Preparation of Amines

by Adam Le Gresley, PhD

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    00:01 Right. Preparation of amines. Nucleophilic substitution on alkyl halides by ammonia looks relatively straightforward at the end of the day. We have an alkyl halide which, from earlier on in this particular module, you should have been familiar with.

    00:16 And this is where we have a chloro, bromo, or iodo group attached to an alkane, again, creating this dipole. You should also have been aware, when we were talking about nucleophilicity, that ammonia and nitrogen-based amines are also very nucleophilic anyway, so they’re more likely or able to displace a chloride, bromide or iodide.

    00:39 And this is the reaction that we see in the presence of ammonia. We have one equivalent of an alkyl halide or halogenic alkane reacts with the ammonia and we get a primary amine.

    00:52 Another equivalent and we get a secondary amine. And then a third equivalent and here we have a tertiary amine. Primary, secondary and tertiary.

    01:04 Now, the highest yields are given by those substrates which favour an SN2 type of attack.

    01:11 Bear in mind, what we’re looking at here is an SN2 reaction on a haloalkane. And so, therefore, the order of reactivity, in this case, is primary haloalkane reacts faster than secondary reacts faster than tertiary. This is because of the nucleophilicity of the nitrogen in the NH3 and NH2 groups. There is, however, a problem with this. This is a rather facile way of looking at it because the reality is, when you actually get to the primary and secondary amines, secondary in particular, this actually becomes more nucleophilic than the starting ammonia. So, the results of this is that the reaction can give a mixture of different amines as the alkylated amines obtained as a product are stronger nucleophiles than the starting ones and can give a second nucleophilic substitution on the haloalkane or alkyl chloride. However, a way around this potentially is either via operating with a large excess of ammonia or occasionally as it’s something that’s done actually protecting one of those hydrogens as an amide in order that there is only one hydrogen available for substitution. But, that’s beyond the terms of reference of this. Reactivity.

    02:26 The chemical behaviour of the amines is due to the tendency of nitrogen to share its lone pair of electrons. So, what that means is we’ll be able to look at the basicity of amines because this is what happens when electrons from the lone pair attack a H+. The reactivity of the amines as nucleophiles in substitution reactions… And here we go. So, here we have an idealised amine. We have an alkyl group (shown here as “R”), it could be alkyl or aryl, it doesn’t really matter and in the presence of an acid, such as hydrochloric acid (shown here as “HCl”), the electron pair from the nitrogen can be donated onto the H+. This gives you an ammonium chloride salt. Now, the free amine, apart from those shortchanged ones which we talked about a little earlier, are insoluble in water. However, if you make the ammonium chloride, it does become soluble in water and the reason for this is hopefully you can appreciate is now we have a formal ionic compound. We have the organic part, which has been converted into something which bears a positive charge and we have the counter-ion, which is Cl-. This facilitates ion hydrogen bond interactions with water, which is what makes it soluble. Now, of course, depending on the basicity of the amine is going to influence how readily it is protonated, as we’ll see. Different types of amines have different degrees of basicity, depending on their degree of substitution.

    04:00 So, to recap, the R-NH3+ ion is known as the ammonium ion and it’s produced when an amine is present… in the presence… sorry, is made in the presence of an acid.

    04:14 So, let’s have a look at the alkylation of amines again, shall we? So, if we take our idealised amine, which is shown here as RNH2 and we have our, again, model haloalkane, R’X, in the first instance, what happens is the nitrogen lone pair attacks and displaces the halogen from our haloalkane and this actually can result in the formation… well, it does result in the formation of HX. There is a problem inherent to this is that HX, which is itself an acid in this particular scenario, if X was chlorine, it would be hydrochloric acid, can go on to protonate our newly substituted and therefore, more basic secondary amine.

    04:59 This in itself can prevent further substitution since it removes the nucleophilicity of the nitrogen by converting it into a positively charged species. So, this reaction can be used to produce amines having different alkyl groups on the nitrogen.

    05:16 Right. Now, we also talked, in the previous lecture set, about the acylation of amines, specifically, their reaction with things like acid chlorides and acid anhydrides in order to produce amides. So, here, again, is an example of this. We have our idealised alkyl or aryl amine and we have, again, our model acid chloride shown here, with the alkyl group correlating to R’. The reaction is nucleophilic addition elimination, which is exactly the same reaction mechanism as we saw in the previous lecture. So, this is the synthesis of an amide via nucleophilic substitution on a carboxylic acid derivative.

    05:58 And in fairness, this is one of the easiest ways to make an amide.

    About the Lecture

    The lecture Preparation of Amines by Adam Le Gresley, PhD is from the course Medical Chemistry.

    Included Quiz Questions

    1. decrease; ortho or para
    2. increase; ortho or para
    3. increase; meta
    4. decrease; meta
    5. None of the above
    1. Amines, being very electrophilic, are not able to displace halide ions from a haloalkane.
    2. The order of reactivity of haloalkanes in the reaction with ammonia is: 1° haloalkanes > 2° haloalkanes > 3° haloalkanes.
    3. The haloalkanes and ammonia undergo SN2 type nucleophilic substitutions.
    4. The reaction between NH3 or an amine with a haloalkane can give rise to a mixture of amines.
    5. The order of nucleophilicity of N atom in amines is: 3° amine > 2° amine > 1° amine > NH3.
    1. ... due to less availability of the lone pair of nitrogen as it gets partially delocalized with the pi electrons of the benzene ring.
    2. ... due to more availability of the lone pair of nitrogen.
    3. ... due to more electronegative nature of nitrogen atom.
    4. ... due to more electron pulling effect of hydrocarbon chain associated with the halogen atom.
    5. ... due to more electronegative nature of the halogen atom.
    1. The electronegativity difference between hydrogen and nitrogen atoms, and the presence of an unshared pair of electrons on the nitrogen atom.
    2. High electronegativity of hydrogen atom and the presence of a lone pair of electrons on the nitrogen atom.
    3. Low electronegativity of nitrogen atom and the presence of a lone pair of electrons on the nitrogen atom.
    4. The electron pulling nature of hydrogen atom.
    5. The electron pulling nature of alkyl or aryl groups attached to nitrogen atom.
    1. Tetramethylammonium bromide (a quaternary ammonium salt).
    2. Dimethylamine and bromoethane.
    3. Ammonia and bromobutane.
    4. Methylamine and bromopropane.
    5. Ammonia, Hydrobromic acid and But-2-ene.
    1. The ionic nature of ammonium salt enables it to form strong intermolecular interactions with water molecules.
    2. The ionic nature of free amine prevents it from forming hydrogen bonds with water molecules.
    3. The free amines lack the unshared pairs of electrons on their hydrogen atoms to form hydrogen bonds with water molecules.
    4. The free amines form strong intramolecular hydrogen bonds which can not be broken by interactions with water molecules.
    5. The free amines lack the unshared pairs of electrons on their carbon atoms to form hydrogen bonds with water molecules.
    1. … the conversion of a tertiary amine to a quaternary ammonium compound.
    2. … the conversion of ammonia into a quaternary ammonium compound.
    3. … the conversion of a primary amine to a quaternary ammonium compound.
    4. … the conversion of a secondary amine to a quaternary ammonium compound.
    5. … the conversion of N₂ and H₂ gases to a quaternary ammonium compound

    Author of lecture Preparation of Amines

     Adam Le Gresley, PhD

    Adam Le Gresley, PhD

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