frequently used in organic chemistry like "activation energy" "charge attraction" (better interaction), "transition state" etc. I did not say that DA mechanism does not involve orbital interactions(as all reactions, not only DA involve it), i just neglected that as not critical in this particular case for understanding the regioselectivity and changed it to charge explanation, which does not violate or conflict with any existing rules or accepted mechanism, being just a simplification of that also in order not to draw orbitals on this board. I was sure you will also not recall about orbitals. But if you did - feel free to explain that my explanation does not fall under Occam's razor(if you want) - not to debate with you, just for you to convince me that my explanation is really a sophistication, or over simplification of existing facts and thus may become wrong(i agree that it is incomplete btw, but it was not a new mechanism proposal, just a simplifacation of existing one).. And i'll change my mind immediately if you do that, Nicodem



[Edited on 29-10-2010 by Ebao-lu]

Quote: Originally posted by Ebao-lu

My point still is, that synchronous rearangements([3+3] [4+2] etc) can be two types - homolytic and heterolytic (or better to say, polar/ non polar) ones. I dont say that N-N bond in fisher's indole synthesis is cleaved _before_ formation of C-C, both processes are synchronous. But the nature of this cleavage is homolytical, so there is no polarization in transition state.

Ok, since Arrhenius have not posted any problems for a while I'll post a problem. Provide mechanism for transformation 1 to 2 in DMF. I'll give a solution proposal on request.

EDIT: It is hard to see from the picture but it should read: "1.) Br2 2.) Base"





Gool luck!

[Edited on 24-12-2010 by Sandmeyer]

hmmmm so first hope your holidays went fantastically grand, second! Sandmeyer, goofed around with it for a bit tonight hope i'm on the right track:

Yeah, you've got it cheezy -- it's an Sn2' all-right...

Could someone explain a mechanism of this sodium sulfite reduction?
The book where it was found is here




[Edited on 1-2-2011 by Ebao-lu]

[Edited on 1-2-2011 by Ebao-lu]

Quote: Originally posted by GreenD

The starting material IS and acid, and there is ONLY the addition of POCl3 and the corresponding amine to give an amide.

Quote: Originally posted by GreenD

Does SOCl2 or oxalyl chloride react with secondary cyclic amines? Indoles? Reactive towards anything other than alcohols and acids? Chemistry book says "Make sure you know the mechanism - thionyl chloride reacts in many ways." It acts as a lewis acid - and I believe an indolic amine is stable enough to go without side reaction.

Ebao-lu:

This is an interesting reduction of tribromoimidazole - primarily because most of us don't often think about simple reagents like sodium sulfite. That being said sodium sulfite is a fairly versatile reducing agent, and is dirt cheap. I don't know the mechanism for sure, but I feel bad that no one's ventured a guess, so I will. This leaves unanswered as to why this reaction can achieve selective (or atleast somewhat selective) di-debromination. Given the yield, it's quite possible that this outcome is controlled by optimizing reaction time rather than pure thermodynamics or so.

What I've drawn is a combination of some literature precedent (see below). Brominated hydroxyphenols are easily debrominated with sodium sulfite, whereas their monomethyl ether counterparts are not reduced under the same conditions. This is likely due to the fact that the hydroxyphenol undergoes facile tautomerization to a keto or quinone form. For this reason, invoking addition of sulfite via a more reactive tautomer of imidazole seems necessary. Given that a solution of sodium sulfite is only mildly basic, a proton catalyzed tautomerization seems OK.

It seems that either sulfite or water can act as the end reductant, yielding either the bromosulfate ion or hypobromite, respectively.



Refs:
1.) Arch. Biochem. and Biophys., (1974), 161(2), 632-637.
2.) J. Am. Chem. Soc., (1952), 74(6), 1601–1602

How's that work?!!?

Hey all. I'm a bit saddened by the Organic stickies. It seems people are more interested in benzaldehyde and Duff reactions than mechanisms!! Shocking! So I thought maybe we could work through some new problems. I'm a firm believer that you should know *how* your synthesis is working, not just how to do it.

Here are a few rules for writing any mechanism:
- Don't break the rules.
- Don't skip steps.
- Identify a nucleophile and an electrophile and:
1.) make a bond
2.) break a bond
3.) draw the result
- Special case (e.g. pericyclic rxns) don't have a nucleophile, so this won't work
- Try to balance reaction equations. Organic chemists lose sight of this, but this basic concept is still important!

Fluorescein:
First synthesized in 1871. Basically, just mix resorcinol, phthalic anhydride, some sulfuric acid, and heat it a bit - someone should write up a prep. The product is intensely fluorescent due to the electronic structure and extended conjugation in 2.
1.) Propose a mechanism for this reaction.
2.) For those unfamiliar, the 'delta' means heating. Why do you need to heat this reaction? What steps require this energy?
3.) Wikipedia calls this a "Friedel-Crafts" reaction. There's no AlCl3, FeCl3 or an acid chloride, so why is this still a Friedel-Crafts reaction?


In the Grignard reaction of ethylmagnesium bromide with benzaldehyde, the anticipated secondary alcohol 3 is isolated as the major product, along with minor impurity 4. Indeed, this minor impurity is found in most reactions with organometal nucleophiles.
1.) Draw a mechanism for the formation of 4.
2.) What is the name of this reaction?
3.) What is the oxidation state of the aldehyde carbon in the starting benzaldehyde? and in the products? What is the oxidant or reducing agent that promotes this redox, and what is its oxidation state throughout the reaction?


Magpie and others have worked on the synthesis of furfural, 6, from pentoses. The Org Synth prep prepares furfural from corncobs.
1.)What is the mechanism (following the rules!) for this reaction? (if you want to cheat, it's hidden in Magpie's thread).
Furfural can be used to prepare butenolide, 7.
2.) What is the mechanism for the reaction of 6 to 7?
3.) What is the name of this reaction?


[Edited on 5-12-2011 by Arrhenius]

I have a question related to a recent synthesis of mine. I was trying to work through the reaction mechanism and came to a sticking point. Please see below. While I made phenylacetylene, from styrene, the common undergrad experiment utilizing trans-stilbene is a simpler system and the same mechanism should apply. First, the alkene is brominated, giving the trans/anti addition product. This is heated with an alkali hydroxide in a high boiling solvent (usually triethylene glycol) to induce a double dehydrohalogenation. I see this described usually as two E2 eliminations. If we do the first E2, we find that the product is always E, which lacks an antiperiplanar H and Br for the second elimination.

I've heard that synperiplanar can E2 as well, but the transition state is significantly higher energy. Does the reaction proceed this way, does the high temperature induce a double-bond isomerization, or does it go by a different mechanism alltogether? E1 would require spontaneous formation of a vinylic carbocation, which I find exceedingly unlikely.



[Edited on 1-30-12 by UnintentionalChaos]

[Edited on 1-30-12 by UnintentionalChaos]

Quote: Originally posted by DJF90

Double dehalogenation should only be possible when the product would be a terminal alkyne, as with styrene dibromide. The product you have drawn (1,2-diphenylacetylene) would likely have to be prepared via a sonogashira coupling. Do you have a reference stating that the reaction you have drawn is possible?

GreenD:

The authors consider this a Beckmann rearrangement. Given that in this paper a variety of metals including nickel, copper and cobalt are demonstrated to affect the isomerization of oximes to amides, the mechanism is likely Lewis acid activation - as opposed to redox. Bare in mind that Brønsted acids catalyze this transformation as well. The mechanism in this case is as follows:


Oximes, in particular those derived from aldehydes (aldoximes), are configurationally stable. That is to say, the cis-/trans- stereochemistry about the C=N bond does not readily interconvert at room temperature. This is important when we consider the mechanism, because only when the aldoxime hydrogen and hydroxyl group are anti-periplanar can the E2 type elimination take place. I've drawn the orbitals involved to make this clear. The electron pair in the C-H bond (large grey lobe) must populate the anti-bonding (small white lobe) of the breaking N-O bond, and symmetry requires they be anti-periplanar. Nickel promotes this reaction by coordinating the oxygen, effectively weakening the N-O bond by pulling electron density away from the oxygen center. You could also think of this as a resonance structure (shown) where there is a positive charge on oxygen and a bond to nickel. From the resultant nitrile, the metal can coordinate nitrogen, making the carbon more electrophilic, and allow water to add. A proton transfer (written ~H+) gets us to the amide.

[Edited on 29-3-2012 by Arrhenius]

Arrhenius, bravo! That was great. The explanation of the anti-periplanar geometry, as well as the complexing. I was also stumped how the oxygen was moving from the aldoxime to the amide, but it is actually from water. The stability of the aldoxime also cleared - thanks.

Here is numero 2. I've never encountered an alpha-alkelation before, and I have no idea where the hell to even start on this one.

GreenD
It seems like you have some training in organic chemistry, but here are a few rules - mentioned previously - that I find extremely helpful for working through 'unknown' mechanisms. Additionally, I've drawn reversible arrows where I believe reactions to be reversible. This is often important to consider why reactions proceed to particular products. A majority of reactions involve a nucleophile and electrophile, and hence three rules for drawing a mechanism to determine reaction producst/intermediates are:
1.) identify a nucleophile and an electrophile
2.) make a bond, break a bond (i.e. use arrows in a valence allowed manner)
3.) draw the result

Here's how to apply these to your second question. I've also drawn partial charges, where applicable, to indicate nucleophilic/electrophilic sites. The key is not to get ahead of yourself, as this often leads to confusion if you try to skip a step (e.g. writing a proton transfer prematurely).

Step 1: The key realization to make here is that primary and secondary amines react with ketones and aldehydes in a somewhat enthalpically favorable reaction, resulting in either an imine/enamine (tautomers) which are moderately stable, or an iminium which is strongly electrophilic. Also, if an acid or base catalyst is present - in this case HCl - it will probably be utilized in the very first step of the mechanism; in this case we protonate a ketone/formaldehyde.

Now, the next bit depends on how you run the reaction. I probably drew it differently than your stepwise reactions suggest. Step 1, strictly speaking, probably forms the dimethyliminium ion of formaldehyde - this is much more electrophilic than formaldehyde itself. However, if the diethylketone were present I believe it would proceed through an enamine catalyzed Mannich reaction as I've shown. Alternatively, the base in step 2 deprotonates the diethylketone, and the resulting enolate adds to dimethylformaldiminium chloride. Enolates and enamines are 'isolelectronic', which is to say in both cases you can consider a resonance structure with a negative charge on the carbon alpha to the carbonyl to suggest it is nucleophilic. While it's of little consequence here, the enamine will be of the E (E=trans Z=cis) stereochemistry for thermodynamic reasons.

Step 3: Here, you must realize that amines react exhaustively with alkyl halides - when present in sufficient amounds - to form tetraalkylammonium halides.

Step 4: The formal positive charge on nitrogen weakens the strength of the C-N bond to the neighboring CH2. Another way to say this is that the NMe3+ becomes a better leaving group. Sodium hydroxide (pKa ~16) can deprotonate (only partially!) the ketone (pKa 20) to give the thermodynamic enolate, which then gives rise to a type of Hoffmann elimination. This is somewhat reversible because the product possesses a Michael acceptor, but is enrtropically driven according to Le Chatelier's principle because trimethylamine is removed from the reaction as a gas.

speak of the mechanisms, I have many interesting problems, I would say that are hard but useful when people want to learn total synthesis.

these problems, may have been known by some of us, called Fukuyama group meeting problems.

Quote: Originally posted by 2bfrank

Im an IT dumbass, hence attached rather than post it directly. (been to busy to sort out how to do that, help would be good) but this mechanism was associated with a synthetic and medicinal unit I am currently undertaking. Its predominantly using an iminium/enamine type catalyst with a Michaels reaction and an Aldol reaction, I just thought it pretty cool. To me its poetic. Im still a little unclear, and taking my time with the stereo aspects to it, but thought it a Pretty cool, albeit a simple mech. Cheers

Quote: Originally posted by PeetPb

hi, I've been searching all over the internet for the mechanism of oxidation of alkanes (aryl derivatives, like toluene) to carboxylic acid by KMnO4. I found that it should be a radical mechanism. The MnO4(-) displaces one hydrogen and makes a free radical, but beyond that I couldn't find anything else. If you could help me I'd really appreciate it. thanx a lot

Quote: Originally posted by flux157

I have stumbled on a reaction on which a 1,2-alkyl halide is converted into a ketone by the reaction with aqueous KOH. This is described in Yuki et al, Japanese Patent 69:10,776; Chemical Abstracts 71, 30220e (1969) and also in this links: http://www.erowid.org/archive/rhodium/chemistry/tcboe/chapte... ; http://www.erowid.org/archive/rhodium/chemistry/tcboe/pictur... Quote: 23.2 g (0.1 mole) of 1-(3,4-methylenedioxyphenyl)-1,2-dichloropropane is refluxed for 10hrs with 75g of 15% KOH (potassium hydroxide) solution. The mixture is cooled extracted with benzene. The benzene is removed in vacuum and the residue distilled to yield approximately 15.2 g of piperonylacetone (bp 149-151°C/10 mmHg). 85% yield from the dichloro compound. If this is true, what is the mechanism behind it? Shouldn't the reaction of a 1,2-alkyl halide with aqueous KOH give a glycol instead of a ketone? If anyone can clear this out it would be great.

I don’t understand where the Proton in the Benkeneser Reaction(or the Birch-Reduction) with Ephedrine comes from. I found that mechanism below, is it right? Does the proton come from the water added to stopp these reactions ?
In the normal Birch-reduction ist the alkanole acting as the donator but in the papers i found THF oder Et2O is used as a solvent and no alkanole or anything else is used as a co-solvent.
Can somebody explain this to me ?
The mechanism i found:




best regards



[Edited on 4-4-2013 by cortex]

Quote: Originally posted by DraconicAcid

Quote: Originally posted by flux157   I have stumbled on a reaction on which a 1,2-alkyl halide is converted into a ketone by the reaction with aqueous KOH. This is described in Yuki et al, Japanese Patent 69:10,776; Chemical Abstracts 71, 30220e (1969) and also in this links: http://www.erowid.org/archive/rhodium/chemistry/tcboe/chapte... ; http://www.erowid.org/archive/rhodium/chemistry/tcboe/pictur... Quote: 23.2 g (0.1 mole) of 1-(3,4-methylenedioxyphenyl)-1,2-dichloropropane is refluxed for 10hrs with 75g of 15% KOH (potassium hydroxide) solution. The mixture is cooled extracted with benzene. The benzene is removed in vacuum and the residue distilled to yield approximately 15.2 g of piperonylacetone (bp 149-151°C/10 mmHg). 85% yield from the dichloro compound. If this is true, what is the mechanism behind it? Shouldn't the reaction of a 1,2-alkyl halide with aqueous KOH give a glycol instead of a ketone? If anyone can clear this out it would be great. It would give a glycol if it were SN2, but with the big aromatic group on the 1 carbon, it will probably eliminate. Or maybe both chlorines get substituted to form the glycol, but then elimination takes place to give 1-(3,4-methylenedioxyphenyl)-1-propen-2-ol, which would then tautomerize to the ketone.

Can some one help me understand or elaborate what is going on in this mechanism? What happens after the radical is formed?
Original paper



[Edited on 30-8-2014 by HeYBrO]

Quote: Originally posted by cheeseandbaloney

I recently have started teaching myself MO theory and have slowly but surely begun to understand it after drawing and building myself some molecular orbital diagrams. Like visualizing when electron orbitals are 'out of phase' and areantibonding...etc.

Quote:

but the one I have with the question was bought used online and doesn't have the solutions manual. I've looked online but the only link available to download the solutions manual .pdf is broken.[/quote ] which book is it,i will try to find the solution manual [Edited on 6-10-2014 by CuReUS]

This is the conversion of pseudoephedrine to methyl amphetamine. The intermediate that is formed is a unstable aziridine. Hence the formation of a partial hydride that should attack on the (partial positive) benzylic carbon.

I think it's very difficult to measure this in the lab and verify the mechanism. The intermediates are so unstable that they react in nanoseconds, I suppose.

I need help with the mechanism below. It is a Michael type addition of enamine to acetylenedicarboxylate.





My questions are:

1.) Is the first step of the mechanism correct?
2.) If it is, what goes on electron-wise in the brackets, so that we get the end product?


Thank you very much!



[Edited on 24-9-2015 by SecretSquirrel]

Quote: Originally posted by SecretSquirrel

1.) Is the first step of the mechanism correct? 2.) If it is, what goes on electron-wise in the brackets, so that we get the end product?

Thank you!

You mean something like this? Hope I got it right this time.








[Edited on 26-9-2015 by SecretSquirrel]

Hey Guys,

So for my advanced inorganic practical course I will have to prepare Dicyclohexanephosphine. And my instructor gave me the hint to prepare for a Grignard, the theoretical part will also be about Grignard reactions and that I will have to add the Grignard Compound to PBr₃.

Makes sense. I'll probably prepare some Cyclohexanemagnesiumbromide and then make the Dicyclohexanephosphinechloride and reduce that with LiAlH₄ to the Phosphine.

The question is how the mechanism works here. I'm pretty sure that I can remember from my lecture on Organometallics that Magnesium and Lithium organometallic compounds tend to form sixmembered ring structures for their reactions.

So I just assumed the following mechanism. The Phosphorus has a positive partial charge due to the more electronegative Bromine atoms and the C-Mg-Br Carbon is slightly negative so I think it could actually work like this.

I didn't care about lone pairs here so you could see everything.

Any suggestions ?

Can this work?