If you have a weak base, you might want to drop out of the race and let a nucleophile take your place! No need to feel bad for this LEAVING GROUP, good ones are happier by themselves, so whoop-dee-doop! But if the colleagues are sad to watch it go, that NUCLEOPHILIC SUBSTITUTION might be a no-go!
Like a LEGO set, sometimes you have to take things apart to put them together in different ways. but if you only want to change a part of it you don’t have to take apart the whole thing – instead just break off the part to swap out and put on the part you want.
Similarly, the “LEGO pieces” of molecules are atoms and they come in different “shapes & sizes” (different elements, like carbon (C), hydrogen (H), oxygen (O), & nitrogen (N)). Instead of bumps and holes, they have negatively charged subatomic particles called electrons that they can share to link together in different ways to give you different things.
But just like LEGO pieces have a limited # of bumps & holes, atoms have limited numbers of electrons and places to put them. So sometimes you have to break off part of a molecule if you want to add on something new. But unlike with LEGOs, what they form is up to the pieces not you!
So what if any swap will be made depends on the pieces themselves. One piece (which can be part of a group) will serve as an “initiator” and go in & attack at a “weak spot” on another group of pieces, knocking off part of that other group and latching on itself. But in order for this to be a favorable reaction, the attacker has to have a reason to attack (it has to be unhappy with its current conditions and think that it’s found better ones) & the kicked off part has to be ok on its own. So the less happy the attacker is on its own, the more likely it is to attack. And the more happy the kicked off part is on its own, the more likely the attack is to be successful.
When it comes to the initiator, we’re often talking about NUCLEOPHILES. These are atoms that have more (negatively-charged) electrons than they can comfortably handle – they seek out something positive (at least partly-positive) to share that negative charge with and where can you find positiveness? The nucleus! That’s the central part of an atom where the positively-charged protons hang out (along with the neutral neutrons). more on atoms: http://bit.ly/2wvkWWv
*All* atoms have protons (and the # of protons defines the element – e.g. whether something is a carbon (6 electrons) or an oxygen (8 electrons)). But NOT all atoms are willing to take on the nucleophile’s negativity. Instead, the nucleophile needs to find something that wants some negativity, and we call things that fit that bill ELECTROPHILES (electron-lovers).
Why would something want electrons? If they’ve “lost” some giving them a “full” charge imbalance (overall #protons > overall # electrons), making it cationic (+-charged). Or if the electrons are still there in the molecule but hanging out with neighboring parts of the molecule more.
In biochemistry, nucleophiles can be found in places like hydroxyl (-OH) groups (especially when they’ve been “de-H-ed” giving them a negative charge that makes them more unhappy in their current conditions. These OH can be “free-floating” as hydroxide ions (OH-) or sticking off of bigger molecules like proteins or sugars. more on nucleophiles: http://bit.ly/2L9Zyga
And they often find electrophilic partners in molecules with major electron-hoggers. We call such hoggers electronegative and O & N are major culprits. A common biochemical electrophilic site is the carbon of a carbonyl group (a C=O) – great for making and breaking links to carbon, which forms the skeleton of most of the molecules in our body but is typically unreactive if left alone (just ask the diamonds!)
Another common electrophilic spot is one that is super useful but can evoke a “wait, what?” response at first glance – the P in phosphate groups like you find in the backbone of nucleic acids (DNA & RNA) and their nucleotide letters – the P in ATP, GTP, CTP, TTP, & GTP. The understandable confusion comes from the fact that phosphate groups are negatively-charged – *overall*, but not the phosphorus! A phosphate ion has a phosphorus atom hooked up to 4 oxygen atoms. And each of those oxygens is pulling electrons away from the phosphorus. So even though the phosphate is – overall the phosphorus at the center is partly positive. And thus electrophilic and attractive to nucleophiles.
This is useful for getting nucleotides to link up to “write” chains of nucleic acids with them (where the leaving group is the phosphates) but if the leaving group is part of the the chain you get breakage. Which is part of the reason why RNA is less stable than DNA. The O in it’s “Extra leg” can act as nucleophile and attack the phosphate, leading to chain breaking. Sometimes though you want to cut nucleic acids at specific sites, so enzymes like RNAses can use nucleophiles in their active sites. more here: http://bit.ly/2TFdQN9 & http://bit.ly/2XHJKWa
So now that we’ve looked at why something would want to seek out a new home & where it might find one, let’s regroup then look at the “tenants” that have to get evicted – the LEAVING GROUP
If you want to swap out chemical groups (atoms or groups of atoms)(A + B-C ➡️ A-B + C), you have to get the new one to latch on & the old one to leave 👉 a common way to do this NUCLEOPHILIC SUBSTITUTION 👍
The attacking group (A) is called a NUCLEOPHILE (sometimes abbreviated Nü) & it attacks an initial SUBSTRATE molecule (B-C) ⏩end up with a PRODUCT (A-B) & a departing group (C) we call the LEAVING GROUP (LG) 👍
They can either do this “at the same time” (new group “attacking” from the back & old group leaving from the front in a concerted fashion ☂️) in which we call it an SN2 reaction 👍 OR in 2 steps 👉old one leaving BEFORE new one joins on in which case we call it an SN1 reaction 👍
🔹 SN1: A + B-C -> A + B + C- -> AB + C
🔹 SN2: A + B-C -> [A- – B – -C] -> A-B + C
The bonds being broken are strong COVALENT BONDS, where 2 atoms share a pair of electrons (e⁻) 👉 when the LG splits 👋 it takes BOTH these e⁻ with it, ⬇️ its charge by 1 👉 so if it were neutral when attached it becomes negatively charged (anionic) ➖⚡️ & it were ➕ charged it becomes neutral 👍
👉 it’s a HETEROLYTIC cleavage 👉 “hetero” meaning different & “lytic” for split bc the 2 parts split the e⁻ they shared “differently” 👉the LG takes it all (ABBA flashbacks anyone? 👩🎤)
Whether a rxn occurs depends on a lot of things including how attracted the new group (Nü) is to the thing it’s adding to (substrate) & how stable the LG is on its own. Being a “better LG” means that if it breaks free, it’s still happy 😃 It doesn’t “need” the thing it was attached to to be stable 👍
And when it leaves it makes the thing it was attached to more attractive to the new group 😍 For example, an LG might leave behind a ➕⚡️ that attracts a new group with a ➖⚡️ Carbon (C) is often used as the basic “skeleton” for molecules, so we’re often talking about groups leaving & joining Cs 👉 a LG might leave behind a ➕⚡️ C, we call a CARBOCATION 👍
Sometimes modifications are made to the “leaving-group-to-be” to make them better leaving groups 👉 we call this “activation” & we can use it to help “direct” the chemical building (synthesis) of new molecules by activating leaving groups at sites we want to swap out 👉 For example, hydroxyl (-OH) is a poor leaving group 👎 BUT adding acid to protonate it (add a hydrogen ion (H⁺)) gives you an oxonium ion (H₃O⁺) group that will happily break off as water (H₂O), freeing up valuable real estate for the new group 👍 In biochemistry, activation is often done by transferring ADP or AMP onto something.
How do you know if something’s a 👍 or 👎 LG? 🤷♀️ Because the LG is getting “extra” e⁻, it needs to be able to handle that extra negativity 👉 so you want to 👀 at what the LG would be & think about how well it could cope 💭 In general, the more electronegative (e⁻-hogging) it is, the better 👍 & the bigger the atom taking the e⁻ the better bc it can “spread out” the extra charge better 👍 & 💬 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 👍)
Another way to think of it is in terms of acids & bases – how much would the left group like help sharing its newfound electron with a proton (H+)? 👉 A good LG 👍 is the conjugate base of a strong acid (so a good leaving group is a WEAK BASE) 👇
Being a strong acid (in 1 definition) means something gives up an H⁺ easily 👉 when it does you get the conjugate base (the H⁺-less version of the acid) 👉 The acid will only give up the H⁺ if it’s stable without it (just like that same group will only leave a substrate if its stable without it💡) And if it’s stable without it, it’s less likely to want to act like a base (accept a H⁺) & take it back, so the conjugate base of a strong acid is a weak base & a weak base is a good LG 👍
So you can 👀 at a potential LG & consider what its conjugate acid would be (add a H⁺ ) ⏩ If that’s a strong acid (like H₃O⁺) you have a good leaving group (H₂O) 👍 but if it’s a weak acid, like H₂O, you have a poor leaving group (OH⁻) 👎 This is why the alcohol part of alcohols (the hydroxyl (-OH) group) doesn’t just “fall off”. BUT if you add an H⁺ to give you H₂O that *is* a good leaving group 👍 so you can remove that group & free up a spot for a new bonding partner 🤗
more on acids & bases:http://bit.ly/30qzHH6
some examples 👇
⭐️⭐️⭐️⭐️⭐️ excellent: TsO⁻, NH3
⭐️⭐️⭐️⭐️very good: I⁻, H₂O
⭐️⭐️⭐️ good: Br⁻
⭐️⭐️ fair: Cl⁻
⭐️ poor: F⁻
very poor: HO⁻, NH₃⁻, RO⁻
Sorry for mishmash of pics from past posts – just wanted to give a flavor of some examples