Alkyne chemistry bears many resemblances to alkene chemistry, but in these first few posts on the subject, the purpose is to illustrate how one seemingly minor change – an extra π bond – can lead to significant differences in chemical behavior. Previously, we saw that the sp hybridization of alkynes leads to increased acidity, and the second π bond of alkynes leads to the possibility for partial reduction to either cis or trans alkenes. In this post we’ll see again how the addition of that extra π bond has a very important and surprising consequence.

Several posts ago we talked about the hydration of alkenes. This can be done either with aqueous acid, or with mercury and water (“oxymercuration” – more on that later). Looking at the reaction with alkenes, the pattern is fairly straightforward: break a C-C π bond, and form a C-H and C-OH bond. Also recall that the oxygen ends up on the most substituted carbon ["Markovnikov" selectivity].

So what happens when we try this reaction on alkynes? We might expect to observe the same pattern, right? After all, it’s just a simple addition reaction.

Well… here’s what we actually observe. We get… a ketone !?

Now what’s going on here? This seems like the type of thing that drives new organic chemistry students around the bend. Just when you think you understand your surroundings, you pick up the most innocuous looking rock, and underneath it find a poisonous snake!

Don’t panic! It’s a new concept in organic chemistry we’ll be exploring here (tautomerism) – one that gets much more discussion in Org 2 – but it’s not as weird as you initially might think.

Look at the bonds formed and broken. The first set we should understand. Form C-O and form C-H, break C-C π.  It’s that next set of bonds formed/broken that are a big surprise.

If you monitor this reaction closely – one way to do it is in an NMR tube – it’s actually possible to observe the first product of this reaction, which is the one shown below. We call this an “enol“, by the way – kind of like a spork (half spoon half fork) it is part alkene, part alcohol.

Over time, this enol spontaneously converts into the ketone. Note that the two have the same molecular formula – they are constitutional isomers.  And they are in equilibrium with each other. We call these constitutional isomers which interconvert, “tautomers”. This equilibrium generally favors formation of the ketone due to the strong C-O π bond (compared to C-C π).

Here’s how the whole process works – arrow by arrow.

Wait – we’re not done! There’s another way to “hydrate” alkynes, just like there was with alkenes. We can also perform the same reaction with mercury, water and strong acid [sulfuric acid, H₂SO₄ is the usual acid of choice]. For interesting reasons we wont get into at the moment, NaBH4 is not generally needed here; it is sufficient to merely have water and acid present.

There’s also hydroboration. Remember how it performs “anti-Markovnikov” hydration of alkenes?

Likewise, we can use the same reaction to perform “anti-Markovnikov” hydroboration of alkynes. [Note: while BH₃ can be used for this, we often use different boranes, such as disiamyl borane or 9-BBN that, due to their greater steric bulk, increase the proportion of addition to the less substituted carbon] .

Just as in the cases above, we initially obtain an enol. However, under the reaction conditions, keto-enol tautomerism results in formation of the aldehyde.

Bottom line here: if we start with a “terminal” alkyne, that is an alkyne where one of the carbons is attached directly to H – then we will obtain ketones with H3O+/H2SO4 or via oxymercuration, and aldehydes via hydroboration.

One final note: if we use an alkyne where both ends are directly attached to carbon, we will obtain a mixture of products. That’s just “Markovnikov’s rule” – remember that if each carbon in the multiple bond is attached to an identical number of hydrogens, then we can’t determine which is the “most substituted” for our purposes. Like in this example.

Do you ever study by making flashcards of reactions?

You might recall that a few months ago Rich Apodaca (of Metamolecular) and myself released the first version of The Organic Reactions Flashcard App for iPhone, a mobile app for learning organic chemistry reactions.

That initial version of Flashcards was pretty basic – 25 reactions and very little in the way of user control over the content. Those who tested this free app told us that it had the potential to be a great app, but it needed

1. more reactions
2. more control over the flashcards they could test themselves on
3. some way of recording their progress.

Ask and you shall receive. Today, Rich and I are excited to announce the newest version of Organic Reaction Flashcards, and it is significantly better in every way.

Here’s the details:

1. More Reactions

Our goal was to build a reasonably comprehensive set of flashcards for first semester organic chemistry. With a total of 100 individual reactions covering 8 major categories,  I believe that this version of Flashcards lives up to the requirement. The content of the app covers the reactions covered in the first 10 or so chapters covered in most organic chemistry textbooks.

This includes reactions in the following categories:

• substitution reactions (S_N1 and S_N2)
• elimination reactions (E1 and E2)
• addition reactions to alkenes
• reactions of alkynes
• acid-base reactions
• rearrangement reactions
• free radical reactions
• reactions of alcohols

There’s also much better organization. The first version of Flashcards had no set organization whatsoever – it was just a stream of flashcards. In this version, the 100 reactions are arranged into categories according to functional group class, making chapter-specific testing a snap. So if you want to test yourself only on alkenes, or just on rearrangement reactions, that’s now extremely easy to do.

2. Customization

Is a certain reaction is giving you a hard time? Flag it! This puts the reaction into a custom deck that you can test yourself on at will. When you feel that you understand the reaction well enough, simply un-flag to remove it from the custom deck.

Furthermore, it’s likely that some of the reactions in the app are reactions you might never see in your course. For example, maybe you don’t need to know the free-radical reaction of HBr to alkenes right now. If you don’t want to have this particular reaction come up, it’s easy to remove it from circulation with a simple tap. If things change and you later realize you do need to test yourself on it, bringing it back is easy to do.

3. Self testing

The testing aspect of Flashcards is one of its most impressive features. After you see a flashcard, the gesture you use to advance to the next card tells the app how you did (up or right for correct, down for incorrect). Flashcards keeps score. With a series of color coded lists, the app tells you what you’re doing right and where you need to improve. See the list of reactions below: it looks like we’re doing OK with acid-base, but our alkene and alkyne chemistry needs work.

Furthermore, each reaction represents three different testing opportunities – to learn the starting material, reactant, or product. When setting up a new test, you can choose which of these variables you’d like to hide. This lets you learn new reactions forwards and backwards (or both at the same time!) depending on your preference.

In Summary: 

• IF you find that you learn well through flashcards, and
• IF you would like a means of testing yourself on 100 of the most important reactions in Org 1…

…you should visit the App Store and download the Organic Reaction Flashcards app.

If you have a chance to use it,  please rate it and let us know how it works for you. We’d like to know how to make it even better.

One note – unlike the initial test versions, Organic Reaction Flashcards  is no longer free. This is a genuinely useful stand-alone app that required significant development time. Charging for its use reflects that. Your support will help us toward the goal of building other great apps for learning organic chemistry.

Organic Reaction Flashcards On The App Store

Alkynes bear many similarities to alkenes, but as we have already seen, their chemistry can differ in subtle and interesting ways. Today’s post is another case in point.

The reduction of alkenes by hydrogen in the presence of a metal catalyst (“catalytic hydrogenation”) is a time-honoured reaction recognized by Sabatier’s receipt of the Nobel Prize for Chemistry in 1904. Incidentally, the products of this reaction are a part of our daily lives – modern margarine is produced from hydrogenation of vegetable oils for example [Trans-fats are an unfortunate byproduct of catalytic hydrogenation].

Bearing two carbon-carbon π bonds, alkynes may likewise be hydrogenated. Under conditions used for the hydrogenation of alkenes, both bonds are reduced, producing alkanes. [You would be reasonable to think you could prevent over-reduction simply by only using one molar equivalent of hydrogen gas; in practice, this doesn't work very well ]

If that’s all there was to the hydrogenation of alkynes, we’d quickly have to move on. The chemistry of alkanes, is – to put it bluntly – kind of dull*, and although reduction of alkynes to alkanes certainly has its place, you won’t find many reactions in organic chemistry which begin with alkanes. If you think of functional groups like airports, with all the reactions they can perform like flights that connect them to other hubs, a reaction that leads only to alkanes is a bit like taking a one-way flight to Saskatoon, Saskatchewan. Not nowhere, mind you, but a little far from the action.*

That’s not the whole story, of course. Imagine for a second that instead of hydrogenating both double bonds, we’d be able to stop at hydrogenating just one. This would allow us to convert alkynes into alkenes. Using the “functional groups as airports” analogy, a reaction that produces alkenes is like flying into O’Hare: as we just saw in the previous series, this will give us plenty of subsequent options in synthesis, as there is an extremely rich variety of alkene addition reactions.

As it turns out, because the second π bond of alkynes is not quite as strong as the first [approx 46 kcal/mol vs 68 cal/mol], conditions have been found that allow for the partial reduction of alkynes.

For our purposes there are two ways to do this.

The first, catalytic hydrogenation, operates on the same principle as described above: treatment of the alkyne with hydrogen gas and a metal catalyst. The trick, however, is to modify the behavior of the catalyst such that it is powerful enough to reduce the first  π bond but not reactive enough to affect the second. In other words, “poisoning” its reactivity. In practice, this is done by combining palladium on carbon with lead carbonate (PbCO₃) and quinoline (an aromatic amine). The resulting mixture, known as “Lindlar’s catalyst” after its inventor, is effective for the partial reduction of alkynes.

Note the stereochemistry! Just as in conventional alkene hydrogenation, both hydrogen atoms are delivered in syn fashion to provide us with the “cis” (Z) alkene.

There’s another way to reduce alkynes that doesn’t involve catalytic hydrogenation. As described in this old Reagent Friday post, sodium metal in ammonia (Na/NH₃) can also reduce alkynes to alkenes. This process is called dissolving metal reduction. It’s a different process than catalytic hydrogenation. In this reaction, electrons from Na metal sequentially add to the alkyne, resulting in an anion that is protonated by the NH3 solvent. An interesting facet of this reaction is, again,  the stereochemistry: due to electronic repulsion, the geometry of the resulting alkene is trans [for the full mechanism see this post].

So the bottom line here is that through using different reducing agents, we can obtain alkenes of different geometries. This might not seem like such a big deal at the moment, but it will have very important consequences for subsequent reactions – stay tuned. I’ve said this before and no doubt I’ll repeat the same comment: stereochemistry is one of the key testable concepts in Org 1, and the reactions of alkynes are a key component.

—–

* Modern advances in C-H activation chemistry excepted, of course

With the series of posts on alkenes in the can, let’s move on and talk about a closely related functional group that shares many reactions in common with alkenes: acetylenes, or as they are more commonly referred to, “alkynes”.

Alkynes, as we shall see, do share many reactions in common with alkenes. However there are some reactions of alkenes which do *not* work for alkynes (dihydroxylation with OsO4 and epoxidation with peroxyacids to give two examples), and conversely several reactions which only apply to alkynes and not to alkenes.

Today we’ll introduce two reactions that are of key importance for alkynes – and don’t have a corollary in alkene chemistry (as far as we’re concerned, anyway).

Let’s start with an important fact. Alkynes are unusually acidic hydrocarbons.  Recall that the acidity of a compound is related to the stability of the conjugate base. In an alkyne, where the carbon is sp hybridized, the lone pair resides in an orbital with 50% s character [the 2s orbital is closer to the positively-charged nucleus than the 2p orbital, increasing stability]. Compare that to alkenes (sp², 33% s-character) and alkanes (sp³, 25% s character) and we have an explanation as to why alkynes have a pKa of 25, which is a factor of 10¹⁷ more acidic than your typical alkene (pKa about 42) and 10²⁵ more acidic than alkanes (pKa 50).

This means that alkynes can be deprotonated without resorting to heavy artillery (i.e. organolithium bases, or Schlösser’s base - not that you probably need to know about that particular reagent) required to deprotonate alkenes. Instead, readily available sodium amide (NaNH₂) the conjugate base of ammonia (pKa 38) can be used, which is a big plus for convenience.

Deprotonation of alkynes with a strong base yields the conjugate base, often referred to as an “acetylide” :

So that’s certainly one way in which the chemistry of alkynes is distinct from that of alkenes: alkynes can be readily deprotonated.

Knowing that, care to take a guess what the next extension of this is? You might recall that in all cases that the conjugate base is a stronger nucleophile. And almost every reaction in organic chemistry involves the attack of a nucleophile upon an electrophile. So one logical application of being able to deprotonate alkynes into acetylide ions is that they are excellent nucleophiles and we can combine them with various electrophiles. 

One of the simplest and yet most powerful reactions in terms of generating a diverse array of functional groups is the SN2 reaction, in which a nucleophile attacks a carbon with a good leaving group (alkyl halides or sulfonates). The “big barrier” to the SN2 is steric hindrance so the reaction works particularly well for methyl and primary alkyl halides (secondary alkyl halides are a bit iffy in this context).

Here’s an example of how the SN2 can be applied to alkynes.

It’s a typical substitution reaction: we’re forming and breaking a bond on the same carbon.

Now comes the important part. This SN2 reaction is particularly useful.

Notice the type of bond that’s being formed  here: we’re forming a carb0n-carbon bond. If you’ve read previous posts leading up to this one, scratch your head for a moment: can you think of any examples where we’re forming a carbon-carbon bond? Probably not! [one example is cyanide ion with an alkyl halide].

Why is this important? Consider that organic chemistry is the study of carbon containing molecules. The reaction of acetylides with alkyl halides, therefore, is a way of extending the carbon skeleton of the molecule. We haven’t yet learned any other reactions that perform this function nearly as well. 

If you are studying alkynes, it is likely that in the near future you will be asked to solve  ”synthesis” problems, where you build more complex molecules out of simpler parts. The SN2 reaction of acetylides with alkyl halides often plays a pivotal role, since it allows for the extension of the carbon chain. So pay particular attention to it!

In the next post, we’ll talk about some other reactions that are unique to alkynes, and see – once again – how stereochemistry can rear its ugly head.

In this post we’ll do a final review of alkene addition reactions and sum up the three major pathways (and two minor classes of reactions worth paying attention to).

Reaction Pathway #1 – The Carbocation Pathway

In the Carbocation Pathway, the alkene acts as a nucleophile and attacks an electrophile, resulting in the formation of a carbocation. The regioselectivity is Markovnikov and the stereochemistry of the reaction is a mixture of syn and anti products. Since carbocations are formed, be alert for rearrangements ! This is the only family where this can happen.

Reaction Pathway #2 – The 3-Membered Ring Pathway

In the so called  ”3-membered ring pathway” the alkene attacks an electrophile and forms a 3-membered ring intermediate. This intermediate is then attacked at the most substituted carbon by a nucleophile via a backside attack, giving rise to anti stereochemistry:

Reaction Pathway #3 – The Concerted Pathway

The “concerted” pathway is not meant to describe a single reaction mechanism, but it does describe similar consequences. In this class of reaction the regioselectivity is generally not relevant (except for hydroboration with BH3, which is anti-Markovnikov). The stereochemistry of the reaction is syn, meaning the two new bonds form on the same face of the alkene.

Two Miscellaneous Minor Pathways

In addition there is a fourth pathway which goes through a free radical addition of HBr in the presence of peroxides. The regiochemistry is anti-Markovnikov and the stereochemistry is a mixture of syn and anti.

Finally in the presence of strong oxidants such as KMnO4 or O3 alkenes undergo a reaction called oxidative cleavage which results in the complete breakage of C=C to form carbonyl compounds.

This sums up the series on alkenes for now. In the next series, we’ll go through the reactions of alkynes.

Today’s post represents not so much a pattern in alkene reactions, so much as it does a very common reaction that bears mentioning along with the rest. What makes this reaction special is that it does not simply break the carbon-carbon π bond, as we have been accustomed to seeing, but additionally breaks the C-C σ bond as well.

This type of reaction is known as oxidative cleavage [i.e. cleavage of bonds, occuring with oxidation] and the most prominent example of an oxidative cleavage reaction is ozonolysis. 

As mentioned on one Reagent Friday back in the day, ozone does more than absorb UV radiation in the upper atmosphere and cause breathing problems in traffic-clogged cities. It’s a powerful oxidant, and since its discovery in the mid 1800′s by (Schönbein) has found use in the cleavage of carbon-carbon multiple bonds.

Here’s the pattern for the reaction of alkenes with ozone:

Note that the carbon-carbon double bond is broken and we are forming a carbon-oxygen double bond on each of the two carbons that originally composed the alkene. The second step in ozonolysis is called the “workup”. There are two different types of “workup”, and the most common is referred to as “reductive workup”. In this step, we add a reducing agent (commonly zinc metal or dimethyl sulfide) that decomposes the intermediate formed at the end of the ozonolysis reaction (called an “ozonide” by the way). If you’re wondering where the third oxygen of ozone went – it’s now attached to what used to be our reducing agent (making either zinc oxide (ZnO) or dimethyl sulfoxide (DMSO). [For more details / mechanism everything is written out in this post.]

Using “reductive workup” preserves all other aspects of the molecule save the double bond. So if we start with, say, a trisubstituted alkene, as in the example below, we will end up with a ketone and an aldehyde. [What happens if the alkene carbon is attached to two hydrogens? It becomes formaldehyde, which is then further converted to carbon dioxide]

Note that although I’ve written (CH₃)₂S as the reductant here, it’s essentially interchangeable with Zn for our purposes.

An interesting consequence of ozonolysis is that if the alkene is within a ring, you end up with a chain containing two carbonyls:

If your molecule has multiple alkenes, then you will end up with more than two fragments. For many years ozonolysis was used as a method for the structure determination of unknown molecules. By analyzing the fragments it is then possible to deduce what the original structure was, through “stitching” together the fragments. [This was particularly important in the case of unsaturated molecules known as terpenes]. Here’s one example:

This isn’t the end of the story with ozonolysis. There’s a second type of workup that can be used, referred to as oxidative workup. Instead of using Zn or S(CH₃)₂, if we use the oxidant hydrogen peroxide [H₂O₂], any aldehydes that form will be oxidized to give carboxylic acids. Like in the example below – notice that the green C-H bond is oxidized to C-OH  [but all the other hydrogens remain intact ].

An alternative to using ozone for oxidative workup is to use the reagent KMnO₄ , especially in the presence of hot acid; this will lead to the same result.

This is the last category of important alkene reactions we’ll cover for now in this series; in the next post we’ll wrap up the reactions of alkenes with a summary post.

NEXT POST: Summary of Alkene Addition Reactions

Here’s another great example of how one reagent used in a certain context performs one thing, and in a different context performs a completely different task. These are the types of inconsistencies which lead students to find organic chemistry difficult, and in many cases to mistakenly believe that it is arbitrary. It is not.

First example. In Org 1 we learn that alkenes can be converted to alcohols when treated with aqueous acid (i.e. H3O+) :

Although these technical details are never mentioned, the laboratory procedure for this reaction  involves treating the alkene with concentrated acid, often at high temperatures [edit: see link in comments for a specific example, done with cooling, not heat. Thanks to Mary Beth for the suggestion] Somewhat forcing conditions, in other words.

All’s well and good. However, skip ahead a semester, to the addition of Grignard reagents to ketones. After the Grignard reagent adds to the ketone, we add H3O+ in a “workup” step to protonate the negatively charged oxygen (alkoxide) to give the alcohol.

Although often not mentioned, in practice, this is done with dilute acid, at room temperature, and briefly (often in a separatory funnel). Mild conditions, in other words.

I recently met a student who was confused by the following problem:

See the issue? We are doing a Grignard in the presence of an alkene. How is the student supposed to know that the second step is merely a workup step and not a hydration of the alkene?

One answer is, “experience”. If you do enough Grignard problems, you see that H3O+ step at the end and you come to associate it with working up a Grignard.

A second answer is “context”. If one is doing problems from a chapter on Grignard reactions, it’s unlikely (although still possible) that alkene addition reactions will be thrown in there alongside.

Regardless, there is an aspect of ambiguity in the use of H3O+ in these two contexts. It’s not unreasonable to suggest that adding the word “workup”  or “dilute” in the case of the second reaction would in some cases  prevent the type of error shown here.

I’ve written that there are three major alkene reactivity patterns [carbocation, three membered ring, and concerted], but there are two minor pathways as well. This post discusses one of them.

As discussed previously, alkenes normally react with HBr to give products of “Markovnikov” addition; the bromine ends up on the most substituted carbon of the alkene, and the hydrogen ends up on the least substituted carbon. However, something interesting happens when the same reaction is performed in the presence of peroxides and  heat / light: the pattern of addition changes! Instead of Br ending up on the most substituted carbon of the alkene, it ends up on the least. [The stereochemistry of the reaction, however, is unchanged: it still gives a mixture of "syn" and "anti" products.]

This so-called “anti-Markovnikov” addition is intriguing. What difference could the presence of peroxides, and furthermore heat (or light) make to this reaction?

To make a long story short [not much mention of free-radical addition reactions have been made yet on this blog, so you'll have to pardon the lack of lead-in], this reaction occurs through a free-radical process.  Here are the essential details:

• Peroxides contain a weak oxygen-oxygen bond [approximately 35 kcal/mol;  compare to C-H at approx 100 kcal/mol]
• Heating leads to homolytic fragmentation of this bond – that is, the bond breaks such as to leave one unpaired electron on each atom. Strong sources of light [e.g. a floodlight or other source of light radiation which reaches into the near UV] can also serve to sever this bond.
• The resulting highly reactive alkoxy radical can then abstract a hydrogen from H-Br, giving a bromine radical. This is the species that adds to the alkene.
• Addition to the alkene will preferably occur in such a way that the most stable free radical is formed [in our case, the tertiary radical]. That’s why bromine ends up on the least substituted carbon of the alkene. 
• This tertiary radical then removes hydrogen from H-Br, liberating a bromine radical, and the cycle continues.

Note that only a trace [catalytic] amount of peroxide is required to get the reaction started, although of course at least one molar equivalent of HBr is required to result in full addition of HBr to the alkene.

Here it is, Chemdrawed:

This initiation step results in homolytic cleavage of O-O. The singly barbed arrows depict the movement of single electrons; two alkoxy radicals are formed. Common “peroxides” for this purpose are t-butyl peroxide or benzoyl peroxide. * [Note 1]. Alternatively other free-radical “initiators” such as AIBN can also be used.

Only a catalytic amount of peroxides are used to initate this reaction (typically 10-20 mole %, although more can be used, especially when added batchwise) , because the next step is for the peroxy radical to remove a hydrogen from H-Br:

Once formed, the bromine radical can then add to the alkene, from either face. Addition occurs in such a way as to give the most substituted radical (tertiary in this case, not secondary).

Finally, the tertiary radical then removes a hydrogen from another equivalent of H–Br, giving the final addition product. A bromine radical is generated by this process, which can then add to another equivalent of alkene.

Note that hydrogen here can attack either face of the free radical [note 2]. Therefore we obtain a mixture of syn and anti products.

This reaction pathway is most commonly observed (in Org 1 and Org 2, anyway) for addition of HBr, although a rich chemistry of radical addition reactions to alkenes exists (particularly for organostannanes).

NEXT POST: Ozonolysis of Alkenes

* Note. Benzoyl peroxide enjoys a common household use as an acne cleanser, and even makes an appearance in this classic ad.

**Note 2. The geometry of free radical carbons is that of a  shallow pyramid with a low barrier for inversion, allowing for reactivity on either face. The exception is in weird cases where inversion would be highly disfavored, such as on a bridgehead.

The other day while going through Claisen condensations with a student, we came upon this pretty typical problem:

The student duly deprotonated the alpha carbon of the ester to give the enolate, but stopped there. “Since there’s just one molecule of ester, I’m not sure what it’s supposed to do next.”

I explained that it’s safe to assume that we’re doing this reaction on about a mole of the ester, which means that there are about 6 x 10²³ other molecules of ester to react with. So even though “2 equiv” isn’t written, you’re supposed to do a Claisen condensation with another molecule of ester, to give you this product:

A few minutes later, we then came across this similar problem:

As before, here we deprotonate the carbon next to the ester to make the enolate. If we were to follow the logic from the previous question, we’d then perform a Claisen condensation with another molecule of the ester to give us the final product. But that, of course, isn’t what happens. Instead, the enolate adds to the ester carbonyl on the other side of the molecule, to give the 5 membered ring:

Why does it react with itself, rather than with another molecule of the starting ester? Because the ester carbonyl 4 bonds away from the enolate has a higher effective concentration, relative to the starting ester. Therefore the intramolecular reaction here is faster than the intermolecular reaction. [This is also the case when six membered rings can be formed, but not in the case where rings smaller than 5 (ring strain for 3 and 4- membered rings) or greater than 6 (ring formation starts to slow down as the reactive ends get farther apart).

Is there any other undergraduate subject which presents students with dilemmas like this, where one set of rules applies in one instance, but can be overridden by a different set of rules in another?

I could sense the frustration from the student. He’d been through nearly two semesters of organic chemistry, to the point where he was starting to feel reasonably comfortable with the course material. Yet here was yet another rule to learn, yet another exception to take note of, yet another snake hiding underneath what seemed like a perfectly innocuous rock.

“It’s almost an exercise in mind reading”, he said. “How are you supposed to know?”

We know this through experiment – and unless you do the experiment yourself, you’re going to have to rely on what you’re told in your class (or in textbooks). The reality is that hanging one little variable – like chain length – can drastically affect the outcome of the reaction. Organic chemistry is deep like that.

For someone who is just trying to get through organic chemistry in order to graduate, or needs organic chemistry for nursing, PA or nutrition school, and comes across a problem like this – they have my sympathy. They are right: organic chemistry has a lot of exceptions and tiny rules to learn, and it can be frustrating.

However, for someone who is thinking about a career in medicine - this is nothing compared to how complicated medical diagnosis can be, when you have to think across multiple variable sets and make judgements where the outcome could be life or death. So with pre-med students who encounter this type of situation- the unexpected outcome, where all our previous rules don’t apply –  this is reality. And reality doesn’t care if you think it’s unnecessarily hard or not.

For some perspective on this from a physician’s perspective, see this fascinating post by Luysii where he walks through the thought process of a physician charged with the care of a diabetic patient who has just been infected with swine flu.

Up to now, drawing out reaction mechanisms using the curved arrow formalism has been fairly straightforward. Yes, sometimes there is some ambiguity with respect to which carbon of a C-C π bond is forming a new bond to an electrophile, but that can be readily solved by adding a few guidelines.

Electrons flow from areas of high electron density to areas of low electron density. The arrow pushing formalism has been crystal clear up till now in helping us identify which atom/group in a reaction is the nucleophile, which is the electrophile, and which is the leaving group. Here’s an example:

Ideally, we’d like to be able to draw all of our mechanisms like this. Take the formation of a bromonium ion through addition of Br₂ to an alkene. Based on every single arrow-pushing example we’ve seen up until now, it might seem reasonable to draw the mechanism like this:

There’s just one problem with the way this mechanism is drawn, above. It implies the existence of a free carbocation. And that doesn’t correspond to reality.  We know that free carbocations aren’t involved in brominations* see here. So even though it might be more “convenient” to draw the mechanism this way, we must throw it out and try something else.

So how might we adapt what we know about the mechanism of bromination to the curved arrow formalism? Here’s one attempt.

Do you see the little dilemma that crops up when we have to draw an arrow pushing mechanism with a concerted addition to an alkene like this one?

There’s a “fork” in the flow of electrons. The Br on the left is involved in three separate arrows. 

It would appear that the C-C π bond is acting both as a nucleophile (attacking Br) and an electrophile (accepting a pair of electrons from Br). Furthermore, the Br is acting both as electrophile (accepting a pair of electrons from the π bond) and nucleophile (donating a pair of electrons to the π bond). Only the role of the second Br is clear. It’s the leaving group!

For concerted reactions of alkenes, we’re going to have to give up our cherished habit of being able to clearly trace the flow of electrons from nucleophile –> electrophile –> leaving group. It’s the price we pay for making our curved arrow mechanisms accurately portray reality.

This goes for certain other “concerted” mechanisms as well – epoxidation and cycloropanation being two prominent examples.

In the next post we will talk about a fourth (although quite minor, for us) reaction pathway for alkenes.

NEXT POST: A Fourth Alkene Addition Pattern – Radical Addition

——-FOR THE CURIOUS ——-

How might we resolve the role of “nucleophiles” and “electrophiles” here? This is not easy, because it entails making further assumptions about the reaction mechanism that might not be based on solid evidence. With that hedge out of the way, here’s a proposal. : instead of thinking of C-C π and Br monolithically,  break down each component into molecular orbitals. The C-C π orbital could act as a nucleophile while the C-C π* acts as an electrophile; the Br-Br σ* orbital could act as an electrophile while the Br lone pair could act as a nucleophile.

As it turns out, calculations indicate the bromination of alkenes with Br2 to be more complex than we might initially suppose. The initial step is coordination of Br₂ to the alkene in a loosely bonded structure known as a “π complex”. The π complex then breaks down to give the bromonium ion. A proper treatment of the orbitals would therefore not strictly be of the alkene and Br₂, but of the orbitals in the π complex itself.

It gets more complicated. In some solvents it turns out to be energetically favorable for a second molecule of Br₂ to be involved in bonding to the Br- that is expelled in the process (yes, a “termolecular” mechanism). For more details see here (J. Phys Chem A, 2007, 111, 13218)

*Most brominations. Where a particularly stable carbocation can be formed – say, in the bromination of trans-4-methoxystilbene – carbocation intermediates are energetically accessible, and the stereospecificity of the reaction breaks down.