Clutch Prep is now a part of Pearson
All Chapters
Ch. 1 - A Review of General Chemistry
Ch. 2 - Molecular Representations
Ch. 3 - Acids and Bases
Ch. 4 - Alkanes and Cycloalkanes
Ch. 5 - Chirality
Ch. 6 - Thermodynamics and Kinetics
Ch. 7 - Substitution Reactions
Ch. 8 - Elimination Reactions
Ch. 9 - Alkenes and Alkynes
Ch. 10 - Addition Reactions
Ch. 11 - Radical Reactions
Ch. 12 - Alcohols, Ethers, Epoxides and Thiols
Ch. 13 - Alcohols and Carbonyl Compounds
Ch. 14 - Synthetic Techniques
Ch. 15 - Analytical Techniques: IR, NMR, Mass Spect
Ch. 16 - Conjugated Systems
Ch. 17 - Aromaticity
Ch. 18 - Reactions of Aromatics: EAS and Beyond
Ch. 19 - Aldehydes and Ketones: Nucleophilic Addition
Ch. 20 - Carboxylic Acid Derivatives: NAS
Ch. 21 - Enolate Chemistry: Reactions at the Alpha-Carbon
Ch. 22 - Condensation Chemistry
Ch. 23 - Amines
Ch. 24 - Carbohydrates
Ch. 25 - Phenols
Ch. 26 - Amino Acids, Peptides, and Proteins
Ch. 26 - Transition Metals
Amine Alkylation
Gabriel Synthesis
Amines by Reduction
Nitrogenous Nucleophiles
Reductive Amination
Curtius Rearrangement
Hofmann Rearrangement
Hofmann Elimination
Cope Elimination

Concept #1: General Reaction


Let's talk about a really efficient way to make primary amines and that's through the Gabriel synthesis. So, guys the Gabriel synthesis is going to use a really weird-looking molecule called potassium phthalimide. Now, I know that's like a lot of consonants at the beginning, you could kind of get jumbled up there but just consider the ph almost be silent, it's phthalimide it's like, I don't know, you gotta move your looks a little bit weird on that one, anyway, the point here being that you need to recognize this molecule will not necessarily draw it from scratch. Now, the potassium phthalimide is a secondary diamide that can yield primary amines in much better yield. Now, obviously I'm talking about something that we haven't mentioned yet, in much better yield in respect to what? what is it better at making primary amines at? you know, then what's the other reaction that we're comparing it to? what I'm talking about here is amine alkylation. So, if you haven't watched this video yet, it's fine, but basically amine alkylation and Gabriel synthesis kind of are compare and contrast because there are two different ways to make primary amines and one of them is very inefficient, amine alkylation whereas Gabriel synthesis is much more efficient, if you haven't watched an amine alkylation yet, then, I mean, you can go ahead and review it but just letting you know, that's what I'm referring to, okay? So, this is going to be really our ideal way to make specific primary amines of our choosing. So, what you do is you take your potassium phthalimide or just phthalimide in general and you're going to use three reagents, you're going to use KOH, we're going to use an alkyl halide. So, I'm going to put here, a primary alkyl halide, that's going to become important in a second. So, I'm going to put here RX, primary alkyl halide and then finally we're going to use hydrazine. So, it's NH2, NH2. So that's called hydrazine, okay? And effectively what winds up happening is that these all serve like their own purpose, okay?

The KOH is going to turn deprotonate the nitrogen, okay? And it's going to turn the phthalimide into what we call potassium phthalimide, okay? So, potassium phthalimide would actually be what it's called after the first step. So, I'd have an N negative, k positive, okay? Now, this happens to be an excellent nucleophile because if you think about it N negative, that's one of the strongest bases that there are, that there is. So, it's going to be pretty good at deprotonating stuff attacking stuff etc. So, I'm going to put here strong nucleophile, okay? What's great about that is that now I can react this with an alkyl halide, let's say a primary alkyl halide like, here we go, you know, a 3 carbon alkyl halide and what we can do guys is just an SN2, so this is just another SN2 mechanism that you need to know, you can never forget the backside attack. So, via SN2 we can do a backside attack, kick out the chlorine, what I wind up getting is I wind up getting an R group. Now, whatever R group that was, let's just go ahead and draw a three carbon chain there but we've got a problem, we've got this great R group on the nitrogen, eventually the goal of this is to release the nitrogen from the phthalimide, I want to completely get rid of the phthalimide and just release this nitrogen, send it off the solution, that's my product, but how do I unlock the nitrogen from the rest of the molecule? guys, that's where the hydrazine comes in and that's going to be the complicated part of this mechanism. So, I'm just going to put here, plus N2H4, right? That's the molecular formula for hydrazine, I'm sorry, my head is in the way, plus N2H4 and what that's eventually going to yield as a product is this, N with my three carbon chain but now it has two hydrogen's, okay? Maybe you're thinking, is that hydrazine to protonate? Well, yes it protonates but it also serves to completely unlock it from the phthalimide, how does that happen? we're going to go to the next video and I'm going to teach you the full mechanism. So, you guys will not only have this like the shortened version, which should be sufficient for most applications, if you just want to know how the reaction is going to work but if you're asked to give the full mechanism, that's we're going to do in the next video. So, let's go ahead and scroll down and do the full mechanism.

Concept #2: Mechanism


Alright guys. So, for this mechanism, remember there's three steps, there's the KOH deprotonating the nitrogen or the phthalimide to make the potassium phthalimide then there's an SN2 back sided hat tap that happens with a primary amine and then there's the hydrazine reaction that's going to follow a mechanism that we're going to talk about. Now, I really just want to focus on the third step here, because the first two we already did on the top of the page. So, here I just want to focus on the third step, which is what happens when you introduce hydrazine to the nitrogen. Now, has an R group. Now, keep in mind for my reaction on top, I think I was using a propyl group, but this will be true of any R group that's attached to the nitrogen, what happens next, somehow we need to get this nitrogen completely off of the phthalimide. Well, this is where the hydrazine kicks in. So, guys the hydrazine is very nucleophilic because it's got these two nitrogens that both have lone pairs, right? On top of that phthalimide even though it's a weird molecule it has some structures you've seen before, for example, it's a diamide, so that means it can react, this carbon apartment can react like any amine would in the presence of a nucleophile and remember amides, if you haven't gone to the section yet, it's fine, but just let you know that amides are considered carboxylic acid derivatives, meaning they follow a mechanism called nucleophilic acyl substitution or NAS, okay? This is the topic of several videos that I have. So, if you want to brush up on NAS feel free to go through those videos and then you'll learn about how other amides react in similar situations. So, anyway guys how is this going to look like? Well, your nitrogen is going to do an NAS reaction forming a tetrahedral intermediate. So, what our tetrahedral intermediate will look like is like this O negative. Now, attached to NH2, NH 2. Now notice, this is going to be positive because now there's an extra bond to that nitrogen, then I've got the rest of the ring and R and my carbonyl, it's getting ugly, and I'm closing out the ring, okay? So guys, this is the first step. Now, the second step is that we wanted to a proton transfer because this nitrogen is actually going to stay in place whereas the nitrogen with the R group I'm are trying to get it to leave.

So, this nitrogen is going to grab a hydrogen from that and we're going to wind up getting is, I'm just going to write here proton transfer, proton transfer, after we get that proton transfer our molecule will now look like this and R, H, and I'm sorry, this should be still a tetrahedral intermediate, O negative and H and H2 perfect, okay? And we've got a formal charge, positive right there on the nitrogen, okay? So, now this next step it's going to be the second part of NAS, you kick out the leaving group. So, I would reform my double bond, kick out my N and what I get now is something looks like this, double bond attached to NH NH2 and then would have done here, double bond attached to N, R and H, and that's neutral now, okay? So, hopefully that's making sense so far. Now, keep in mind that N R is the important part, this is the part that I'm trying to release, remember this is going to be N R, that's my amine that I'm trying to get out of here? Well, guys the next step is just going to be times 2, it's going to be then now basically this whole reaction that I just drew happens twice, okay? So, one more time, what you're going to get is that now this nitrogen attacks and forms the tetrahedral immediate eventually kicking out the nitrogen. So, what we're going to wind up getting and doing a proton transfer. So, eventually, what you wind up getting is something that looks like this, carbonyl, nitrogen, nitrogen, carbonyl and these nitrogen's now have one H each and what are we saying, why do they only have one H when before the hydrazine had two H's, because they did true proton transfers, but the guys the really important part isn't that part, what I really care about is this, that I'm going to have now, NH2 because we have two proton transfers and R, this is the product I care about, because this is my primary amine and guys, this is a very consistent easy way to make primary amines without having to worry about polyalkylation, without having to worry about mixture of products the Gabriel synthesis even though it uses a weird molecule, the whole point is that we can now release the primary amine, really of our choosing and I don't have to worry about cross products or any kind of weird polyalkylated products as opposed to some other forms of making primary amines that are less efficient. Alright guys, so that's it for that mechanism, let's close up this video.