Problem 4. Early Russian Organic Chemists and Markovnikov’s Rule

The last year was devoted to the 150th anniversary of the discovery of Markovnikov's rule, formulated by Vladimir V. Markovnikov in 1869. Markovnikov was a PhD student of the famous early Russian scientist Alexander Butlerov. In his PhD thesis in 1869, Markovnikov discovered the famous rule that exists in almost every textbook on organic chemistry. According to Markovnikov’s rule, when an unsymmetrical alkene or alkyne reacts with a hydrogen halide (hydrogen chloride, hydrogen bromide, or hydrogen iodide), the hydrogen atom of HX adds to the carbon atom having the highest number of hydrogen atoms. However, depending on the reagent or substrate, in some cases, opposite results could also be possible, and these kinds of reactions are called anti-Markovnikov addition. Although Markovnikov's rule was developed for and is specifically applied to the addition of hydrogen halides to alkenes or alkynes, many other additions are also described as Markovnikov or anti-Markovnikov depending on the regioselectivity of the addition reaction.

Actually, the rule should be revised as follows: “addition to this kind of double or triple bond proceeds through more stable intermediates”. In some cases, besides electronic effects, steric effects can also affect the formation of Markovnikov or anti-Markovnikov addition products.

The following problems are mainly related to discoveries described by the student of the more distinguished organic chemist Alexander Butlerov or his colleagues at Kazan University, Tatarstan, Russia.

4.1. Draw the structures of major products A-E, including the appropriate stereochemistry (ignore optical isomerism).

4.2. Draw the structures of major products F and G for the following reactions.

Wagner–Meerwein Rearrangement (WMR)

Wagner is another famous scientist who worked at Kazan University contemporaneously with Butlerov and Markovnikov. Wagner proposed that bornyl chloride undergoes an internal rearrangement to form pinene. Meerwein then generalized this type of rearrangement. Thus, this kind of reaction was named Wagner–Meerwein rearrangement. These reactions take place when a carbocation is formed. Generally, a carbocation is rearranged to a more stable

carbocation, if possible, by neighboring group migration. In addition, if the reaction does not proceed through a carbocation or borderline carbocation intermediates, rearrangements do not take place.

4.3. Considering the formation of intermediates for every reaction, draw the structures of reagents H and I and major products J–M.

Acid-catalyzed Wagner–Meerwein Rearrangement

The acid-catalyzed reaction of 4,4-dimethylcyclohexa-2,5-dien-1-one resulted in the formation of a compound, the NMR data of which are given below.

For N; 1H NMR (300 MHz, CDCl3): δ = 6.95 (d, J = 8.0 Hz, 1H), 6.61 (d, J = 2.8 Hz, 1H), 6.57 (dd, J = 8.0, 2.8 Hz, 1H), 5.39 (bs, 1H), 2.16 (s, 3H), 2.14 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 153.4, 137.9, 130.4, 128.6, 116.6, 112.3, 19.8, 18.7.

4.4. Find the structure of product N and propose a plausible mechanism.

4.5. What kind of difference do you expect in the 1H NMR spectrum after a drop of D2O is added to the solution in the NMR tube?

Zaitsev’s Rule

Zaitsev, who described a rule named after him (Zaitsev's or Saytzeff's or Saytzev's rule), was another PhD student of Butlerov’s. Zaitsev's rule is an empirical rule for estimating preferred alkene product(s) in elimination reactions. At Kazan University, the chemist Alexander Zaitsev studied various elimination reactions and observed a general trend in the resulting alkenes. More generally, Zaitsev's rule stipulates that in an elimination reaction the most substituted product will be formed. The following problem is mainly related to Zaitsev’s rule. 4.6. Draw the structures of elimination products O–Q and compound R. What is the major product formed by the thermal reaction of R described in the following scheme?

4.7. Which base(s) can be used to increase the ratio of Q relative to EtONa?

☐ NaOMe ☐ KOMe ☐ i-PrOK ☐ t-BuOK ☐ NH3 ☐ DBU ☐ i-Pr2NEt

Solution:

4.1.

4.2.

4.3.

4.4.

4.5. The phenolic proton at 5.39 ppm (bs, 1H) will exchange with the deuterium in the D2O and disappear from the spectrum.

4.6.

4.7.

☐ NaOMe ☐ KOMe ☒ i-PrOK ☒ t-BuOK ☐ NH3 ☒ DBU ☒ i-Pr2NEt