4-Chloropyridine undergoes reaction with dimethylamine to yield 4-dimethylaminopyridine. Propose

4-Chloropyridine undergoes reaction with dimethylamine to...

Key Concepts

Nucleophilic Aromatic Substitution (SNAr)

SNAr is a reaction mechanism wherein a nucleophile attacks an electron-deficient aromatic ring, leading to substitution of a leaving group. The process typically involves the formation of an intermediate complex (often referred to as a Meisenheimer complex) before the expulsion of the leaving group. This mechanism contrasts with classical electrophilic aromatic substitution and is facilitated by electron-withdrawing substituents on the ring.

Electron-Withdrawing Effects

Electron-withdrawing substituents on an aromatic ring decrease electron density, making the ring more susceptible to nucleophilic attack. In the case of pyridine and similar heterocycles, the electronegative atom within the ring exerts an inductive effect, enhancing the electrophilicity of the carbon bonded to a leaving group like chlorine. This effect is a key factor in promoting the nucleophilic aromatic substitution mechanism.

Meisenheimer Complex Formation

The formation of a Meisenheimer complex is a critical step in the SNAr mechanism. This intermediate is characterized by the addition of a nucleophile to the aromatic ring, which temporarily disrupts the aromatic system and results in a delocalized negative charge over the ring. The stabilization of this complex by electron-withdrawing groups makes its formation and subsequent re-aromatization possible.

Leaving Group Ability

The success of a nucleophilic aromatic substitution reaction depends heavily on the quality of the leaving group. In this mechanism, halides such as chloride serve as good leaving groups due to their ability to stabilize the negative charge once they depart from the aromatic system. The ease of removal of the leaving group facilitates the reformation of the aromatic stabilization after the nucleophile has attacked the ring.

Transcript

0:00 All righty.

00:02 We have this chloropyridine undergoing some kind of addition or a substitution of that chlorine for this dimethylamine.

00:14 So you might recognize that it looks like a nucleophilic acyls, oh my god, a nucleophilic aromatic substitution only because you don't have an electrophile here and you're replacing a chlorine with an amine, which is a base.

00:29 So bases can be nucleophile as in this case.

00:33 That is the case.

00:35 And you may be thinking, okay, so what is the, where is the electron withdrawing group? so in puridine, that nitrogen being more electronegative than the carbon atoms around it can act as an electron withdrawing group in this example.

00:50 So in terms of our, in previous video explanations, i've described the nucleophile aromatic substitution mechanism as almost a pull push.

01:00 Type arrow pushing cascade where you're first pulling the electrons towards the electron withdrawing group after nucleophilic attack on the ring and then you push them back towards the leaving group to force that leaving group out.

01:14 So i just want to give a minute or two to talk about why you don't make this nucleophile n -minus, right? so why don't you make an anionic base here.

01:29 And you might just be able to think, like, well, matt, obviously, that's not an acidic proton.

01:34 And it's not, right? so these amines, so ammonia, for example, has a pca of roughly 36.

01:44 These dialkal amines might be somewhere in the mid to late 20s, so maybe 25 to 30.

01:52 Puridine, on the other hand, or the pyridinium, so let's say we were to protonate that pyridine, this pyridium cation has a pca around five.

02:05 So this periodidium is similarly acidic to acetic acid, for example.

02:11 So it's a weak acid pretty close to hydronium.

02:14 I mean, it's 10 ,000 times weaker than hydronium, but it's a much stronger acid than then this guy, right? so therefore you're going to shift the equilibrium to keeping the pyrodine deprotonated, keeping the amine protonated, keeping the amine as nh or r2nh, as dimethylamine.

02:41 So you're going to leave the species as they are.

02:44 You may, just from a pga argument, also, because this is a weak acid, the n, the n, the n, anion is a strong base.

02:56 So even if you did form this periodidium, it would immediately deprotonate.

03:02 But you're not going to do that.

03:03 Kinetically, that's impossible.

03:05 So bottom line, i just wanted to make a quick pca discussion to show that you're going to have to react your nitrogen nucleophile as is.

03:13 So it does have that loan pair.

03:18 And therefore, that's what we're going to use to conduct our chemistry here.

03:30 Right.

03:31 So you know that the first step in electrophilic aromatic substitution is nucleophilic attack...

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