in this video we're going to focus on the gabriel synthesis reaction mechanism this reaction typically begins with a thalamide which is the structure that i'm currently drawn this thalamide which is the name of the molecule has a functional group called an imide this functional group is basically the nitrogen version of an acid anhydride it's a nitrogen between two carbonyl groups or two acyl groups now there's two types of versions of the gabriel synthesis reaction that you need to be aware of let's talk about the first version the purpose of the gabriel synthesis reaction is to produce primary amines in the first step we are going to add potassium hydroxide in water in step two we're going to add an alkyl halide in this case one bromobutane and in step three we're going to add hydrazine h2n and h2 you can also write it as n2h4 if you want to so what is the product of this reaction now to find the product of the reaction is pretty straightforward look at the alkyl halide all you need to do is replace the br with an nh2 and that's going to be the amine that you want to create or that will be created now what about the side product if you use hydrazine at the end the side product will look like this the name of this molecule is called thalamide hydrazide initially we had a five carbon ring or five atom ring but now it's expanded to a six atom ring which is more stable six atom rings have less ring strain than five atom rings so this is thalamide hydrazide that's the side product if you decide to use hydrazine now let's talk about the other version of the gabriel synthesis reaction now in the first step you're going to use a strong base so we're going to keep that the same potassium hydroxide the second step is going to be the same you can use any alkyl halide but we're going to use a different alkyl halide let's use in this case um one bromohexane and in step three we're going to use water with hydrochloric acid in the presence of heat and step four we're going to use potassium hydroxide so what is the major product of this reaction what type of amine will we get as our answer now keep in mind all you need to do is replace the bromine atom with an nh2 group and so this is going to be the amine that we're going to get it's going to have six carbons and an nh2 group at the primary carbon so the gabriel synthesis reaction is very useful in making primary amines that's the purpose of it it converts an alkyl halide into a primary amine now what about the side product so notice that we're not using hydrazine so we're going to get a different side product if we use uh acid hydrolysis the side product will still contain the benzene ring whenever you have a carboxylic acid derivative if you mix it with h3o plus you're going to get a carboxylic acid but because we have two carbonyl groups it's going to cleave and produce two carboxylic acids but notice that the final solution is basic so the carboxylic acid will be in its deprotonated form you can write it like this or you can write it as c-o-o minus those two are exactly the same so notice that the end result the amine used in both variations are the same however the side product changes if you use acid hydrolysis you're going to get two carboxylic acids at the end of step three this is going to be protonated and the amine will be prone to this will be nh3 but at the end of step four everything is deprotonated since the solution is now basic instead of acidic let's go over the mechanism of the first example so let's begin what is the first step of the gabriel synthesis reaction that is the first version that we mentioned we know the first step is the addition of a base so what do you think the base is going to do because this nitrogen is next to two carbonyl groups this hydrogen is relatively acidic and so potassium hydroxide is strong enough to remove that hydrogen and that's what it's going to do in the first step so that's the purpose of adding a strong base is to get rid of this hydrogen once we do that we're going to get an intermediate that looks like this the nitrogen is going to have two lone pairs and so it's going to bear a negative charge and the reason why the hydrogen is acidic is because the conjugate base is relatively stable it's stabilized by two carbonyl groups we can show one of the resonance structures by taking the lone pair and from an uh double bond with it so now the negative charge is not only present on the nitrogen atom but is shared by the two oxygen atoms so in this particular drawing we can see that the oxygen on top now bears the negative charge in this particular resonance structure and the nitrogen is neutral so that's why this hydrogen is acidic it's due to the resonance stabilization of the conjugate base so what's going to happen in the next step once we add butyl bromide or one bromobutane the nitrogen with the negative charge is going to attack the carbon that bears the bromine atom the reason why it attacks that carbon is bromine is more electronegative than carbon so the carbon bears a partial positive charge bromine bears the partial negative charge so the nitrogen is repelled by the bromine atom so it approaches it from the back but it's attracted to the partially positive carbon atom because opposites track and so this is an sn2 backside attack and we're going to get this particular structure the nitrogen atom now bears the butyl group it no longer has two lone pairs but it only has one and so that's the product after the second step so for both versions of the gabriel synthesis reaction after the first two steps you're going to end in this situation the only thing that may differ is the number of carbon atoms attached to the nitrogen group so for the second example that we use since we use uh one bromohexane this will have six carbons but we're going to use this particular form for both examples now in step three for the first version we're going to add hydrazine for the second version at this point we would add water and hcl so keep this point in mind because we're going to come back to it when using the second version we're going to start here but let's continue with the first version and let's uh make some space first let's put this on top so now we're going to add hydrazine which i'm going to write as h2n and h2 the nitrogen atom in hydrazine is a good nucleophile it has a partial negative charge and is attracted to the carbon atom which has a partial positive charge so this nitrogen is going to attack this carbon from the back causing the pi bond to break and so we're going to get this particular structure so this oxygen now has a negative charge it has a single bond and this carbon is attached to a nitrogen that has two hydrogens which is attached to an nh2 and let's not forget the lone pair that is on this nitrogen and it still has four carbons now the nitrogen with four bonds has a plus charge so what do you think is going to happen by the way this step is reversible this could form a double bond and expel the nh2 group or the hydrogen group taking it back to the left side now instead of pushing this group out what it can do is break this bond because by doing that it can obtain a six carbon ring instead of a five carbon ring and so the driving force here is stability so let's go ahead and take a lone pair and form a double bond causing the bond between a carbon and a nitrogen to break and those electrons will be used to form a double bond here causing this pi bond to break let's not forget the bonds in the benzene ring so right now we have this potential i mean this particular structure so this nitrogen still has two protons and we still have let's see if i can put this over here we still have the nitrogen which is still attached to four carbons the nitrogen still has a lump here but there's going to be a double bond here now the nitrogen with the plus charge has a relatively acidic hydrogen the nitrogen with the lone pair is basic because the negative charge on the oxygen bears down on it so this oxygen is going to form a double bond causing the electrons in a pi bond to be more negatively charged thus being attracted to the partially positive hydrogen so it's going to act as a weak base grab the hydrogen causing this bottom break pushing two electrons on that nitrogen so what we now have is this structure so this is back to a carbonyl group this nitrogen now has a hydrogen attached to it and it still has four carbons we have another carbonyl group with a nitrogen and another nh2 group this nitrogen has one hydrogen and a lone pair our goal is to put two nitrogens i mean two hydrogens on this nitrogen because we need to leave as nh2 right now it only has one so we got one more to go now before we carry on with the next step let's make some space first we have a lot of stuff on the board and let's move this to the top so what do you think is going to happen next this carbon here has a partial positive charge even though that partial positive charge is weakened by this lone pair now which of these two nitrogens will attack it if this one attacks we're going gonna get the five carbon ring but if this one attacks we're gonna get the six membered ring i said five carbon ring but really five membering but if this one attacks it's gonna produce a more stable six membering another reason why that nitrogen is going to attack it as well is because the lone pair is localized therefore those electrons are more reactive this lone pair is delocalized by the carbonyl group so it doesn't want to react because it's busy resonating with the carbonyl group and so if we draw the resonance structure for that this nitrogen has a positive formal charge and so those electrons aren't available for nucleophilic attack so therefore this is the candidate that's going to attack this carbonyl group and so now we have another six membered ring which looks like this so this nitrogen now has a positive formal charge and we still have the other nitrogen so what do you think is going to happen in the next step now keep this in mind this double bond could reform expel in this group so that step is reversible but what we want to do is we want to get rid of this group because that's the amine that we're trying to acquire in this reaction the only way to do it is to turn it into a bad leaving group right now it's a terrible leaving group if the nitrogen leaves it's going to have a negative charge and it's not going to be stable so what we need to do is transfer hydrogen from this nitrogen on to this nitrogen how can we do that how can we transfer a hydrogen from one region of the molecule to another and the answer is the solvent the solvent can transfer a hydrogen from one place to another now the solvent that we're going to use we're going to keep it simple is water depending on your particular reaction the cell it might be an alcohol or something else so you can always just change it but we're going to use water so what is going to grab a hydrogen from the nitrogen that has a positive charge because that hydrogen is a weak acid it's relatively acidic and then this bond is going to break it's going to put a lone pair on that nitrogen so these two nitrogens only have one hydrogen so now we're going to use water to transfer the hydrogen that it just acquired so once water grabs the hydrogen now it's in the form of h3o plus so this nitrogen being a weak base that it is is going to take the hydrogen from h3o plus and so now we're going to have this structure it's a lot of drawn in this particular video so now this nitrogen has two hydrogens so now has a plus charge which makes it a better leaving group than what it was before so now this oxygen is going to form a double bond breaking the carbon nitrogen bond expelling the nh2 group so at this point this is going to lead us to our final answer which is thalamide hydrazide that's the side product and also the product that we're trying to get which is the primary amine attached to four carbon atoms so that's the mechanism for the first version of the gabriel synthesis reaction now what about the second version let's start from the point where we had the four carbons first attached to the nitrogen even on the example that we used it had six carbons but let's keep it at four so starting from this example what we're going to add is uh water and hcl now when you mix water and hcl you're going to get an acid-base reaction and this reaction is going to be driven towards the right it's not reversible because hcl is a strong acid and it's going to generate h3o plus and cl minus so when you put water and hdl together you're going to get h3o plus which if we want to we can just write it like this now here's a question for you who is going to receive the acidic hydrogen is it the nitrogen or is it the oxygen of the carbonyl group think about it to answer this question let's draw the resonance structure of the molecule the lone pair of the nitrogen is busy resonating with the carbonyl group so it's not available to grab a hydrogen if we draw the resonance form notice that the oxygen now bears the negative charge and that the nitrogen bears a positive formal charge therefore the nitrogen doesn't have a strong affinity for the partially positive hydrogen compared to the oxygen so the oxygen is going to be the part that's going to be protonated in a molecule so it's going to grab a hydrogen and it's going to expel water so now we have an activated carbonyl system so what is going to happen next so what would you say the next thing that's going to happen is water is going to behave as a nucleophile and it's going to attack the carbonyl group now that this carbonyl group is activated by the h plus this carbon bears more partial positive charge and then this pi bond is going to break so now let's draw the structure that we now have so this is now just a single bond attached to an o h we still have the carbonyl group beneath that and we also have water attached to that carbon this oxygen now has a positive charge and it's still a lump here on the nitrogen so now in the next step another water molecule will act as a weak base and it's going to take away a hydrogen atom giving us two hydroxyl groups so we're going to have this structure so now that the water molecule has acquired a hydrogen it's now in the form of h3o plus now in order to break the ring we need to activate the carbonyl group and to activate it towards a reaction we need to protonate it with a hydrogen so what do you think is going to happen now so this ring is going to break at this point so this oxygen is going to use one of its lone pairs to form a double bond and as that occurs this bond is going to break the two electrons in that bond will be used to form a double bond and this pi bond is going to break so as you can see due to the positive charge the electrons are going to flow from one side of the molecule towards the other side due to this positive charge so that activated carbonyl group pulls the electrons toward itself causing the ring to collapse and break apart so now this is going to be a carbonyl group we have an oh this bond is no longer there this is now a hydroxyl group next to a nitrogen now what i'm going to do at this point is flip this group with this group so let's put the hydroxyl group on top and the carbonyl group towards the right now notice that this nitrogen with the lone pair is basic because the electrons of the hydroxyl group bear down on the double bond this is going to form a double bond causing this double bond to grab a hydrogen producing the carboxylic acid on top so this we can just leave it as c-o-o-h at this point so we don't have to worry about that part of the molecule over here we have a carbonyl that is activated we have a nitrogen with its uh four carbons and now it has a hydrogen so we need to add one more hydrogen to it before we can get rid of it from the structure so what is our next step what do you think is going to happen at this point in order to get rid of this group we need to pronate it with a hydrogen we can't do it right now because these electrons are not localized they're delocalized into the carbonyl group so they're not available to grab a hydrogen so for now water is going to act as a nucleophile it could act as a base take away this hydrogen but that's not going to give us the product that we want so we want it to act as a nucleophile and so here is the oh2 group that we now have it has one lone pair and a positive charge next we're going to use the solvent to transfer hydrogen from the oxygen to the nitrogen so another water molecule will be used to take away this hydrogen giving us this structure so we're going to have two hydroxyl groups and now water has been converted to h3o plus so notice that this nitrogen can no longer resonate with a carbonyl group since it's not there so now it can accept a proton from h3o plus so now we can convert it into a good leaving group so it's going to grab a hydrogen and we're going to have this structure now let's keep in mind this nitrogen has a positive formal charge so now it's about a leaving group so this oxygen is going to use this lump here form a double bond kick out the nitrogen and so what we now have is the protonated carboxylic acid but we do have a primary mean now the solution is acidic so it's not going to remain in this form the amine can either grab a hydrogen from the solvent or since it's very close to the carboxylic acid as soon as it is expelled it can grab a hydrogen from it so now this is the answer after the third step we haven't reached a fourth step yet but after the third step we can see that we have phthalic acid which is fully pronated and in addition to that we have a protonated primary alkyl ammonium ion so we have a nitrogen with four carbons and three hydrogens attached to it so in step four we're going to add potassium hydroxide the hydroxide ion will deprotonate the carboxylic acid the carboxyl gas is a weak acid and hydroxide will immediately get rid of these hydrogen atoms generating water so we're going to get this side product under basic conditions so this is the deprotonated form of phthalic acid and also hydroxide will remove a hydrogen from the nitrogen atom giving us our desired amine so that's the end of this video i know it's been a long one but now you have the mechanism for both versions of the gabriel synthesis reaction so if you like this video feel free to subscribe and also check out my channel if you want to find more organic chemistry video tutorials i also have videos on algebra physics general chemistry pre-calc trigonometry and at the time of making this video not geometry yet but maybe in the future so thanks for watching