Organic Mechanisms. Xiaoping Sun

while the corresponding neutral molecule has two lone pairs of electrons in the oxygen atom. Clearly, for each pair of the species, the anion has greater electron density in the reactive center than the corresponding neutral molecule, giving rise to stronger nucleophilicity.

      2 For the same group of elements, the atomic radii increase from the top to bottom. As a result, for species containing the atoms of the same group of elements as reactive centers and having the same number of electron pairs in the reactive centers, their nucleophilicity increases as one moves from the top to the bottom along the group of elements. For example, the nucleophilicity of halides increases in the order of fluoride (F−), chloride (Cl−), bromide (Br−), and iodide (I−). All of them have four electron pairs. Another example is that the nucleophilicity of hydrogen sulfide (SH−) is stronger than hydroxide (OH−). For both of them, the central atoms contain three lone pairs of electrons.

      Some molecules do not contain any lone pairs of electrons. However, a bonding electron pair in these molecules may be donated to an electrophile making them nucleophilic. In this category, compounds containing a C–M [M = Li or MgX (X = Cl, Br, or I)] bond are strong nucleophiles because the C─M bonding electron pair is active and has strong tendency to be donated to an electrophilic center. For example, a Grignard reagent undergoes nucleophilic addition to a carbonyl group (a carbon electrophile) as shown below:

      The C=C π bond in alkenes is nucleophilic. They are characterized by electrophilic addition reactions (e.g., Reaction 1.64). The aromatic rings are nucleophilic due to the activity of the conjugate π electrons. Therefore, arenes undergo extensive electrophilic substitution reactions as illustrated below:

      

1.10 ISOTOPE LABELING

The enrichment of specific isotope of an element for an atom in a compound molecule is called isotope labeling. It is a very useful technique for studying kinetics and mechanisms for organic reactions. For example, let us first consider the acid‐catalyzed hydrolysis of esters such as ethyl acetate (Reaction 1.69) [1]

(1.69)

      From the overall reaction, it is not clear what bond, the acyl‐oxygen bond or the alkyl‐oxygen bond, is broken. Cleavage of either bond could lead to the formation of the products.

In order to establish the mechanism for the reaction, the oxygen atom of the alkoxide group (–OEt) in the ester is labeled (enriched) with the oxygen‐18 isotope (¹⁸O) and the hydrolysis of the ¹⁸O‐labeld ester is conducted in the same condition (Reaction 1.70):

(1.70)

Et¹⁸OH is identified from the products by mass spectrometry, but EtOH is not found. MeCO¹⁸OH is not found either [1]. The results unambiguously show that the acyl‐oxygen bond is broken in the reaction giving the observed products. However, the alkyl‐oxygen bond remains intact, as cleavage of the alkyl‐oxygen bond would lead to MeCO¹⁸OH, but it is not observed. On the basis of the oxygen‐18 isotope labeling experiment and other supporting data, the reaction mechanism is established and described in Figure 1.18. The acyl–oxygen bond cleavage, unambiguously identified from the isotope labeling experiment, is accomplished via the combination of a nucleophilic addition of water and a subsequent elimination of Et¹⁸OH.

Very often, isotope labeling on a compound may alter the rate constants for certain reactions of the compound. This is referred to as the kinetic isotope effects [1, 3]. In principle, a heavier isotope of an element has a lower zero‐point energy. Therefore, a bond to a heavier isotope (such as C─D bond) possesses a lower energy level than a bond to a lighter isotope (such as C─H bond) (Fig. 1.19). More energy is required to break a bond to a heavier isotope (such as C─D bond) than a bond to a lighter isotope (such as C─H bond). Since breaking of a C─H/C─D bond has a late transition state, the difference in energies of the transition states for breaking these bonds is much smaller than the difference in energy levels of the C─H and C─D bonds. Thus, the activation energy for breaking a C─D bond (E_a,D) is greater than that for breaking a C─H bond (E_a,H) (Fig. 1.19). This means the activation energy for a reaction that involves breaking a bond formed on a heavier isotope (such as C─D bond) is greater, corresponding to a smaller rate constant at a given temperature, if (only if) breaking of the bond is the rate‐determining step for the studied reaction. If breaking of this bond occurs prior to or after the rate‐determining step, the kinetic isotope effect is very minor. This effect is most remarkable for substitution of deuterium (D) for hydrogen (H) because the ratio in masses between these two isotopes (D/H = 2) is larger than those for any other pairs of isotopes. In general, if a bond to hydrogen (such as C–H) or deuterium (such as C–D) is being broken in the rate‐determining step of a reaction, the ratio of k_H (rate constant for the reaction involving breaking the bond to hydrogen, such as C─H bond) to k_D (rate constant for the reaction involving breaking the bond to deuterium, such C─D bond), k_H/k_D, is typically 2–8. This is termed kinetic deuterium isotope effect. If the k_H/k_D values are found between 1 and 1.5, the corresponding bond breaking does not occur in the rate‐determining step.

FIGURE 1.18 Reaction mechanism for acid‐catalyzed hydrolysis of the oxygen‐18 isotope labeled ethyl acetate.

FIGURE 1.19 Energetics for C─H and C─D (deuterium) bonds.

Kinetic deuterium isotope effect is often used in studies of the C─H bond functionalization. For example, the radical bromination of toluene (PhCH₃) to benzyl bromide (PhCH₂Br) has the kinetic isotope effect k_H/k_D ~ 5 [3]. This shows that breaking of the C─H bond in the methyl group of toluene by a bromine radical (Reaction 1.71) is the rate‐determining step for the overall bromination reaction:

(1.71)

      The mechanism of radical halogenations of alkanes will be discussed extensively in Chapter