Every organic reaction occurs by an ordered series of steps that convert the reactants into products. The detailed step-by-step description of this process is known as the reaction mechanism, and the purpose of a mechanism—as written by organic chemists—is to show in a clear manner how the electron reorganization between reactants and products may be rationalized. In the process, the mechanism provides a framework for discussing the reaction and for proposing modifications to a reaction.
Writing Mechanisms
All reactions involve, at their core, the breaking and making of chemical (usually cova- lent) bonds. When we are dealing with a covalent bond, there are only two ways in which this may be accomplished. In the first, the bond may break in such a fashion that both atoms retain one unpaired electron, a process known as homolysis. Alternatively, the bond may break in such a fashion that one of the two atoms retains both electrons of the bond- ing pair, a process known as heterolysis.
A B A + B A B A• + •B
homolysis
heterolysis
In writing modern mechanisms for organic reactions, the focus is on the movement of electrons, although this emphasis arose only slowly during the middle decades of the 20th century, due largely to the work of Sir Robert Robinson21 and Sir Christopher Ingold.22 Today, arrows are used to specify the relocation of electrons during a reaction step.23 When the movement of an unpaired electron is shown, the arrowhead has a single “barb” (this type of arrow is often called a “fish-hook”); when the movement of a pair of electrons is shown, the arrowhead has both “barbs.” This modern differentiation between the two types of arrows did not become commonplace until the 1960s. Prior to that time, the double-headed arrow was used to designate the movement of electrons without regard to the number of electrons.24 In either case, the arrow shows the movement of the electrons from their initial location to their final location during that particular reaction step.
21. Sir Robert Robinson (1886-1975) was educated at Manchester (BSc, 1906; DSc, 1910) and in 1912 became the first Professor of Pure and Applied Organic Chemistry at Sydney. After time in industry following his return to Britain in 1915, eventually becoming Waynflete Professor of Chemistry at Oxford University. He received the Nobel Prize in 1947; for a more complete biography see: Todd, Lord; Cornforth, J.W. Biogr. Mem.
Fellows Roy. Soc. 1976, 22, 414.
22. Sir Christopher Kelk Ingold (1893-1970) was educated at Southampton and London, where he also spent the major part of his career. Ingold was a pioneer of physical organic chemistry with his student and collaborator, E. D. Hughes. For a more complete biography, see: Shoppee, C.W. Biogr. Mem. Fellows Roy. Soc. 1972, 18, 348.
23. Early papers on use of “curly arrows” to rationalize reactivity used the arrows to designate movement of one or two electrons at a time: (a) Kermack, W.O.; Robinson, R. J. Chem. Soc. 1922, 121, 427. (b) Robinson, R. J.
Soc. Chem. Ind. 1924, 43, 1297. (c) Allan, J.; Oxford, A.E.; Robinson, R.; Smith, J.C. J. Chem. Soc. 1926, 401.
The use of the two-barbed arrow to indicate movement of an electron pair was proposed by Lowry and expanded on by Ingold: (d) Lowry, T.M. J. Chem. Soc. 1923, 123, 822, 1886. (e) Lowry, T.M. Nature 1925, 114, 376.
(f) Ingold, C.K.; Ingold, E.H. J. Chem. Soc. 1926, 1310.
24. Ingold and Robinson entered into a lifelong dispute over priority claims for this useful concept; although history shows that Robinson first used the “curly arrows,” it was Lowry and Ingold who gave the concept its modern usage. The differentiation between arrow types did not appear in advanced textbooks in organic chemistry until after 1962; until then, the movement of one or two electrons was commonly shown by the same type of arrow.
01-Lewis-Chap01.indd 13 14/08/15 8:05 AM
14 advanced organic chemistry | chapter one
# 158318 Cust: OUP Au: Lewis Pg. No. 14 K DESIGN SERVICES OF
S4CARLISLE
Homolysis
O Br O
O O
+ Br (1.1)
Me N Me N
Br + Br
Me Me
(1.2)
During a homolysis, the two electrons of the rupturing (or forming) bond are distrib- uted equally—basically the same situation as in the intact bond. Therefore, the formal charges on both atoms of the bond being cleaved remain the same, because the two atoms formally control one electron of the pair when bonded, and each has one electron when the bond is broken.
The simplest case of a homolysis reaction is the homolytic cleavage of one bond, as shown in Examples 1.1 and 1.2. In Example 1.1, the atoms at both ends of the reacting bond are uncharged in the starting compound, so they remain uncharged in the final free radi- cals. In Example 1.2, the nitrogen carries a formal positive charge in the starting ion, and it retains that formal charge in the product.
The same situation—that the charge on the atoms involved does not change during the course of the reaction step—holds true when an atom is transferred from one site in a radical to another, or when a radical fragments. In Example 1.3, which is taken from photochemis- try, the hydrogen atom is transferred from carbon to oxygen; none of the atoms involved is charged in the starting species, and no atom is charged in the final product. In the hydrogen atom transfer reaction shown as Example 1.4, the nitrogen atom carries a formal positive charge in the starting radical, and it retains that formal positive charge in the product. In the radical fragmentation reaction shown as Example 1.5, the same principles obtain.
Problem
1-4 Write mechanisms to account for each of the following homolysis reactions.
(a)
(b) OO
O
O
∆
H2C (c)
N N
hν O H
CH2
OH
N H N CH2
R R
R R
H
(1.3)
(1.4)
CH2 O Me O
Me (1.5)
01-Lewis-Chap01.indd 14 14/08/15 8:05 AM
the Fundamentals revisited 15
# 158318 Cust: OUP Au: Lewis Pg. No. 15 K DESIGN SERVICES OF
S4CARLISLE
Heterolysis
In contrast to the homolysis case, heterolysis of a covalent bond leads to a change in the formal charge of both participating atoms, with the atom retaining the two electrons from the bond gaining a unit of formal negative charge and the atom losing the two electrons of the bond gaining a unit of formal positive charge.
O H
O O
H O
+ (1.6)
S Br S + Br (1.7)
In the first simple heterolysis shown as Example 1.6, the carbon-oxygen bond is broken.
The carbon atom, which is at the origin of the arrow, gains one unit of formal positive charge to become a carbocation. The oxygen atom, which is at the terminus of the arrow, gains a full unit of formal negative charge to become an anion.
OMe CO2H Me
HCl H2O
O CO2H Me
C8H10O3 C8H10O3
OMe CO2H Me
OMe CO2H Me
OMe CO2H Me
OMe CO2H Me OMe
CO2H Me
OMe Me
OH OH
D
E
F OMe
CO2H Me A
B
C H
In Example 1.7, two bonds—one being formed, and one being broken—are involved at the same time. The negatively charged sulfur, which is at the origin of one arrow, loses one unit of formal negative charge, and the bromine, which is at the terminus of gains one unit of formal negative charge, becoming a bromide ion. The formal charge on the carbon atom, which is at the origin of one arrow and at the terminus of another, remains unchanged.
O NN H H
O R
NN H
OH R
O +
(1.8)
The same situation applies in more complex mechanistic steps where electrons around carbon reorganize (e.g., in the fragmentation reaction shown in Example 1.8, the negative
Figure 1.3 Potential initial protonation sites of the start- ing compound.
01-Lewis-Chap01.indd 15 14/08/15 8:05 AM
16 advanced organic chemistry | chapter one
# 158318 Cust: OUP Au: Lewis Pg. No. 16 K DESIGN SERVICES OF
S4CARLISLE
charge on the alkoxide oxygen eventually ends up on the other oxygen atom; because the nitrogen and carbon atoms are at the origin of one arrow and the terminus of another, none of these atoms undergoes a change of formal charge).
Let us now look at how one approaches writing mechanisms for reactions, by using the reaction highlighted in Figure 1.3. A quick examination of the molecular formulas of the reactant and the product shows us that CH2 is lost—the methyl group of the ether is now gone. Checking the molecular formulas this way is often very helpful in determining what might have happened during a reaction (the author of this book has used the tech- nique more than once the past year in reading papers in catalytic synthesis). The remain- ing parts of the molecule show that the substituents have not moved (with the exception of the double bond in the ring), so we do not have skeletal rearrangements to contend with. There are six sites where the proton from the HCl may attack the ring, and the re- sults of these attacks are shown in Figure 1.3, but only one of them has the effect of chang- ing the structure adjacent to the OCH3 group that is going to be lost and that is intermediate E, which places a new positive charge adjacent to the group that is going to be lost. If that cation reacts with water (not hydroxide anion, which is totally incompatible with the hydrochloric acid), we get the reaction in Figure 1.4 to give intermediate cation (i). This cation now has relatively few options for reaction, and the simplest is to lose a proton to give the hemiacetal (ii). Reprotonation of this hemiacetal can occur on either the OH or the OMe oxygens; protonation of the OH is nonproductive, so we protonate on the other one to give the new oxonium ion (iii). This now allows us to lose the methyl group as methanol by heterolysis of the C–O bond, giving us the new cation (iv). If this cation loses a proton from carbon, as in the second step of the E1 mechanism), we get a diene (v). Protonation of the diene at the terminal carbon gives an allyl cation (vi) that can now lose a proton to give the final product. Note how in every heterolysis of a bond during this mechanism, one of the atoms gains a unit of formal positive charge relative to its charge in the reactant state, and the other gains a unit of formal negative charge rela- tive to its charge in the reactant state.
OMe CO2H Me
O H
H
CO2H Me
MeO O H H
CO2H Me
O O H Me
H
CO2H Me
O O H Me
H
OH CO2H Me
H OH
CO2H Me H
O CO2H Me
O H CO2H Me
(i) (ii) (iii)
E
(iv) (v)
(vi) OMe
CO2H Me
H
Figure 1.4 The complete mechanism.
Worked Problem
1-4 Write a mechanism that accounts for the formation of the product below. (Hint:
CF3CO2H behaves like a strong acid with a non-nucleophilic anion.)
O
1) CF3CO2H/∆
HO
O
2) H2O
§Answer on next page.
01-Lewis-Chap01.indd 16 14/08/15 8:05 AM
the Fundamentals revisited 17
# 158318 Cust: OUP Au: Lewis Pg. No. 17 K DESIGN SERVICES OF
S4CARLISLE
Problems
1-5 Write mechanisms for each of the transformations shown below:
O
+ CN
O CN
(a)
(b) H2O OH2
(c) C N
N OH2
+ H2O
(d) OH (cat.)H O
CH3 CH3
(e) H
(cat.) O
OH OH
O O
+ H2O
(f) + CCl4 •CCl3
Cl
CCl3
(g) + S S RS• S S
(h) O + N
O
(i) C C H + H2O H OH H O
cat. cat.
(j) N + OH N
H2N HN
+ H2O
§ Answers for Worked Problem:
HO HO HO
CF3 O O
H O
HO
OCOCF3 H
HO
OCOCF3 H2O
HO
OCOCF3 O
H H
HO
OCOCF3 O
H
HO
O
Although the trifluoroacetate anion is generally considered a non-nucleophilic anion, it traps the vinyl cation as a vinyl trifluoroacetate because the vinyl cation is such a high-energy cation.
(continues)
01-Lewis-Chap01.indd 17 14/08/15 8:05 AM
18 advanced organic chemistry | chapter one
# 158318 Cust: OUP Au: Lewis Pg. No. 18 K DESIGN SERVICES OF
S4CARLISLE
1-6 Write a mechanism that accounts for the formation of each of the products in the reactions below:
(e) O
HN N Ts
KOCMe3 Me3COH
H H
H O
(f) O hν
OI
I
(g)
CO2H H
O
(a) H
(b) HH OH
2O
(c) Me CHOH
2SO4 O
O Me
Me
(d)
O O
O
HO OH
H2SO4
Kinetic Order, Molecularity, and Mechanistic Type
Much of the experimental evidence for the mechanism of an organic reaction is deduced from kinetics. Kinetics is the study of the relationship between the rate of a chemical reaction and two experimental parameters that the chemist can vary: the concentra- tions of the reactants and the reaction temperature. Kinetic measurements give the chemist a rate law, which relates the rate of the reaction to reactant concentrations. Rate laws are all of the form
Rate = k[A]m[B]n . . . (Eq. 1.10)
where [A], [B], and so on, are the concentrations of the reactants and m, n, and so on, are mathematical exponents. Only those reactants that participate in the reaction before or during the rate-determining step appear in the rate law.
In 1889, the great Swedish chemist, Svante Arrhenius,25 studied the mutarotation of glucose in aqueous solution, and from his studies, he derived what is now known as the Arrhenius rate equation:
k = A•exp(–Ea/RT) (Eq. 1.11)
where k is the rate constant, A is the “pre-exponential” factor and is related to entropy, Ea is the activation energy of the reaction, and T is the Kelvin temperature. Inherent in this equation is the observation that all reactions have to surmount an activation energy in order to occur.26
One way to visualize the processes occurring in a reaction is to use a reaction coordi- nate diagram or reaction energy profile.
25. Svante August Arrhenius (1859-1927) was educated at Uppsala (PhD, 1884, but with the lowest possible passing grade). After being appointed to the physics faculty at Uppsala, he studied with Ostwald, van’t Hoff, and Boltzmann. In 1903, he received the Nobel Prize in Chemistry. A more complete biography is available at the Nobel website, and at: Snelders, H.A.M. Dictionary of Scientific Biography (Charles Scribner’s and Sons:
New York, 1970); vol. 1, p. 296.
26. Arrhenius, S. Z. physik. Chem. 1889, 4, 226.
Problems (continued)
01-Lewis-Chap01.indd 18 14/08/15 8:05 AM
the Fundamentals revisited 19
# 158318 Cust: OUP Au: Lewis Pg. No. 19 K DESIGN SERVICES OF
S4CARLISLE
Energy Energy
Extent of Bonding Change
(Reaction Coortdinate) Extent of Bonding Change (Reaction Coordinate)
reactants reactants
products products
transition state
‡
transition state 1
‡ transition state 2
‡
intermediate
determiningrate
step fast
step
CONCERTED STEPWISE
This diagram has its ultimate origin in the Arrhenius equation and followed from the construction of reaction potential energy surfaces27 by American chemist, Henry Eyring,28 in the early 1930s. In these diagrams, the pathway between reactants and products lay along a trench or “valley” in the surface, with the high-energy point being a saddle point.
The simplification that is made to give the modern reaction coordinate diagram was to use the path along the bottom of the valley as the x-axis and energy as the y-axis of the dia- gram. In this way, the “reaction coordinate” now corresponds to the progress of each mol- ecule individually through the bonding changes needed to be converted to products.29
The high-energy point on the diagram is unusual, in that it represents a structure that is inherently unstable, as well as the highest energy point of the reaction pathway. Eyring called this the activated complex,30 a name that emphasizes its structure, whereas Evans and Polanyi called it the transition state,31 which emphasizes its ephemeral existence.
Reactions can be divided into two broad categories based on the timing of the bonding changes involved. Reactions that occur in a single step—in which all the bonding changes occur simultaneously—are called concerted reactions. They proceed through a single ac- tivated complex, and there is only one transition state in the reaction coordinate diagram.
In contrast to a concerted reaction, a stepwise reaction proceeds through two activated complexes, and an intermediate is formed during the reaction. In stepwise reactions, only those species involved prior to the highest energy step, known as the rate-determining step, appear in the rate law of the reaction. The reaction coordinate diagrams for a typical concerted and stepwise reaction are compared in Figure 1.5.
27. (a) Eyring, H.; Polanyi, M. Z. physik. Chem. 1931, B12, 279. (b) Eyring, H. J. Am. Chem. Soc. 1931, 53, 2537;
1932, 54, 3191. (c) Eyring, H. Chem. Rev. 1932, 10, 103.
28. Henry Eyring (1901-1981) was born in Juarez, Mexico, and educated at Arizona and Berkeley (PhD, 1927).
After graduating, he worked at Wisconsin, Berlin, and the University of California at Berkeley before moving to Princeton in 1931. In 1946 he moved to Utah, where he spent the rest of his career. For a more complete biography, see: Kauzmann, W. Biogr. Mem. Nat. Acad. Sci. (National Academies Press: Washington, D.C., 1996), 47.
29. One of the first appearances of the reaction coordinate diagram in the modern form in a textbook is in Glasstone, S.; Laidler, K.J.; Eyring, H. The Theory of Rate Processes (McGraw-Hill: New York, 1941), pp. 97-100.
30. The activated complex was first proposed by Eyring, who applied statistical methods to the calculation of reaction rates: (a) Eyring, H. J. Chem. Phys. 1935, 3, 107. (b) Eyring, H. Chem. Rev. 1935, 17, 65. (c) Eyring, H.
Trans. Faraday Soc. 1938, 34, 41.
31. (a) Evans, M.G.; Polanyi, M. Trans. Faraday Soc. 1935, 31, 875; 1937, 33, 448. (b) Polanyi, M. J. Chem. Soc. 1937, 629.
Figure 1.5 Reaction coordinate diagrams for concerted and stepwise reactions. The concerted reaction occurs in a single step through a single activated complex. In the stepwise reaction, more than one acti- vated complex is involved, and at least one intermediate is formed. In this example, the first step is rate determining because the energy of transition state 1 is higher than the energy of transition state 2.
01-Lewis-Chap01.indd 19 14/08/15 8:05 AM
20 advanced organic chemistry | chapter one
# 158318 Cust: OUP Au: Lewis Pg. No. 20 K DESIGN SERVICES OF
S4CARLISLE
Two particularly important parameters used to describe a reaction are its kinetic order and its molecularity. It is important to distinguish between these two. The kinetic order of a reaction is the sum of the exponents in the rate law. It is an experimental quan- tity that is directly related to the algebraic form of the rate law, it can be determined by appropriate kinetic measurements, and it relates the rate of the reaction to the concentra- tions of the reactants. The molecularity, on the other hand, is a theoretical concept that is used to describe the relationship of the activated complex to the reactants. Reactions where the activated complex is derived from a single distinct chemical species are unimo- lecular, those where two distinct chemical species combine to form the activated com- plex are bimolecular, those where three distinct chemical species form the activated complex are termed termolecular, and so on. Unlike kinetic order, molecularity depends on the assumed mechanism of the reaction. In some ways, this gives molecularity an advantage compared to the kinetic order of a reaction, and it is constant for all reactions of a given mechanism type. However, one must remember the caveat that, unlike the ki- netic order of the reaction, molecularity may be subject to reinterpretation as the pro- posed mechanism changes.32
Most of the time, the kinetic order and the molecularity of a reaction correspond, but this is not universally the case, as the acid-catalyzed reaction between tert-butyl alcohol and bromide ion shows. As shown in Figure 1.6, the reaction mechanism involves the formation of two reactive intermediates—the oxonium ion, which carries the actual leav- ing group that is replaced, and the carbocation, which reacts with the nucleophile. Of these two, the carbocation is the higher-energy intermediate, so its formation is more endothermic.
In this reaction, the slow step is the heterolysis of the carbon-oxygen bond of the oxo- nium ion, and only the oxonium ion is involved in the slow step. This makes this reaction unimolecular because only one particle is involved in the rate-determining step. However,
32. Molecularity: Hughes, E.D.; Ingold, C.K.; Patel, C.S. J. Chem. Soc. 1933, 526. For discussions of molecularity and kinetic order, see Ingold, C.K. Structure and Mechanism in Organic Chemistry (Cornell University Press: Ithaca, N.Y., 1953), pp. 308-316; Gould, E.S. Mechanism and Structure in Organic Chemistry (Holt, Rinehart and Winston: New York, 1959), p. 164.
OH
OH2
Br OH2
Br
δ δ
δ δ
‡
‡
Extent of Bonding Change (Reaction Coordinate)
Energy
O H
Hδ δ ‡
oxonium ion
carbocation OH
H
OH2
Br Br
Figure 1.6 The reaction between tert-butyl alcohol and bromide ion in the presence of a strong acid catalyst. Note how the oxonium ion is formed in a rapid pre-equilibrium step.
01-Lewis-Chap01.indd 20 14/08/15 8:05 AM