Organic Chemistry Acids and Bases #2

Which of the following types of reactions will be favored by t-butoxide reacting with a secondary halide? 

A. S_N2          

B. E2          

C. E1          

D. S_N1

Answer:  B

SHORT-AND-SWEET:

When it comes to the substitution and elimination reactions, which particular reaction will occur is largely determined by the attacking nucleophile/base, so always start there!  Our attacker is t-butoxide, a very bulky molecule, whose negative charge makes it a strong attacker.  But will it be a strong nucleophile or a strong base?  Most of the time, the basicity and nucleophilicity track together.  Rarely, however, this is not the situation.  T-butoxide is the perfect example!  Because it is so bulky, it will be very hard for it to get to the heart of the electrophile, and attack the carbon -- therefore, it is a weak nucleophile.  However, it will have a very easy time stealing a proton, which makes it a strong base.  

In general, a strong attacker will favor a single-step reaction (either SN2 or E2) -- a strong base will promote E2, and a strong nucleophile will promote SN2.  Because t-butoxide is such a strong base it will promote E2 (answer B).

If the attacker is not this strong, the other factors to consider are the bulkiness of the substrate (only SN2 will prefer a less bulky substrate), and the solvent.

THE WHOLE STORY:

The substitution and elimination reactions are reactions between nucleophiles and electrophiles.  Nucleophiles (Lewis bases) are the electron-rich molecules, and they love the positively charged nucleus, to which they like to donate their lone pair of electrons.  Electrophiles (Lewis acids) accept these electrons because, like their name suggests, they love electrons!

The best analogy for reactions between nucleophiles and electrophiles is between guys and girls.  The "attacker" is typically the guy -- let's call him Justin.  He is our nucleophile, and he approaches the electrophile, the girl -- we'll call her Jane.  Let's see what happens with Justin and Jane.....

In SUBSTITUTION, the end result of nucleophilic attack is that the nucleophile substitutes for a group on the electrophile, i.e. Justin substituting for Jane's boyfriend!  

•  In SN2, the nucleophile attacks the electrophile, at the same time kicking the leaving group out.  In this dramatic scenario, Justin walks in, and the boyfriend gets the boot, all at the same time! 
• In SN1, the leaving group leaves first, and the remaining carbocation is attacked by the nucleophile.  Here, Jane's boyfriend leaves first, and then Justin swoops in!

In ELIMINATION, the end result of the attack is the elimination of a group on the electrophile, with the formation of a new double bond.  In the Justin-Jane story, elimination would lead to the boot to the boyfriend, and Jane deciding to be single for some time! 

• In E1, the leaving group leaves first, leaving a carbocation.  The base comes next, stealing a proton from the carbon adjacent to the positively charged carbon, facilitating the double bond.  In our love triangle that translates into the boyfriend deciding to leave Jane, followed by Justin coming by and snatching....not Jane's heart, but Jane's friend, the proton!
• In E2, the base steals the proton and the leaving group leaves at the same time.  In this scenario, Jane's proton gets stolen by Justin, and her boyfriend leaves her.  That's what we call a bad day!

Why are there two elimination reactions and two substitution reactions?  The answer has to do with the kinetics!  SN2 and E2 have the 2nd-order kinetics, which means that the reaction rate depends both on the nucleophile/base, and the electrophile substrate.  Why?  Because these reactions occur in a single step, which has a high-energy transition state.  This "transition" molecule in which the bond between the nucleophile and electrophile is forming, and the bonds within the electrophile are breaking requires presence of both reactants at the same time.

On the other hand, SN1 and E1 have the 1st-order kinetics, and their reaction rate depends on the substrate only.  These reactions occur in two steps, the first of which involves only the substrate.  Only after the substrate had finished the first step does the nucleophile/base step in.

How can we determine which reaction will dominate -- substitution or elimination, first-order or second-order?  Often, it's enough to look at the ATTACKER (NUCLEOPHILE / BASE), so always start there!

Because the reaction rate in SN1 and E1 depends only on the substrate/electrophile, how good the attacking nucleophile is does not matter.  On the contrary, SN2 and E2 will happen only with a strong nucleophile/ base around.  Why?  If you have a strong nucleophile/base, it will not sit around waiting for the substrate to do the first step on its own.  A weak nucleophile/base will be perfectly content with twiddling its thumbs while the substrate completes the first step independently.  If our friend Justin is super cool and confident, he won't wait around for Jane to dump her boyfriend (or get dumped).  Oh, no, no, no!  He will step in and do what he's gotta do!  On the other hand, if Justin is not as confident, he'll be OK with letting Jane get rid of the boyfriend, and then he will come in.

Hold on for a minute!  We keep talking about Justin acting as a nucleophile and a base.  "The two are the same, right?", you ask.  Though they are frequently thought of as the same thing, they are not!  The difference between a nucleophile and a base is in what each wants: a base wants to bind a proton, and a nucleophile wants to bind a carbon atom.  Because a base comes just close enough to the molecule to snatch a proton (which usually hangs out peripherally), the bulkiness of a molecule will not affect how strong a base it is.  On the other hand, a nucleophile needs to attack the carbon directly, and if it has a lot of side chains, it can forget about it!  A way that we can tie this to our analogy is that Justin The Nucleophile is interested in getting to Jane.  Justin The Base is interested in getting anything -- he will be satisfied with the proton sitting on the side.

Because of this, the reactions preferred by a strong nucleophile will differ from reactions preferred by a strong base.  Because a strong base will be satisfied with snatching a proton and going about its business, it will prefer elimination E2.  A strong nucleophile will want to attack a carbon, so it will promote substitution SN2.

Remember:  if you have a STRONG nucleophile or a STRONG base, the reaction will go with the second-order kinetics (number 2 = SN2 or E2, respectively).

After analyzing the attacker, what should you look at next?  The SUBSTRATE -- its overall structure and its leaving group!

Side chains on the substrate/electrophile are like Jane's girlfriends -- they intimidate Justin!  Similarly, a bulky substrate, like a tertiary substrate, will not allow enough room for a nucleophile to approach and attack in the SN2 fashion.  A methyl or a primary substrate, on the other hand, will be very inviting for a nucleophilic attack.

A bulky substrate will be perfect for the first-order kinetics reactions, such as SN1 and E1, because these reaction involve carbocation formation.  A tertiary substrate, with multiple carbon side chains, will help pull away some of the positive charge, and will stabilize the carbocation.  And the more stable the intermediate, the more likely will the reaction occur.  Therefore, tertiary substrate (and resonance stabilization) are ideal for SN1 and E1.  It's like breaking up with a boyfriend or a girlfriend -- after that happens, it's nice to have friends around to cheer you up, right?

The tertiary substrate will work best for E2 as well, because it the most substituted alkene possible is preferred (Zaitsev rule), which is easiest to do with a tertiary substrate.

All four reactions require a good leaving group, a molecule that will be stable on its own when it leaves (read: a mentally stable person!  Otherwise, the boyfriend will cling on to Jane indefinitely!).  A good leaving group will be a weak base (a conjugate base of a strong acid).  Halides are great leaving groups, unlike -OH, -NH2, or alkoxides (RO-), which are terrible!

The last factor is the solvent in which the reaction occurs.  A solvent affects nucleophile strength.  Let's go back to Justin for a second.  Justin (whose last name is Bieber -- we forgot to mention, oops!), has his own girl fan base surrounding him at all times.  If he is attracted to these girls, what will happen with his interest in approaching Jane?  It will dissipate.  What if he is not so attracted to these other girls?  Well, that will help him be more determinate about approaching Jane.  Let’s look at an example of a reaction.  In a protic solvent (one that has -OH or -NH2 groups) SN2 is less likely to happen, because protic molecules create a cage around the nucleophile (attractive girls around Justin), making it less interested in attacking another molecule.  Therefore, aprotic solvent is perfect for SN2!  SN1, on the other hand, will be promoted by a protic solvent, which will stabilize its carbocation.


Let’s finally go back to our question, in which t-butoxide is attacking a secondary halide!  Where did we say you should start?  With the attacker!  Look at t-butoxide!  

t-butoxide is a negatively charged molecule, so it will want to bind something positive, either a proton or a carbon.  The former makes it a strong base, and a STRONG base  will favor the second-order kinetics, either SN2 or E2 (eliminate C and D).  But which one?  As a strong base it could undergo E2 easily.  What about SN2?  Because t-butoxide is very bulky – just look at those three methyl groups – it will not be able to squeeze in all the way to the carbon of the secondary halide, so there will be no substitution (eliminate A)!  Which is why it will sweep by, steal the proton, which will facilitate the formation of the double bond, and boot the leaving group out!  E2 is the correct answer (answer B).

THE BIG PICTURE:

1.  Difference between a nucleophile and a base --  a nucleophile wants to bind a carbon, and the base would rather bind a proton.  The former will promote substitution, and the latter will promote elimination.

2.  Follow the algorithm:  first decide between number 2 (SN2, E2) and number 1 (SN1, E1) by looking at the strength of the attacker.  A strong attacker (either a nucleophile or a base) will want to attack immediately, and will want to finish the reaction quickly, in a single step (NUMBER 2).  The opposite will happen with a weak attacker (number 1).  The next decision is substitution versus elimination.  A bulky attacker will prefer elimination. 


3.  The molecular structure tells the story!  Bulkiness means a lot of steric hindrance, not much room to work in (elimination sounds good in this scenario), but it also stabilizes your carbocation (SN1 works, also).

~The MCATPOD Team~