the synthesis of amine is going to be the topic in this lesson and we're going to go through several synthesis for amines the first few are all going to be review things we learned earlier in the course so i'm going to present them very briefly but then we're going to learn several new syntheses as well including the hoffman rearrangement including the courteous rearrangement the schmidt reaction the gabriel synthesis and reductive amination now this lesson is part of my organic chemistry playlist i'm releasing these lessons weekly throughout the school year so if you want to be notified every time i post a new lesson or when i begin working on a new playlist subscribe to the channel click the bell notification all right so we're going to start these syntheses with a review of several reduction reactions and i say review one of them actually is new but the rest are all review and the one that's new is very similar to the ones that are old so uh in this case we'll start with just reduction of a nitro compound and you guys learned back in the uh side chain reactions of benzene uh uh section that we can reduce the nitro group either with catalytic hydrogenation or with one of three active metals either zinc tin or iron with acid and in this case you can turn your nitro group to an amine group instead so there's first one we've just made aniline next one here is the reduction of a nitrile and we can turn our carbon nitrogen triple bond into a carbon nitrogen single bond with lithium aluminum hydride here and so we've added two h's to the carbon and two h's to the nitrogen overall cool finally we've got reduction of azides and this one i don't actually think we covered earlier in the course so it's new here but it's overall very similar to what we saw with with this guy here and in this case we're going to lose two of those nitrogens in the process so but the remaining nitrogen of the the original azide ion is going to be part now an amine once again with lithium aluminum hydride or catalytic hydrogenation so the last reduction uh we're gonna take a look at that synthesizing amine is the reduction of an amide and you guys might recall with lithium aluminum hydride and h3o plus you're just going to lose the oxygen here as your leaving group instead of that nitrogen so leaving with this one in case and i want to put this separate presented separately from the other reductions because it is going to look very similar to a new one here the hofmann rearrangement and students often confuse the two but the final product is going to actually end up being one carbon difference so in the case of lithium aluminum hydride reduction we're going to lose this oxygen so in the reduction reaction replace it with two hydrogen atoms now that carbon's bonded to two hydrogens so but in the case of the hoffmann rearrangement we're going to find out we're going to lose the entire carbonyl as a part of the process we not only lose the oxygen we lose a carbon atom in the process here as well and so we're going to end up with an amine in either one of these reactions and starting with the same reactant though we see we've got the same number of carbons in our product as the reactant with lithium anhydride but one fewer carbons in our product than our reactant in the hoffman rearrangement so let's take a look at the mechanism for that hoffmann rearrangement so before we dive into this mechanism i just want to point one thing out here so some of you won't even see this reaction in your curriculum and for those that see it some of you won't be on the hook for the mechanism and for those of you that are on the hook for the mechanism some of you will only be on the hook for the reaction to form the isocyanate uh intermediate and probably not the hydrolysis of it so uh and then some of you very few of you will probably be on the hook for the whole thing so but we're gonna cover the whole thing but i will point out when we get to that isocyanate intermediate uh for those you that's that's all you're on the hook for so all right let's take a look at this here so first thing we're gonna do here is nucleophilic attack and we're gonna do nucleophilic attack on the bromine here break the bond to the other bromine so now your nitrogen is going to be bonded to a bromine and still two hydrogens and that's when your hydroxide here is going to come and deprotonate now one thing to note is we did a nucleophilic attack first and then deprotonated a hydrogen second there are reports of the mechanism uh out there in the literature where the hydroxide comes and deprotonates first and then we'll do nucleophilic attack second so but you're more commonly going to see it represented this way which is why it's the way i'm going with all right so from here we're going to get our big rearrangement and in this case what you're going to have happen is you're going to have this bond right here is going to break and this carbon is going to come and bond to the nitrogen and the nitrogen is going to have the bromine leave to make room for that to happen as a leaving group so that's what's going to have happen here so in this case if we take a look at what this looks like now we're bonded to the nitrogen instead that nitrogen is still bonded to a hydrogen but now it's bonded the nitrogen's bonded to this carbon still that's bonded to an oxygen now one thing to note here this carbon right here is going to have a positive charge and our nitrogen still has a lone pair and so it's a resonant stabilized carbocation here and so we could dump this in to form a resonant structure where the nitrogen would have the positive formal charge and it turns out that's going to be the major resonance contributor and so what you'll often see as well is you'll see these electrons dumped into here from the get go that way you're already into a position here where you've got that nitrogen carbon double bond and the positive formal charge on the nitrogen and oftentimes you'll see only the major resonance contributor here presented you sometimes you'll see both sometimes you'll see just the second one you usually don't see just the first one so but here we've got this lovely resin stabilized intermediate and then we'll have another hydroxide come in and deprotonate cool this is the species we refer to as the isocyanate get that in there so cool some of you on the hook for the mechanism only up until this point forming that isocyanate intermediate so but this is under gonna undergo hydrolysis it'll lose co2 in the process and eventually form our product amine here let's take a look at how that works here so we need a water molecule here in fact i'm going to erase this water molecule and just draw another one in so this water molecule is going to come and attack the carbonyl push the electrons over to the nitrogen technically it could push it over the oxygen as well and you got some residents going on so you've got a positive formal charge on the auction negative formal charge on the nitrogen and what you're going to have happen and often the way we represent this here is we do a little proton transfer and we say plus h plus minus h plus and so you're going to protonate this nitrogen and you're going to deprotonate the oxygen it's not that this nitrogen deprotonates the hydrogen there might be too far apart for that to happen but both these proton transfers are going to take place that the nitrogen gets protonated the oxygen gets deprotonated you end up with this lovely species which is a type of carbamic acid i believe and then from here we're going to do the same exact thing and we're going to represent it in a very similar way we're going to say plus h plus minus h plus and we are going to plus h plus we're going to protonate the nitrogen we're also going to deprotonate this oxygen right here giving you this lovely intermediate and here's where we're going to form the carbon dioxide so wherever these electrons come down so give you a carbon double bonded to two oxygens but so we don't violate the octet rule this bond has to break so and that's where we get our final product here so you're going to get this guy left over on this half of the molecule and then obviously plus carbon dioxide for the right hand side and that is the rest of that hydrolysis mechanism so again some of you are going to be on the hook all the way only up until isocyanate formation so and a few of you will be on the hook for the whole thing including the last half the hydrolysis of the isocyanate to form your amine and co2 now this is important we'll find out that the next couple of syntheses also end up going through an isocyanate intermediate that also gets hydrolyzed in exactly the same fashion and so when we cover those two synthesis i'm not going to cover the mechanism all the way through to the like we did here i'll probably just uh kind of more summarize and just say hey there we go from the isocyanate all the way to the amine and co2 so the next reaction we're going to cover is the courteous rearrangement it's going to have a lot of similarities to the hoffman rearrangement here and we're still going to ultimately lose a carbon but in this case instead of starting with an amide we're starting with a carboxylic acid but we will lose a carbon in the process along the way to forming an amine cool now part of this we already know and take a look at kind of we're not going to look at the mechanism with all the arrow pushing detail but take a look at what we do know about this mechanism in this case if you look at carboxylic acid socl2 you guys already know that that converts a carboxylic acid into an acid chloride so in that chloride is a good leaving group then we're going to do nucleophilic acyl substitution with the azide ion replacing the chloride and so and then this azide ion let's just show you what that azide ion looks like a little bit so in this case what you're going to have happen is a similar arrangement to the one we saw with the hofmann rearrangement and this carbon is going to end up coming and bonding to this nitrogen over here to make room for that happening we're going to break that bond and this is where nitrogen gas forms and bubbles away and then we'll also come back here and have this guy form a double bond to the carbon that's double under the oxygen which is where you form your isocyanate and so in this case so this carbon now is bonded to the nitrogen that nitrogen is double bonded to a carbon that is double bonded to an oxygen still and so there you've got your isocyanate so and then again it undergoes hydrolysis to turn into your amine plus carbon dioxide so notice didn't go through any detailed arrow pushing here but one to give you just kind of a mechanistic outlook of how this reaction is actually happening so lots of similarities to our huffman rearrangement and we'll see the same in our next one the schmidt reaction all right so your schmidt reaction accomplishes the exact same net result as your courteous rearrangement here and you've got your carboxylic acid same one here and it's going to form exactly the same amine here as well so it's just an alternative to actually carry out the exact same process and the way this works instead of going through an acid chloride we're just going to add sodium azide with sulfuric acid to bypass this process and go straight to this intermediate right here this acyl azide we say and from there it's pretty much the same that isolation is going to turn into isocyanate and that isocyanate is then going to get converted into your corresponding amine with one fewer carbons and then carbon dioxide all right the next amine synthesis is the gabriel synthesis it starts with thalamide here and before we get anywhere caught up into the gabriel synthesis itself we gotta talk about why it's necessary and what it accomplishes so the gabriel synthesis is another template synthesis it is for making primary amines and it turns out primary means are rather difficult to make apart from this gabriel synthesis by normal conventional means you might have learned already and i'm talking about sn2 reactions you might think oh chad you know we can do this so if we take ammonia and add an alkyl halide we can do backside attack kick off that leaving group get this lovely intermediate it's going to get deprotonated maybe we just write minus h plus not too concerned about the arrow pushing mechanism here and voila we get our lovely primary amine done by reactions we already know and problem is is uh we're not going to get a good yield and we're technically not done so it turns out that this lovely species right here is on par about the same nucleophilic strength as the original ammonia that you started with here and so all of a sudden now you know let's say you've got you know 50 of these guys reacting with 50 of these guys well by the first time the first 10 of these react to form 10 of these now you've got 10 of these you've still got 40 ammonias you still got 40 the alkyl halide and these guys are like oh let us react with the alkyl halide and so some of that's going to happen as well and so a couple steps down the road you're going to have now a secondary amine and some of these get to react with the alkyl halide potentially and you get a tertiary amine and then some of these get to react with the alkyl halide forming a quaternary ammonium ion and all of a sudden now you've just got a huge mixture in your solution that includes primary amine secondary means tertiary means quaternary ammonium ions and so if your goal had been to just make this one primary amine uh you didn't do a great job of it so we've got to come up with an alternative to this or else you're just going to have a big mixture of different sn2 products and so that's what the gabriel synthesis is for it's for making a primary amine in a much better yield than we can accomplish with sn2 so this is a funky word here only time i can think of where you see a ph and a th side by side like this and this is phthalamide the ph the f sound there so phthalamide and it is not an amide it's an imi this nitrogen is not just adjacent to one carbonyl it's adjacent to two carbonyls and so turns out this nitrogen can have delocalization with two carbonyls and whereas an amide is not the most acidic thing in the world an imide with an eye is a little more acidic to the point where it can be deprotonated by potassium hydroxide here so got potassium hydroxide and we're going to have that hydroxide ion come and deprotonate this hydrogen first step and then we're going to react it with an alkyl halide this thing is a great nucleophile and so now you're going to choose your alkyl halide of choice and in this case if this was the amine i was looking for then this would be the alkyl halide i'd be using and so in this case i'm gonna go back in and throw in our three carbon alkyl halide and this guy's gonna come around and do backside attack what's nice though is that whereas an amine here itself can act as a nucleophile an imide cannot so the mite again that lone pair is delocalized uh with resonance with both oxygens here and as a result it's much more stable than an amine and it's not a good nucleophile with a negative charge it's a decent nucleophile but neutral not so much and so we don't have to worry about this reacting any further and so from here an imide you can look at as another carboxylic acid derivative and so we have a couple of different options here so from this stage we could add barium hydroxide and the key part here is the hydroxide a strong base and just like all those carboxyl gas derivatives what you're going to do is nucleophilic acyl substitution we're going to break both of these bonds with the nitrogen acting as a leaving group so to speak so we're going to do it twice once with the carboxyl group on top once with the carboxyl group on bottom we're gonna have hydroxide come and attack so and eventually end up with something looking like where the ohs of the hydroxides have replaced the amine group here so but if you recall just like we did with carboxyl gas derivatives when this happens under basic conditions and barium hydroxide's a strong base then these end up deprotonated as just carboxylates there now they're not my desirable product this is just what i'm going to recycle and i'll probably turn this back into thalamide later so i can do more gabriel synthesis what i want though was the leaving group and that's actually the product of interest here and that leaving group that nitrogen along the way is going to get protonated a couple times forming your primary amine in a nice creative way now i do want to make you aware of one other way this reaction is actually completed instead of barium hydroxide you will see it also completed with n2h4 hydrazine or nh2h2 so in that case you end up with a slightly different reaction instead of hydroxide doing your nucleophilic acyl substitution it's going to be the hydrazine doing it so in your hydrazine here one of the nitrogens hydrolyzes one side one of the nitrogens hydrolyzes the other side and there is your the remnants of your hydrazine right there in your product and then the other two hydrogens that are missing are the ones that actually result with your primary the two hydrogens on your primary amine and so depending on which of your reagents you do step three in with here either barium hydroxide or hydrazine it doesn't change your amine product which is the goal in this reaction but it will change your side product here but in either case either one of these it's probably going to be recycled and converted back into thalamide so that you can do gabriel census another day all right so the last synthesis for amines we're going to look at is not only a synthesis of amines it's a reaction of amines and so it turns out one of the reactants is either going to be ammonia or primary or secondary amine so it's a reaction of these amines but it's also going to form amines as well and it turns out it's going to form an amine that is one degree more substituted than the one you use so like ammonia is not really an amine it's an uncompletely unsubstituted but when you do reductive amination it's going to form a primary amine as we'll see when you start with a primary amine and reductive amination you get a secondary amine as we'll see and when you start with a secondary mean you'll get a tertiary amine and result as we'll see so it always gets one degree more substituted than the original amine you start with now notice this is reductive amination not animation it's going to be difficult to say and i guarantee you're going to say it wrong at least once but it's not animation it's amination so uh and we'll see why they call it reductive ammunition in just a second here so you guys learned when you take a ketone aldehyde and react it with either ammonia or a primary amine you form an immune where your carbon oxygen bond is converted into a carbon nitrogen double bond and if you start with ammonia your nitrogen still bonded to a hydrogen but if you start with a primary amine your nitrogen is still bonded to whatever alkyl group you had with as part of your primary amine now with a secondary amine it's going to be a little bit different you guys learned that instead of ending up with a carbon nitrogen double bond you end up with an enamine a carbon-carbon double bond instead so once again we've got with ammonia the intermediates and immune also with the primary amine but with the secondary amino intermediate is an enamine cool and now all these need to be reduced so it's amination and is reductive as well in the second step and the most common reducing agents a little bit funky this is sodium cyanoborohydride so kind of like sodium borohydride where one of the four h's in sodium borohydride nabh4 is replaced by this cyano group so it turns out this is decreases its reactivity just a little bit so this is less reactive than sodium borohydride now turns out you can also do this with catalytic hydrogenation h2pdc in this step you can also actually use sodium borohydride the problem though is that you mix all this together in one step and if you sodium borohydride some of it's actually going to reduce your ketone to a secondary alcohol or your aldehyde to a primary alcohol and so but if we use sodium cyanoborohydride it'll reduce your amines or enamines but it actually is not strong enough to react with your ketone or aldehyde so it's kind of a nice choice and it's the most common one so it's the one i'm going to kind of run with here so but in this case you're going to reduce that carbon nitrogen double onto a carbon nitrogen single bond and so we've added a hydrogen to the carbon and a hydrogen to the nitrogen same thing when we started with the primary amine and with the enamine you'll just reduce the carbon-carbon double bond so if we go back and take a look here again we started with a primary amine here and a secondary amine here in ammonia here and now we've ended up with a primary amine here a secondary amine here and a tertiary amine here and so again ammonia which is unsubstituted goes to primary a primary amine results in a secondary mean and a secondary mean results in a tertiary mean and so again this is your reductive amination not only is it a reaction of amines but your product is also naming so it's also a synthesis of amine so this is a good bridge because uh in the next lesson we're going to start covering all the reactions of amines and technically with kana in a certain way covered one already now if you found this lesson helpful would you consider giving me a like and a share best things you can do to make sure other students get to see this lesson as well if you're looking for the study guide that goes to this lesson if you are looking for practice problems on amine synthesis 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