mechanisms in organic chemistry, building bridges to knowledge

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Mechanisms in Organic Chemistry

Building Bridges to Knowledge

Most introductory organic chemistry courses present mechanisms of organic reactions in an abbreviated format. Frequently, mechanisms are presented using arrows to show movement of electrons via homolytic cleavage or heterolytic cleavage. This approach has pedagogical value, and demonstrates bond formation and bond disruption. Also, it gives a sense of what occurs with the flow of electrons, insight into electron accountability, and the rearrangement of atoms that justify the formation of the products. However, it does not give the complete picture of a step-by-step process that correlates with the stoichiometry of the reaction. A stepwise approach accounts for the stoichiometry of the chemical reaction and a link with the kinetics of the reaction. The traditional approach to writing organic mechanisms frequently omits the stoichiometry of the chemical reaction and the physics of molecularity. Stoichiometry and molecularity are important in accounting for the simplicity of molecular interactions. Most reactions occur in a stepwise sequence that is unimolecular or bimolecular. The accountability of chemical reactions is based on that simple concept. Each elementary step in the mechanism should

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show that one (unimolecular) molecule produces an intermediate or activated complete or two (bimolecular) molecules produce an intermediate or activated complete. A termolecular reaction rarely occurs. Molecularity is defined as the number of chemical entities involved in an elementary step. Sometimes this leads to the formation of an intermediate, and other times it leads to the formation of an activated complex if the elementary step involves a transition state before it goes to the next step. For example, a simple nucleophilic bimolecular substitution reaction leads to the formation of an activated complex before forming the products. The activated complex is formed at the transition state and can be illustrated by the following potential energy diagram:

A bimolecular reaction requires two molecules of the reactants to form the transition state. The bimolecular reaction occurs in one elementary step. An SN2 (substitution nucleophilic bimolecular) reaction can be explained by a single step mechanism involving nucleophilic attack on a substrate producing an activated complex. The activated complex is found at the transition state and the resulting product can be a variety of chemical entities. The reaction is second order, meaning that the rate of the reaction depends on

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the concentration of the substrate to the first power and the concentration of the nucleophile to the first power as represented by the following simple mathematical expression. Rate = k [Nu][substrate] where k is the rate constant in molarity-1 time-1

[Nu] is the molarity, concentration in mol/L of the nucleophile [substrate] is the molarity, concentration in mol/L of a chemical species If the concentration of the nucleophile equals the concentration of the substrate, then Equation 1 may be used to express the rate of the reaction. Equation 1:

where x = concentration of product formed [ao – x] = concentration of nucleophile and the substrate at some given point in time ao = the initial concentration of the substrate and the initial concentration of the nucleophile. The solution to Equation 1 is Equation 2, where the concentrations of the substrate and the nucleophile are equal.

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Equation 2:

Equation 2 results from integrating Equation 1.

If ao – x = s then –dx = ds and

Integrating the equation between s1 and s2 and t1 and t2 gives

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s = a0 -x and at t1 =0 , no product has yet formed x = 0 and s1 = a0 – 0 = ao at t2 = t and s2 = a0 – x

Equation 2:

This equation is analogous to the equation for a straight line, i.e., y = mx + b where

and t = time

y = xa0 (a0 -x)

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and m, the slope, is equal to the rate constant k. Figure 1 is a plot of concentration versus time. If a straight line is obtained, then the reaction is first order in both the nucleophile and the chemical species; therefore, the rate is second order overall.

Figure 1 Plot of concentration versus time If the initial concentrations are not equal, i.e., [Nu] ≠ [RX], then the initial concentrations of the two substances can be represented by a0 and b0 respectively; therefore, the rate of the reaction can be described by Equation 3. Equation 3:

Equation 4:

1ao -bo

log bo ao -x( )ao bo -x( ) = kt

2.303

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or

1ao -bo

ln bo ao -x( )ao bo -x( ) = kt

Equation 4 results from integrating Equation 3.

Equation 4

or

1ao - bo

ln bo ao - x( )ao bo - x( ) = kt

This is an equation for a straight line, i.e., similar to y = mx’ + b Where

and x’ = t and m , the slope, is equal to k/2.303

y = 1a0 -b0

log b0 (a0 -x)a0 (b0 -x)

⎡

⎣⎢

⎤

⎦⎥

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or

y = 1ao - bo

ln bo ao - x( )ao bo - x( )

and x’ = t and m, the slope, is equal to k A plot of y versus time gives a straight line (Figure 2) indicating that the reaction is first order with respect to the starting materials, and second order overall where the two concentrations have two different initial concentrations.

Figure 2 Plot of concentration versus time for a chemical species and the nucleophile where the initial concentration of the chemical species is different from the initial concentration of the nucleophile. In many instances, a simple unimolecular reaction may lead to a molecule forming an intermediate. Using alkyl halides as an

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illustration for an SN1 (substitution nucleophilic unimolecular) reaction, the reaction can be explained by a two-step mechanism involving the formation of an intermediate in a slow step followed by a fast step to form a product. The first step, the rate-determining step, occurs with the formation of a carbocation stabilized by hyperconjugation. Consequently, a tertiary carbocation would favor an SN1 reaction. A tertiary carbocation is stabilized by hyperconjugation as indicated in the following structures.

The tertiary carbocation assumes a trigonal planar arrangement with a bond angle of approximately 1200.

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Winstein provided evidence for an SN1 reaction when he added LiClO4 to a solvent separated ion pair and observed a salt effect. The salt effect results in an increase in the rate of the SN1 reaction because the perchlorate anion, ClO4

-, intercepts the solvent separated ion pair preventing the carbocation- X- ion-pair from undergoing internal return. Consequently, the carbocation is more susceptible to nucleophilic attack. SN1 mechanisms also proceed with racemization or loss of optical activity. As an example, (R)-3-halo-3-methylnonane is converted into optically impure 3-methyl-3-nonanol. The reaction conditions are ideal for a substitution nucleophilic unimolecular process, and two products are possible. One product would have the nucleophilic group with the same spatial arrangement as the original alkyl halide, and the other product would have the nucleophilic group with a spatial arrangement that would be opposite to that of the original alkyl halide. The following illustrates how this process works. Step 1 a unimolecular slow step; therefore, the rate-determining step. This means that the rate of the reaction is dependent on the concentration of R-3-halo-3-methylnonane.

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Step 2 is a bimolecular fast step that can occur with two pathways resulting in the formation of optically impure products.

Step 3, a fast step, is a unimlecular deprotonation step.

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Where x+ y= 1.00 and x > y The alkyl halide ionizes in a slow step to form the halide ion and the flat alkyl carbocation. The flat alkyl carbocation is attacked by the H2O nucleophile as indicated, i.e., inversion of configuration or retention of configuration. Random attack would produce a racemic mixture (an equal mixture of both isomers); however, the proximity of the halide ion at the reaction’s initiation prevents the attack from proceeding randomly; therefore, backside attack, the inversion product, would predominate. That is why x is greater than y. The rate expression for the substitution unimolecular mechanism for the conversion of (R)-3-halo-3-methylnonane into optically impure 3-methyl-3-nonanol is rate = k[(R)-3-halo-3-methylnonane]. The reaction is first order in the alkyl halide; therefore, varying the concentration of the alkyl halide would impact the rate of the reaction. The industrial preparation of methyl bromide from methanol and hydrogen bromide illustrates how kinetic experiments may be used to ascertain the mechanism of a chemical reaction. Concentrations of methanol and HBr versus time data at fifty degrees centigrade are tabulated below: [Methanol], moles/liters [HBr], moles/liters Time, seconds

0.10 0.10 0 0.050 0.050 60 0.025 0.025 177 0.0125 0.0125 412

A plot of x

ao ao − x( )⎡⎣ ⎤⎦ versus time gives a straight line. This indicates

that the reaction is second order overall -first order in methanol and first order in HBr.

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xao ao − x( )⎡⎣ ⎤⎦

time (second)

0 0 10 60 30 177 66 412

The equation for the line is

Therefore, a plot of

gives a straight line with a slope equal to 0.16 L mole-1 s-1, and the intercept equals 0.

Note that the units are 1/Ms or M-1 s-1 or L mol-1 s-1. The units are obtained from the change in concentration (M/M2 = 1/M) divided by the change in time (seconds).

y"="0.1617x"

0"

10"

20"

30"

40"

50"

60"

70"

0" 50" 100" 150" 200" 250" 300" 350" 400" 450"

x/[a(a&x)])

*me,)second)

xao (ao -x)

= kt

xao (ao -x)

versus t

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The rate constant is the slope of the line; therefore, k is 0.16 L mole-1 s-1. The mechanism is a one step bimolecular process that forms a transition state, and then the products, CH3Br and H2O Step 1, a fast protonation step of methanol

step 2 is a slow step (the rate determining step) that involves a nucleophilic attack on the protonated methanol.

The biomolecular attack of bromide on protonated methanol forms an activated complex at the transition state on the way to methyl bromide and water. Incidentally, bridgehead alkyl halides such as 1-halobicyclo[2.2.2]octane will not undergo SN2 or SN1 reactions.

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The bridge alkyl halide cannot undergo an SN1 reaction because the resulting carbocation that would be formed cannot assume a trigonal planar or flat arrangement. The bridge alkyl halide cannot undergo an SN2 reaction because the bridge alkyl halide cannot undergo the inversion transformations required for SN2 reactions. Kinetic information is important in establishing the series of elementary steps resulting in molecular interactions during chemical reactions. Kinetic data help to determine if a reaction follows a nucleophilic bimolecular pathway, a nucleophilic unimolecular pathway, an elimination bimolecular pathway, an elimination unimolecular pathway, a free radical pathway, or some other pathway. In addition to kinetic information, experiments that lead to trapping an intermediate can help to verify that a particular mechanism or pathway has occurred. Consequently, there should be experimental evidence in support of a proposed mechanism. Mechanisms for organic chemical reactions should include steps that are accountable for the formation of the product or products, and the sum of the elementary steps should be in agreement with the stoichiometry of the balanced chemical equation. The series of proposed elementary steps would be an educated scientific guess based on sound scientific principles. Also, the mechanism is only verifiable when it is supported by kinetic experiments and other chemical experiments that could substantiate the suggested intermediates in the proposed mechanism. Benzyne is a unique molecule in that it is an aromatic compound containing a triple bond.

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Benzyne The existence of benzyne has been suggested and, in some respects, has been indirectly substantiated. For example, reacting chlorobenzene with a strong base such as potassium amide results in the formation of aniline.

If ortho-methylchlorobenzene is treated with potassium amide, two products are obtained, ortho-methylaniline and meta-methylaniline. The following chemical equations address these issues, and the results suggest that benzyne could be a possible intermediate.

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Also, when p-methylchlorobenzene is treated with potassium amide, p-methylaniline and m-methylaniline are produced. When m-methylchlorobenzene is treated with potassium amide, m-methylaniline, p-methylaniline, and o-methylaniline are produced. J.D. Roberts in 1953 labeled the carbon atom attached to the chloro group in chlorobenzene. He reacted the labeled chlorobenzene with potassium amide and obtained the resulting labeled aniline in two places. These results are indicated in the following equation. The percentage of labeled products is indicated below. The results give strong evidence for the existence of a benzyne intermediate.

The following sequence of elementary steps could explain the formation of two labeled products. Step 1 is a bimolecular step

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step 2 is a unimolecular step

benzyne step 3 is a bimolecular step that can happen in two ways

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step 4 is a bimolecular step that can occur at two different sites

Also, benzyne can be formed by treating o-fluorobenzene with magnesium.

The suspected benzyne is then trapped by a Diels-Alder reaction. The Diels-Alder reaction involves adding 1,3-cyclohexadiene to the reaction mixture in hopes of isolating 5,6-benzobicyclo[2.2.2]oct-2-ene (I).

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When o-fluorobenzene is treated with magnesium and 1,3-cyclohexadiene is added to the reaction mixture, 5,6-benzobicyclo[2.2.2]oct-2-ene, compound I, is obtained.

I 5,6-benzobicyclo[2.2.2]oct-2-ene The formation of benzyne could be viewed as suspicious, because the triple bond in benzyne cannot assume a bond angle of 180o for a (2sp + 2sp) sigma molecular bond, and two (2p + 2p) pi molecular bonds. The six “2p” atomic orbitals on each carbon atom of benzyne must be perfectly parallel and the carbon atoms must be coplanar in order to fulfill the criteria for aromaticity. Coplanarity of the carbon atoms is not an issue; however, the bonds in the ring system would prefer to be 120o and not 180o.

There may be an alternative consideration that would satisfy the 120o and could possibly rationalize the products. In the presence of a strong base, perhaps benzyne exists as structures I and II rather than as an isolated triple bond. Such a model would satisfy the

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labeling experiments and chemical evidence suggested by the formation of a benzyne intermediate

Structures I and II (carbanion/cabocation) have two electrons in a 2sp2 hybridized atomic orbital of carbon adjacent to carbon atom with an empty 2sp2 hybridized atomic orbital. These two hybridized atomic orbitals will be available to form bonding molecular orbitals that will result in identical products formed in benzyne reactions.

Labeled chlorobenzene could give rise to labeled aniline via structures I and II as described by the following equations.

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step 1 a bimolecular step

Step 2 is a unimolecular step that generates a chemical entity analogous to benzyne, but with charge separations that could exist in two ways.

The intermediate could exist as structures I and II rather than as a triple bond.

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Step 3 is a bimolecular step that can occur by two pathways.

Step 4, the final step, is a bimolecular step that can occur by two pathways.

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A similar argument could be used to rationalize other products suggested by benzyne. For example, the formation of 5,6-benzobicyclo[2.2.2]oct-2-ene could be rationalized in the following manner.

5, 6-benzobicyclo[2.2.2]oct-2-ene In 1975, Richardson and Alger performed several kinetic experiments that focused on alcoholic metal solvation via substitution nucleophilic bimolecular processes. They used proton magnetic resonance spectroscopy to study the solvation of aluminum and gallium ions in methanol and ethanol (Journal of Physical Chemistry, June 1975). The work showed that the reactions followed substitution nucleophilic bimolecular pathways, and they were able to calculate the rate constants at various temperatures and a variety of thermodynamic parameters, e.g., energy of activation, enthalpy of activation, entropy of activation, and Gibbs free energy of activation for various solvolysis reactions in compliance with

where n equals 6

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and Theoretically, y can equal 0, 1, 2, or 3 A specific example is

Where the perchlorate anion has spherical characteristics. The kinetic studies were instrumental in determining:

for the solvolysis reactions. One important aspect of the solvolysis research was to demonstrate that experimentation is necessary for definitively determining the mechanisms of chemical reactions; consequently, without experimental evidence, the proposed mechanism is only a scientific guess. The primary purpose of this paper is to acknowledge that mechanisms (whether supported by experimental evidence or a scientific guess) should be presented as a series of elementary steps that clearly indicate the formation of products with details showing stoichiometry and molecularity. Following are examples using a stepwise approach to describe the mechanisms of ten familiar organic reactions.

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1. Mechanism for the Reduction of Nitrobenzene to Anilinium Chloride

Anilinium chloride can be synthesized from nitrobenzene by reducing nitrobenzene with tin and hydrochloric acid. The resulting anilinium chloride is treated with base to produce aniline. This process is represented by the following reactions.

The following balanced chemical reactions represent the reduction of nitrobenzene by tin and hydrochloric acid followed by the neutralization of anilinium chloride with base to form aniline. (1)

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(2)

The series of elementary steps that explain the formation of anilinium chloride is: Step 1 is a bimolecular step.

Step 2 is a bimolecular step.

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Step 6 is a unimolecular step.

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30





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The sum of steps 1-15 would give the balanced chemical equation. The fifteen steps rationalize the stoichiometry of the balanced chemical reaction. The mechanism is a scientific guess, because the result is not based on kinetic studies or characterizations of trapped intermediates. In order to verify the mechanism, a careful kinetic study must be performed in order to develop a rate expression that would agree with the proposed mechanism. This would involve finding the appropriate rate determining step, and performing calculations that would correlate with the suggested rate expression.

the anilinium salt Treating anilinium chloride with sodium hydroxide produces aniline.

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aniline 2. Mechanism for the Bromination of 4-Octanone in Acidic

Solution A specific example of a reaction that uses kinetic studies to demonstrate the validity of a mechanism is the reaction of 4-octanone and bromine in acidic solution.

This sum of the elementary steps of the suggested mechanism correlates with the stoichiometry of the chemical reaction. The mechanism is a four-step process beginning with a fast equilibrium bimolecular step.

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Step 1 is a rapid equilibrium step.

Step 2 is a slow step involving the abstraction of a hydrogen atom on the α carbon atom.

Slow equilibrium

(an enol)

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Step 3 is a fast step leading to the protonated α-bromoketone.

Fast Step

The final step, step 4, a fast step, is the deprotonation of intermediate3 (a protonated α-bromoketone) is transferred to water to give the desired product. Step 4, a fast step

product The following equation is obtained upon adding equations 1-4

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This equation correlates with the observed balanced chemical equation. Definitive mechanisms (not scientific guestimations) are based on the kinetics of reactions. Kinetics experiments support the above mechanism. The rate of the reaction depends on the slow step of the proposed mechanism, and step 2 is a reversible step that favors the keto form over the enol (the reason for being the slow step) form. Therefore, it is the rate- controlling or rate-determining step. In this step, the rate of the reaction depends on intermediate1 and water. The rate expression for step 2 is represented by Equation 1

The concentration of intermediate1, formed in a fast prior equilibrium reaction, cannot be measured, but the following equation from step 1 can be used to determine the concentration of the ketone: Equation 2

Solving for the [intermediate1]

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[intermediate1] = k1 [ketone] [H3O+ ]

k−1 [H2O]

ratereaction = k2k1 [ketone] [H3O+ ]

k−1 [H2O] [H2O]

ratereaction = k2k1 k−1

[ketone] [H3O+ ]

where k is k2k1 k−1

a ratio of rate constants

and the intermediate1 is

and the ketone is

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The rate of the halogenation reaction is second order, first order in the ketone and first order in the acid that is used to catalyzed the reaction. The overall order of the reaction is second order, and the rate of the reaction is independent of the concentration of the halogen. Changing the concentrations of the bromine and observing the affect on the rate of the reaction, and changing the concentration of the acid and observing how the changes affect the rate of the reaction can verify the dependence of the rate of the reaction on the concentration of bromine and the mineral acid. Such an experiment would show that the rate of bromination depends on the concentration of the acid used to catalyze the reaction and the concentration of bromine to facilitate the bromination of 4-octanone. Clearly, the mechanism of an organic reaction should be listed as a series of elementary steps that result from performing kinetic measurements (concentration changes versus time), trapping of intermediate, and other experiments that can validate a selected mechanism. In the absence of evidence, a proposed mechanism can be based on scientific guestimations and logic. The fifteen suggested steps for nitrobenzene to anilium chloride is an example of a scientific guess. 3. Mechanism for the formation of 1,2-Dibromocyclohexane from Cyclohexene and Bromine The series of elementary steps (two steps) for the formation of 1,2-dibromocyclohexane from cyclohexene is another example of how to properly write mechanisms for organic reactions. The process involves the formation of a cyclic bromonium ion. This is suggested because of experiments and product observation that validate such a process. The cyclic bromonium ion forms a trans product; however, the formation of the trans product can occur by two different pathways. Step one of the mechanism is a bimolecular process that results in the formation of a cyclic bromonium ion.

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Step 2 of the mechanism involves a trans attack of a bromide ion on the cyclic bromonium ion to form trans-1,2-dibromocyclohexane.

The two products in the bromination of cyclohexene are stereoisomers. 4. Mechanism for the formation of a cis-Glycol from the

Reaction of Dilute Potassium Permanganate with an Alkene

Another example is the mechanism for the formation of a cis glycol from the addition of dilute potassium permanganate to an alkene. The series of elementary steps rationalize the formation of products.

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To understand the reaction and gain insight into the fourteen steps (a scientific guesstimation) that lead to the formation of the vicinal glycol, the reduction-oxidation (REDOX) balanced equation between an alkene and dilute potassium permanganate in acidic medium should be considered. The oxidation half-reaction of the REDOX reaction is

and the reduction half-reaction of the REDOX reaction is

The number of electrons lost must equal the number of electrons gain; therefore, equation (1) must be multiplied by 3 and equation (2) must be multiplied by 2 to give: Oxidation

Reduction

Adding equations (1) and (2) would give the following results:

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or

This is the net ionic equation for the REDOX reaction. This reaction can also be written in its molecular form.

Note that only two moles of permanganate will react with three moles of alkene to produce 3 moles of the diol. This information gives insight into a possible mechanism for the reaction. The following series of fourteen (14) steps could represent a plausible mechanism for the formation of vicinal glycols from alkenes and dilute potassium permanganate.

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Step 1, a bimolecular ring formation process, explains the formation of the cis product as well as the beginning of the reduction process for manganese.

Mn has oxidation state equal to +7 Mn has oxidation state equal to +5 Step 2, a bimolecular process

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Step 3, a unimolecular process, explains ring opening.

Step 4 is a unimolecular process.

Step 5 is a unimolecular process.

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Step 6 is a bimolecular process and a repeat of step 1.

Step 7 is a repeat of step 2

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Step 8 is a repeat of step 3.



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Step 11 uses the product of step 5 in an analogous manner that the permanganate that was used in steps 1 and 6. In addition, the manganese undergoes further reduction.

Mn has oxidation state equal to +3 Step 12, a unimolecular step, leads to ring opening.

Step 13 is a unimolecular step that results in the formation of the cis-glycol.

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Step 14 explains the formation of manganese dioxide from the manganese intermediates that are suggested in the proposed mechanism,

The formation of manganese (IV) oxide from the interaction of HMnO3 and HMnO2 can be explained by the following series of steps. (a)

(b)

(c)

manganese (IV) oxide Mn has oxidation state equal to +4

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Manganese can have an oxidation state of +7, +6, +5, +4, +3, and +2. In reality, the structure of manganese (IV) oxide is more complicated than the simple structure in step 14(c). Electron Spin Adding steps 1 through 14 would give the net ionic equation for the REDOX reaction:

5. Mechanism of the Iodoform Reaction Methyl ketones, as well as methyl groups attached to carbon atoms adjacent to a carbon atom that contains a secondary alcohol, react with iodine in sodium hydroxide to form a yellow precipitate. The reaction of methyl ketones with iodine in sodium hydroxide is referred to as the iodoform reaction. The yellow precipitate is triiodomethane or iodoform, the name that gives rise to the nomenclature of the reaction Following is an example of the iodoform reaction showing the stoichiometry of the reaction. The stoichiometry of the reaction gives insight into the series of elementary step that could rationalize the formation of the products.

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The following series of elementary steps explain how methyl ketones can form iodoform (a yellow precipitate). Step 1, a bimolecular step involving an abstraction of a hydrogen atom on a carbon atom adjacent to a carbonyl group.

Step 2 is a unimolecular step resulting in the formation of an enolate.


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50





yellow precipitate The sum of the elementary steps 1-11 gives

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The mechanism for the iodoform reaction is the stepwise process that should be used in writing any and all reaction mechanisms regardless of whether you have kinetic data or chemical data , i.e., scientific guesses should use guidelines concerning the behavior of organic molecules. For example, negative charges in acidic medium would be disfavored. Positive charges in basic medium would be disfavored. Nucleophilic attack at an 2sp2 hybridized carbon-oxygen double bond to form a tetrahedral 2 sp3 hybridized carbon atom is highly favored.

6. Mechanism of the Baeyer-Villiger Reaction

The Baeyer-Villiger reaction is the synthesis of an ester from a ketone. Ketones react with peroxy acids to insert an oxygen atom between the carbonyl group and the larger of two attached alkyl or aryl groups to form an ester. For example, the reaction between methyl phenyl ketone and peroxyacetic acid (peracetic acid) in methyl chloride will produce phenyl acetate as the major product.

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The two-step mechanism that leads to the formation of the ester includes the migration of the alkyl group with retention of configuration; therefore, if stereochemistry is possible, the reaction leads to the retention of configuration, i.e., the reaction is stereospecific.

Step 1 a bimolecular step

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Step 2 is a unimolecular step that forms an activated complex.

7. Mechanism of the Clemmensen Reduction

A good reducing agent for converting a carbonyl group to a methylene group is zinc amalgam, Zn(Hg), in concentrated hydrochloric acid. This reduction method is referred to as the Clemmensen Reduction where the carbonyl group is reduced to a methylene group.

The equation is incomplete, because it is not balanced. In addition to the arene, what are the other products, and how is the reaction accomplished? This type of equation is generally presented to organic chemistry students, and they have to memorize it, but what if they could scrutinize what is occurring and offer a suggested mechanism compliant with the rules involved in writing acceptable mechanisms. This is the kind of analytical thinking that would occur

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by taking a stepwise approach to a possible mechanism.

Analogous to catalytic hydrogenation, the Clemmensen reduction occurs on the surface of zinc, and mercury helps to facilitate the reaction (more about that after proposing a mechanism).

Step 1 is a fast equilibrium bimolecular protonation step.

Step 2 is a bimolecular step involving transfer of an electron from zinc to the protonated ketone.

Step 3 is a bimolecular equilibrium step involving a second protonation step.

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Step 4 is a unimolecular step involving transfer of electron from zinc in a +1 state to obtain the more stable Zn2+ ion.

Step 5 is a bimolecular step leading to the resonance stabilized aryl carbocation (also a tertiary carbocation).

Step 6 is a bimolecular step involving transfer of electron from zinc to the intermediate formed in step 5.

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Step 7, the final step, is a bimolecular step involving a transfer of electron an addition of H+ to form the arene.

The sum of steps 1-7 would give a balanced chemical equation that illustrates the conversion of the carbonyl group attached to the aromatic nucleus to a methylene group.

The molecular form is

Unlike

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is a balanced chemical equation showing the stoichiometry of the of the products and the reactants. Mercury (not shown in the balance equation) is important, because it helps to supply electrons in the reduction process. Steps 2,4,6, and 7 of the mechanism show zinc as a metal or as Zn+ supplying electrons to the system. Zinc mixed with mercury increases the tendency of Zn and Zn+ to release electrons to the system. Also, note that the carbonyl group is adjacent to the aromatic nucleus. The proximity of the carbonyl group to the aromatic nucleus allows each intermediate in the mechanism to be resonance stabilized.

8. Mechanism of the Wolff-Kishner Reduction

The Clemmensen reduction can be used to reduce a carbonyl group to a methylene group in molecules that are not sensitive to acids or contain groups that could be impacted by reductions in amalgamated zinc and concentrated hydrochloric acid (e.g., double bonds). Compounds containing amine groups will be sensitive to a

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reduction in concentrated hydrochloric acid. Consequently, the Clemmensen reaction will not be as effective with a molecule containing a carbonyl group and an amine group.

A method for reducing carbonyl groups in compounds containing amino groups is the Wolff-Kishner reduction. The reagents for the Wolff-Kishner reduction are hydrazine and a strong base such as sodium hydroxide or potassium hydroxide.

The following series of elementary steps rationalizes the conversion of a carbonyl group to a methylene group by the Wolff-Kishner reduction.

Step 1 is a bimolecular process involving nucleophilic attack on an sp2 carbon atom to produce an sp3 intermediate.

Step 2 is unimolecular step moving the proton proton from a nitrogen atom to the more electronegative oxygen atom.

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Step 3 is a bimolecular step involving base abstraction of a proton generating a stronger base.

Step 4 is a unimolecular step releasing hydroxide ion.

Step 5 is a bimolecular step abstracting a proton attached to an electronegative atom (an acid-base reaction).

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Step 7 is a bimolecular step (acid-base reaction).

Step 8 is a bimolecular step (acid-base reaction).

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Step 9 is a unimolecular step that releases nitrogen, one of the products of the Wolff-Kishner reduction.

Step 10, the final step, is a unimolecular step that produces the product of the reaction.

The sum of steps 1-10 gives the balanced chemical equation for the Wolff-Kishner reduction. Note that the hydroxide ions cancel when the steps are added. This indicates that the hydroxide ion acts as a catalyst in this reaction.

Showing the catalytic affect of the hydroxide ion, the equation could be written in the following manner.

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In addition to aromatic ketones where the carbonyl group is adjacent to the aromatic nucleus, the Clemmensen and the Wolff-Kishner reductions can be used to reduce carbonyl groups of aliphatic and aromatic ketones to methylene groups.

9. Mechanism of Ozonolysis

Ozonolysis of alkenes can be used for structural identification since the products give insight into the location of the double bond in an alkene. Ozonolysis proceeds through the formation of a molozonide first. The molozonide then rearranges to form the ozonide.

Step 1 is a bimolecular step that forms the molozonide.

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Step 2 is a unimolecular step rearranging the molozonide in preparation to form the ozonide.

Step 3 is a bimolecular step forming the ozonide

Cleavage of the ozonide can be accomplished with Zn in water to produce formaldehyde, ketones, and/or aldehydes depending on the attachments to the double bonds.

Step 1 is a bimolecular step involving transfer of an electron from Zn to the ozonide.

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Step 2, the final step, is a unimolecular step showing electron flow to produce carbonyl compounds and zinc oxide.

The sum of the steps of the mechanism gives the stoichiometry of the reactants and products of the reaction.

The proposed mechanism addresses stoichiometric issues.

10. The Synthesis of 7-Ethyl-5-Methyl-6,8-

Dioxabicyclo[3.2.1]Octane (Compound I), a Five-Step Proposed Mechanism, and a Final Consideration

Finally, from a scientific intuitive approach, let’s suggest a stepwise mechanism for the conversion of Compound I from 6,7-dihydroxy-2-nonone.

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Compound I 7-Ethyl-5-methyl-6,8-dioxabicyclo[3.2.1]octaneThenomenclatureforCompoundIisbasedonthefollowingnumberingsystem

Step 1 is a bimolecular equilibrium protonation step

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Step 2 is a unimolecular step involving intramolecular nucleophilic attack on an sp2 hybridized carbon atom converting it to an sp3 hybridized carbon. This should be the rate determining step of the mechanism.

Step 3, a fast equilibrium step, is a unimolecular step involving the transfer of a proton.

Step 4 is a unimolecular step involving a final nucleophilic attack generating the bicyclo ring system.

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Step 5, the final fast equilibrium step, is a bimolecular step involving transfer of a proton.

without considering the stereochemistry of the bicyclo ring system,

7-Ethyl-5-methyl-6,8-dioxabicyclo[3.2.1]octane The sum of steps 1-5 is the acid catalyzed synthesis of 7-ethyl-5-methyl-6,8-dioxabicyclo[3.2.1]octane from 6,7-dihydroxy-2-nonone.

In conclusion, every mechanism in organic chemistry should be written as a series of elementary steps, and the sum of the elementary steps must correspond to the stoichiometry of the balanced chemical equation. So, analogous to inorganic reactions, let’s consider presenting organic reactions as balanced chemical reactions, and mechanisms as a series of elementary steps that rationalize the balanced chemical reactions.

mechanisms in organic chemistry, building bridges to knowledge

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