It’s a drizzly day and whenever I take out my umbrella I think about SN1 and SN2 reactions! In these Nucleophilic Substitution reactions, molecules divorce and marry and the ways they do it can at first glance seem scary. But I surely hope it can help you out hella if you picture an inside-outing umbrella!
Note: today’s post is especially in-the-weed-y but it’s written mainly for all those o-chem students who may be needy (though hopefully more broadly accessible too so I hope everyone will try to stick around…)
SN1, SN2, what’s it to you? You might have heard of “nuclear families” – but it’s really the electrons where the bonding happens! Molecules are made up of atoms of elements like carbon (C), hydrogen (H), and oxygen (O) which “marry” by sharing pairs of electrons – 2 for a single bond, 4 for a double, 6 for a triple.
Atomic polygamy is allowed – they can be married to more than other atom, but each atom is limited in how many electrons it can share, so in order to form new bonds they have to get divorced (with each taking their other partners with them). And there are different ways this can play out including NUCLEOPHILIC SUBSTITUTION, where a nucleophile (something that has “too many electrons” to handle) “marries” an electrophile (something that wants electrons).
More on nucleophiles and electrophiles here: http://bit.ly/nucleophilefiles
But today I want to talk about the actual reactions (marriages requiring divorces). The “new flame” is the nucleophile, the “original couple” is the substrate and the “dumper” the “leaving group” (LG)
So in the case of X + Y-Z –> X-Y + Z
our nucleophile is X, the substrate is Y-Z, and the leaving group is Z. I’m not using A, B, C because I don’t want you to confuse C for Carbon. Carbon puts the O in O-chem (we call molecules with carbon-based “backbones” organic so we’ll see C a lot!
LG’s can contain carbon, but they don’t have to – common ones you see in lab reactions are things like halogens (things in the second to last column of the periodic table (e.g. Cl, Br, I) or tosylates (OTs) & mesylates (OMs)
In an SN1 mechanism, atoms get divorced and then the atom that got dumped finds a new partner – a bond is broken before a new bond is formed. The reaction happens in 2 steps
SN1: X + Y-Z -> X + Y + Z- -> X-Y + Z
In an SN2 mechanism, one atom “has an affair” while it’s breaking things off with its old partner – a new bond is being formed at the same time an old bond is being broken. The reaction happens in a single step.
SN2: X + Y-Z -> [X- – Y – -Z] -> X-Y + Z
Where do the “SN1” and “SN2” come from? SN stands for Substitution, Nucleophilic and the # is the # of molecules in the rate-limiting step NOT the # of steps!
Ever been in a traffic jam that’s backed up for miles before the actual holdup? Chemical reactions can be like that too. If reactant supply isn’t a problem, the rate of a reaction is backed up by the slowest step, so we call that slow step the rate-limiting step.
What’s the holdup?
SN2 mechanisms only have 1 step (divorce WHILE marrying) so that step’s both the rate-limiting step and the fastest one. And the 2 in SN2 indicates bimolecular – the rate-limiting step involves 2 molecules – the original molecular “couple” and the “new flame” and the reaction rates depend on how much of both molecules (substrate & nucleophile) you have.
And the holdup’s how much the “new flame” wants to marry it (strength of nucleophile) and how well it can access it (if the nucleophile or the substrate are bulky it causes STERIC HINDRANCE that makes SN2 harder). So SN2 often involves non-bulky substrates and strong (often negatively charged) nucleophiles.
In contrast, SN1 reactions happen in 2 steps (divorce THEN marriage) so now we *do* have a rate-limiting step – but which step is rate limiting? The 1 in SN1 indicates unimolecular – it tells us the rate-limiting step involves a single molecule. And the step in our reaction that involves a single molecule is the divorce – you go from 1 molecular “couple” to 2 molecular “singles”
Since SN1 reactions have a single molecule in the rate-limiting step (the substrate) it’s the concentration of that molecule that’ll impact how fast the reaction goes (assuming you have enough nucleophile to keep up).
So the rate of an SN1 reaction will depend on how likely the molecule is to “get divorced” and that depends on a few things including how happy the “dumper” (LG) is on its own – the happier the better an LG it is. But it’s not “cruel” – it wants to make sure that the molecule it leaves behind can cope. What’s there to cope with?
When the LG leaves in these reactions, it does so through “heterolytic cleavage” – the “hetero” indicates “different” telling you that in the divorce, the electrons get divided up unequally, with the leaving group getting both of the shared pair – not because it has a better divorce lawyer but instead because it’s more electronegative (electron-hogging). Since it now has an extra electron, its charge decreases by 1 – so if it were neutral when attached it becomes negatively charged (anionic) & it were positively charged (cationic) it becomes neutral.
Earlier I talked about how we can think about valence electrons as dogs. http://bit.ly/2kytAkw
When the atoms get divorced, the LG takes both of the dogs so it has to be able to handle the extra responsibility. In general, the more electronegative (e⁻-hogging) it is, the better & the bigger the atom taking the e⁻ the better because it can “spread out” the extra charge better. And speaking of spreading out charge, resonance (where e⁻(s) are shared among multiple atoms) makes for a great LG as well (this is why triflate, tosylate & mesylate are good LGs. more about what makes a good leaving group here: http://bit.ly/2ADSbcH
And the “left” group has to be able to cope with having lost a dog. It’s 1 electron down, so its charge increases by 1 (going from neutral to + or – to neutral). When we’re dealing with organic molecules, often the atom getting dumped is a carbon. And that C was probably neutral, so now it’s positive, and we call a CARBOCATION (CARBOn CATION).
It’s better at coping if it has other partners to provide “emotional support” in the way of connected atoms sharing a bit of their electron density with them. H’s aren’t very good at this (they only have 1 electron), but C’s are much more helpful in this regard.
We often classify individual carbon atoms based on how many other C’s they’re bound to: when C is married to 3 Cs we call it tertiary (3°); 2’s secondary (2°) and a single C’d be primary (1°) (found at chain ends). You’ll also see 0 (so 0°)- like Methane (CH₄).
The non-C’s are often hydrogens, which are much smaller and “swappable” so a 3° C (C attached to 3 other Cs & 1 H) is much harder to access than a 1° (attached to 1 C & 3 H). So It’s harder for the nucleophile to get to, which is a big problem for SN2 reactions.
So, in terms of favorability for SN2: 1° >2°>>>3°
But a “benefit” of having already been dumped is that it leaves a bit more room around the C so bulkier nucleophiles are okay. And the 3° C has more friends to offer emotional support in the way of electron-sharing, so it can form a more stable carbocation and participate in SN1 reactions.
So, in terms of favorability for SN1: 3° >2°>>>1°
Another difference – since the nucleophile now doesn’t have to kick anyone off, it doesn’t have to be as strong as with SN2, so SN1 reactions can involve weak nucleophiles.
So 2 paths to X-Y + Z:
The SN1 way: X + Y-Z -> X + Y + Z- -> X-Y + Z
and the SN2 way: X + Y-Z -> [X- – Y – -Z] -> X-Y + Z
But is X-Y the same as X-Y? We need to talk STEREOCHEMISTRY – it’s not the chemistry of music stereos – instead, it refers to the arrangement of atoms in 3D space. If molecules are drawn with normal straight lines, they’re not meant to convey stereochemistry, just what’s attached to what.
If we want to show stereochemistry, we can use triangles that are shaded to indicate coming out of the page & dashed to indicate going into the page. And in this context, a “normal” line indicates in the plane of the page. More here: bit.ly/2Q8Dnax
If you think of the substrate as a room with 2 doors that you can come in and out of but only one person at a time…
In an SN2 reaction, the nucleophile is coming in as the LG is leaving, so they each have to go through separate doors. And there’s only 1 open for the nucleophile to chose.
In an SN2 reaction, you have what’s called backside attack and you get inversion of stereochemistry, like an umbrella turning inside out. Instead of wind attacking, it’s the nucleophile attacking – and all the other groups shift to accommodate it.
In an SN1 reaction, once the LG leaves, there are “2 doors” to choose from – the nucleophile can attack from either side, and the stereochemistry you end up with depends on which side the nucleophile attacks from. So you get a mix or inversion and retention. This can be a big source of annoyance if you’re trying to manufacture a pharmaceutical drug and half of it is “backwards”
That backwardness can make it inactive in our cells, where molecules are shaped to recognize a specific other shapes. In our bodies, these reactions are often happening with the help of enzymes, which hold the molecules in place to promote attacking the way you want so that you get the stereochemistry you want (e.g. L-amino acids). But when you’re synthesizing stuff without enzymes you often have to separate the stereoisomers afterwards.
Another thing to keep in mind is the solvent (the liquid all these molecules are dissolved in).
Remember how we needed a strong nucleophile to get SN2 because we have to actually kick something off as opposed to just wait for it to leave? Well, polar protic solvents can hydrogen-bond with the nucleophile, shielding it in a “solvent cage” and thus weakening its strength, making SN2 less favorable. So SN2 works better in polar Aprotic solvents (acetone, acetonitrile, dimethylformamide (DMF), dimethylsulfoxide (DMSO), etc.)
What about SN1? The nucleophile isn’t part of the rate-determining step, so it isn’t negatively impacted by protic solvents. And the protic solvents are often helpful for stabilizing the carbocation. So polar protic solvents (look for -OH and -NH es like in water, methanol, form amide, etc.) favor SN1.
- stereochemistry: mix of retention & inversion at chiral centers
- rate law: reaction rate only sensitive to substrate
- substrate preference: want stable carbocation 3° >2°>>>1°
- mechanism: stepwise mechanism: X + Y-Z -> X + Y + Z- -> X-Y + Z
- solvent preference: prefer polar protic solvents
- stereochemistry: all inversion
- rate law: reaction rate sensitive to concentrations of both substrate and nucleophile
- substrate preference: want less bulk 0° >>>1° >2°>>>3°
- mechanism: concerted backside attack mechanism X + Y-Z -> X + Y + Z- -> X-Y + Z
- solvent preference: favors polar Aprotic solvents
word of caution: be careful with “nucleophilicity” vs “basicity.” If an atom donates a pair of e to form a new bond to an H call it a “base” but link onto anything else (often carbon(C)) & we call it a nucleophile. The same thing can act as a “nucleophile” in some cases & as a “base” in other cases. So “basicity” in the Bronsted sense is a special type of “nucleophilicity.” And they don’t always follow the same trends. Much more here: http://bit.ly/2ZvFU7s
When nucleophiles act as bases, in addition to (or instead of) substitution you can get something called ELIMINATION. This is where, instead of finding a new partner, the dumped atom becomes decides to invest more in one of its other partners, forming a double or triple bond. so…
SUBSTITUTION: nucleophile attacks the CARBON in C-LG -> forms Nu-C bond -> R-LG bond breaks -> left w/ Nu-C & LG (C can form up to 4 bonds & the LG is just one “branch” so there are still 3 “branches”
ELIMINATION: base (B) attacks the HYDROGEN in H-C-C-LG -> forms B-H bond & breaks H-C bond -> the C “panics” because it’s left with extra electrons -> uses those electrons to form an even stronger bond with the carbon next to it -> C=C-LG now that 2nd carbon has too many bonds -> kicks off a LG -> C=C + LG + BH