Steric hindrance is an important consideration when evaluating nucleophility. For example, tert -butanol is less potent as a nucleophile than methanol.
This is because the comparatively bulky methyl groups on the tertiary alcohol effectively block the route of attack by the nucleophilic oxygen, slowing the reaction down considerably imagine trying to walk through a narrow doorway while carrying three large suitcases!
It is not surprising that it is more common to observe serines acting as nucleophiles in enzymatic reactions compared to threonines - the former is a primary alcohol, while the latter is a secondary alcohol. What is a nucleophile? Protonation states and nucleophilicity The protonation state of a nucleophilic atom has a very large effect on its nucleophilicity.
Periodic trends and solvent effects in nucleophilicity There are predictable periodic trends in nucleophilicity. Moving horizontally across the second row of the table, the trend in nucleophilicity parallels the trend in basicity: The reasoning behind the horizontal nucleophilicity trend is the same as the reasoning behind the basicity trend: more electronegative elements hold their electrons more tightly, and are less able to donate them to form a new bond.
Relative nucleophilicity in a protic solvent This of course, is opposite that of the vertical periodic trend for basicity, where iodide is the least basic. Protic solvent molecules form very strong ion-dipole interactions with the negatively-charged nucleophile, essentially creating a 'solvent cage' around the nucleophile: In order for the nucleophile to attack the electrophile, it must break free, at least in part, from its solvent cage. Relative nucleophilicity in a polar aprotic solvent The reason for the reversal is that, with an aprotic solvent, the ion-dipole interactions between solvent and nucleophile are much weaker: the positive end of the solvent's dipole is hidden in the interior of the molecule, and thus it is shielded from the negative charge of the nucleophile.
Resonance effects on nucleophilicity Resonance effects also come into play when comparing the inherent nucleophilicity of different molecules. Steric effects on nucleophilicity Steric hindrance is an important consideration when evaluating nucleophility. Example Which is the better nucleophile - a cysteine side chain or a methionine side chain? Explain your choice.
Skip to main content. Search for:. Reaction of RX with NH3 and amines Unfortunately, the primary amine product is also a powerful nucleophile, and so some of it will attack a second molecule of the alkyl halide. For example, consider a reaction between ethylamine a primary amine and bromoethane a primary alkyl halide : In the first stage of the reaction, you get the salt of a secondary amine formed.
In the first stage, you get triethylammonium bromide. Making a quaternary ammonium salt The final stage! Licenses and Attributions. On the other hand, if you want a slightly more quantitative approach to nucleophilicity, read on.
An impressive body of work on the relative power of nucleophiles comes from the lab of Herbert Mayr , who for the past few decades has compiled various reactivity scales for a number of different nucleophiles and electrophiles. Given the large number of variables involved, no scale will ever perfect under all conditions, but the values obtained do give us a relative sense of the impact of various factors in the nucleophilicity of amines.
Like pK a values, the Mayr nucleophilicity parameters are logarithmic. In the case of the Mayr tables, the higher the number, the better the nucleophile. Here is the the list of amine nucleophilicities that this part of the post is based on. Having a set of nucleophilicity parameters allows us to answer: how much? The answer appears to be by at least a factor of , if we compare the nucleophilicity parameters of ammonia in water and acetonitrile. If time is money, what does that make polar aprotic solvents?
The Mayr nucleophilicity parameters have the same broad trend. For water as solvent, the nucleophilicity parameter for NH3 is 9. This starts to put some perspective on the question of why the reaction of ammonia with alkyl halides is not a useful reaction for preparing primary amines ; the product is times more nucleophilic! Another example where basicity correlates with nucleophilicity is in the effect of electron-withdrawing groups.
Compare the nucleophilicity of piperidine The electron-withdrawing oxygen has the effect of reducing nucleophilicity by a factor of The Mayr parameters for t -butylamine, isopropylamine and n- propylamine show a clear trend, going from in water as solvent The measured set of nucleophilicity parameters give an estimate that hydroxylamine is about times more nucleophilic than ammonia in water , while hydrazine is about 10, times more nucleophilic.
Useful tidbit: never, ever use CH 2 Cl 2 or chloroform as solvent for any reaction involving the azide ion. The azide ion is so nucleophilic it will displace the chlorides, leading to the formation of a potentially explosive diazidomethane. Conspicuously absent from this whole discussion has been the question of tertiary amines. So are tertiary amines better or worse nucleophiles than secondary amines? In acetonitrile, it looks like tertiary amines are at least one, if not two orders of magnitude more nucleophilic than comparable secondary amines.
The nucleophilicity paramter of quninuclidine in acetonitrile is A caveat: Remember that the Mayr parameters work best with non sterically hindered electrophiles. So expect the reaction rate of a tertiary amine with a hindered electrophile to fall off a cliff, relative to a less hindered electrophile.
Sometime in the future we can address hard soft acid base HSAB theory. On the other hand, at a lecture I saw Mayr give once on his reactivity tables, he was asked where hard and soft acid-base theory effects were in his data. First, I think the blog is fantastic. Sometimes there is a turn of phrase or a description that helps when thinking about something differently, making it all the clearer.
Second, here are a couple of papers from Mayr relating to, specifically, the alpha effect and HSAB for interest. In order for the lone pair to donate into the aromatic ring, it has to adopt a conformation where the substituents on nitrogen are in the same plane as the aromatic ring. As steric bulk increases on the nitrogen, this conformation will become less favorable due to allylic strain.
I have a question about the using N-methyl hydrazine as a nucleophile. Aprotic solvents, like protic solvents, are polar but, because they lack a positively polarized hydrogen, they do not form hydrogen bonds with the anionic nucleophile.
The result, with respect to solvation, is a relatively weak interaction between the aprotic solvent and the nucleophile. The consequence of this weakened interaction is two-fold. First, by using an aprotic solvent we can raise the reactivity of the nucleophile.
This can sometimes have dramatic effects on the rate at which a nucleophilic substitution reaction can occur.
For example, if we consider the reaction between bromoethane and potassium iodide, the reaction occurs times faster in acetone than in methanol. A second consequence that results from the weak interaction that occurs between aprotic solvents and nucleophiles is that, under some conditions, there can be an inversion of the reactivity order.
An inversion would result in nucleophilicity following basicity up and down a column, as shown in the following diagram. When we considered the effects of protic solvents, remember that the iodide anion was the strongest nucleophile.
Now, in considering aprotic solvents under some conditions, the fluoride anion is the strongest nucelophile. Thus far, our discussion on nucleophilicity and solvent choice has been limited to negatively charged nucleophiles, such as F - , Cl - , Br - , and I -.
With respect to these anions we learned that, when using protic solvents, nucleophilicity does not follow basicity, and when using aprotic solvents, the same relationship can occur, or there could be an inversion in the order of reactivity. What happens as we move up and down a column when considering uncharged nucleophiles?
It turns out that, in the case of uncharged nucleophiles, size dictates nucleophilicity. This is because larger elements have bigger, more diffuse, and more polarizable electron clouds. This cloud facilitates the formation of a more effective orbital overlap in the transition state of bimolecular nucleophilic substitution SN 2 reactions, resulting in a transition state that is lower in energy and a nucleophilic substitution that occurs at a faster rate.
In the section Kinetics of Nucleophilic Substitution Reactions , we learned that the SN 2 transition state is very crowded.
Recall that there are a total of 5 groups around the electrophilic center.
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