Update + DoM

Hello folks and apologies for the late installation of the blog. I hope you didn’t miss me too much.
A long week off dealing with family issues, a trip to Rome and a long solid week of chemistry after.
Before I race off into the fray I shall update all from previous blog RE arguing PIs. All ok as I said it would be. Just one of those.
I have done a monumental amount of chemistry since my last entry (despite a week away) and even got to do one of my fave reactions, lithiation.

Organolithium chemistry has a large range of versatility and applications. In this study, organolithium chemistry was applied to selectively remove 1 hydrogen from a molecule of BOC protected THIQ and replace it with a lithium ion. The organolithium compounds used are nucleophilic in nature and fall under the category of Bronsted bases. The level of nucleophilic character is determined by the steric hindrance of the molecule. This explains why n-butyl lithium is of more nucleophilic character than tert-butyl lithium and sec-butyl lithium (Clayden 2002).

Organolithium reagents exist in space as hexamers or tetramers and are not found alone as monomers. This aggregation is visualised below.


Organolithium cluster (Clayden 2002).

The organolithium clusters are electron deficient and this causes coordination with Lewis bases. When organolithium reagents coordinate with these Lewis bases, the carbon-lithium bond becomes polarised. For this reason, solvents used in organolithium reactions must be aprotic such as THF.

The reactivity of organolithium species can be increased exponentially when used in conjunction with certain Lewis bases, such as TMEDA. The reason for this is not entirely known but it is believed that the base lowers the amount of aggregation within the molecules and functions as a donor ligand. It is speculated to convert tetramers to dimers and even form open tetramers however this is less common. This, as a result, increases the nucleophilic character of the molecules (Clayden 2002).

Ortho lithiation can be induced by the addition of a heteroatom ortho to a benzylic proton. This chemistry known as heteroatom promoted lithiation or DoM was first reported over 70 years ago by Wittig and Gilman (Wittig and Fuhrmann, 1940), (Gilman and Bebb, 1939). These were the first to show DoM to anisole with high yields. This led to a massive influx of research into the DoM of anisole and anisole derivatives that is still carried being carried out today (Gooch, Rossington and Wilkinson, 2015).  Initially n-BuLi was used as an alkyllithium reagent though recently sec-BuLi, tert-BuLi and methyllithium have been successfully employed.
Although well over 50 years of research has been carried out in this area, the full mechanism of directed ortho metalation (DoM) is not still fully understood.

A general scheme for DoM is shown below.


  An over view of DoM


Although no single mechanistic process has been confirmed for explaining all the chemistry observed during DoM, all ideas lead ultimately to the insertion of a Li atom into a C-H bond ortho to the DMG.

One of the more recent and in depth studies suggests a complex induced proximity effect known as CIPE. At its foundations, CIPE suggests simply that the molecule incorporates itself into a complex with the organolithium reagent before metalation occurs. The “complexed” refers to the molecule complexion to a dimer and is due to its close proximity to the active C-H bond. The active C-H bond is ortho to the DMG (Ajani et al., 2015).

The DMG is often of Lewis basic character and undergoes complexation with the Lewis acidic Li cation. This allows for the deprotonation by the alkyl lithium molecule.

CIPE is a multistep mechanism where literature suggests that prior to coordination; the first step is the dimerization of the organolithium species and incorporates four molecules of solvent. It is thought that this must be achieved for the reaction to proceed. If this is the case, the substrate molecule must be accepted by the saturated organolithium species and complexation can occur. For this substitution to be carried out, one molecule of solvent on the organolithium dimer must be displaced by the substrate molecule. This displacement can occur by a dissociative pathway (SN1 like) or an associative route (SN2 like) (Whisler et al., 2004).

This is all illustrated below.


Associative and dissociative routes to coordination with anisole


The dissociative method is where the substrate molecule, in this example anisole, replaces one of the solvent molecules to produce a new dimer containing anisole and three molecules of solvent. This occurs in an SN1 like reaction. If this proves correct then the rate determination of this is mostly down to the nucleophilic character of the DMG as well as the solvents able-ness to function as a leaving group.

Conversely, an associative route may be carried out where by a solvent molecule leaves the organolithium dimer and the substrate then reacts with the open coordinating site to form a dimer containing three molecules of solvent and one molecule of substrate said to be complexed. This is determined entirely by the solvents ability to function as a leaving group.

Whichever pathway ultimately prevails, the common species formed is the dimer containing three molecules of solvent and one molecule of substrate to allow the insertion of a Li molecule into the C-H bond. A second solvent molecule must be lost for this to happen. Regeioselectivity is granted due to the proximity of the carbon-hydrogen bond to the lithium and the carbanion. This CIPE mechanism shows that only the ortho C-H bond is correctly positioned to allow for the Li insertion.




The CIPE mechanism for insertion of Li into ortho C-H bond


This CIPE mechanism is an update and addition to original theories where the reaction was driven solely by the acidity of the ortho proton. In this instance there is no coordination between the substrate molecule and the organolithium species. This is when the insertion of the Li into the ortho carbon-hydrogen bond is driven entirely by the electron withdrawing properties of the DMG. The electron withdrawing properties of the DMG dictate that the ortho situated proton is most acidic in character. This controls the regiospecificity of the reaction. Therefore, an increase in the electron withdrawing properties of the DMG gives a stronger chance of high enough acidic character of the ortho proton to force lithiation to occur. This electron withdrawal occurs through the σ-bond and is mediated through the inductive effect. This mechanism is often referred to as the overriding base mechanism (Woosley, 2004).


Overriding base mechanism: Acidic proton removed in favour of Li ion and ionically bonded to aromatic anion



This chemistry (albeit dated and un-scalable) is beautiful and such a synthetically useful reaction.
It also gave some of the purest NMR spectra I’ve ever witnessed (after a long column of course).

No reaction recap this week due to no time sadly and is also the reason this post has been written rather hastily.
Hopefully over the weekend I can post a follow-up to this to talk more about my thoughts and feelings of the past two weeks and not pure chemistry.
As always drop me a line @LewisMGooch and look forward to a follow-up post over the weekend.


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