Figure 1. Taken from [1].
One aspect of organic chemistry that has always fascinated
me is the possibility of ‘chemical memory’. In an organic molecule, the
information is designated in the structure of the molecule itself – what
formula (i.e. what atoms in it), how the atoms are arranged and most
importantly, its stereochemistry (i.e. its 3D-arrangement). For the stereochemical
information, chirality is the more important aspect, as it is the signature
that distinguishes two molecules which has exactly the same atom arrangement
and same formula.
It is well known that some chemical reactions can destroy
the stereochemical information of the starting material. Take the classic
example, a first-order, nucleophilic reaction – a SN1 reaction (Figure 2). The
mechanism dictates that the leaving group first departs to generate a planar,
positive-charged carbocation. The essential detail here is that it is planar.
Because of this particular shape, an incoming nucelophile will have a 50% / 50%
chance of either attacking from the top of the carbocation, or from the bottom.
That means, judging from the stereochemistry from the product (‘R’ or ‘S’
form), that is absolutely no way you will know which starting isomer makes the
product, because the sterochemical information is lost upon the formation of
the planar carbocation.
Figure 2. For the SN1 type reaction, the stereochemical information is lost upon the formation of the relatively stable tertiary / secondary carbocation, leading to a racemization of product. Taken from Clayden et. al., Organic Chemistry P.421.
In contrast, this is not the case for a SN2
reaction, which always results in an inversion of stereochemistry (if there is
no neighbouring group participations), which means, for example, if you have a
product as a ‘S’-isomer, you know it originates from a starting reactant in
‘R’-form, and vice versa (Figure 2).
The loss of stereochemical information can be really tragic,
especially in the field of asymmetric synthesis, as a racemization via a
proposed strategy basically suggests that your method is heading towards a
dead-end. There are, however, examples that stereochemical information can be
preserved. One of them is the ferrocene-based carbocation, which is
conformationally stable, and therefore when the carbocation is attacked by a
nucelophile, it will lead to a retention of configuration – which means the
molecule ‘remembers’ its past stereochemistry (Figure 3). This type of chemistry is good
news – because by design, we can control the outcome of the reaction
confidently now!
Figure 3. Taken from [1].
The Organic Letters article I share with you this time is
related to molecular memory, and the reaction is the classic Friedel-Crafts
reaction [1]. As you may have learnt in high school, the key step of a
Friedel-Crafts alkylation is the generation of a stable carbocation, via the
action of a Lewis Acid (AlCl3, FeBr3, to name a few). The
researchers have demonstrated that, with the inclusion of a silicon
functionality, a retention of configuration can be achieved for the product,
that means the compound has shown ‘molecular memory’ and remembers its initial
stereochemical configuration.
The model reaction of the substrates without a silicon group
shows that, upon reaction, a racemic mixture results. So, the planar
carbocation leads to same amount of both the isomers (Figure 4).
Figure 4. Control experiment leads to racemization, as expected. Taken from [1].
Upon the use of the silyl group and an iron salt as Lewis
acid, a retention results for the product. Note the alcohol group in the
starting material and the indole ring in the product are both pointing into the
plane (Figure 5).
Figure 5. Retention of configuration from silyl substrates. Taken from [1].
They have provided a mechanistic rationale. They believe
that the ‘molecular memory’ originated from the β –silyl effect, which leads to
the stabilization of the carbacationic intermediate. Thus, the iron salt activates
the –OH group and generates the conformationally stable carbacation, then the
indole attacks and leads to the final product, with a net retention of
configuration (Figure 6).
Figure 6. Mechanistic rationale of the Friedel-Crafts alkylation. Taken from [1].
With iron man, I can remember my past now!
The β‑Silyl Effect on the Memory of
Chirality in Friedel−Crafts Alkylation Using Chiral α‑Aryl
Alcohols
Toshiki Nokami,Yu Yamane, Shunsuke Oshitani, Jun-ka
Kobayashi, Shin-ichiro Matsui, Takashi Nishihara, Hidemitsu Uno, Shuichi
Hayase, and Toshiyuki Itoh
Org. Lett., 2015, asap
DOI: 10.1021/acs.orglett.5b01582
