Mehanizmi organskih reakcija

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Drawing Simple Resonance Structures

Structures such as those shown below for nitromethane are referred to as equivalent contributing structures and the resonance hybrid is the single structure which represents the equal contribution of both of the contributing structures. It is very important to note that a resonance hybrid is not the average of a number of rapidly interconverting forms. The hybrid is the molecule and the resonance forms which we draw are simply devices to represent the limits of electron distribution within the hybrid. By convention, resonance forms are shown connected by "double-headed arrows" to stress the fact that they are not separate valence isomers in some sort of rapid equilibrium. Resonance hybrids are useful to draw because they can often be utilized to predict regions of electron density, or of cationic character which can be useful in predicting or explaining the effects of the structure of organic molecules on their reactivity.

A device which is often used to show the interconversion of resonance forms is the "curved arrow" (shown above). These arrows are designed to show the movement of valence electrons and should begin centered on a bond or a pair of electrons, and end in the final position of the electrons flow. The flow of electrons among resonance forms follows a set of simple rules; electrons may flow: from an atom to an adjacent bond, or from a bond to an adjacent atom, or from a bond to an adjacent bond.

Since the atoms involved must remain bonded, the bonds which are most commonly involved in constructing resonance forms are double and triple bonds and the most common source of electrons on individual atoms are unshared pairs.
While the first two resonance forms shown above are clearly equivalent forms, the third form, involving electron flow from the nitrogen, differs from the first two and is classified as a nonequivalent form. Guidelines for estimating the relative importance of various resonance forms follows: For Resonance forms, Equivalent structures contribute equally,

structures in which all atoms have filled valence shells contribute more than structures in which one or more valence shells are partially filled, structures which involve the generation and separation of charge contribute less than neutral structures, or structures with the same charge, and, structures with negative charges on electronegative atoms contribute more than structures with negative charges on more electropositive atoms.

For the example shown above, the third (nonequivalent) form involves the generation of new charge and will contribute less than the first two. In the example shown below for acetophenone (acetylbenzene), the first two resonance forms involve equivalent, neutral structures in which electrons are simply moved between adjacent sp2 centers and are the most important. The third form, shown below, involves generation of charge, with the electrons on the more electronegative oxygen atom and would contribute more than a form in which the oxygen carried a positive charge, with the carbon being anionic. You should note that all of these are "legal" resonance forms, but that the first two are considered the "major" forms. The third form is useful in explaining why anionic compounds often attack carbonyl carbons (they bear a partial positive charge), but the form shown is of much less importance in the "real" structure of the hybrid than are the first two (neutral) forms. When you are asked to write "major resonance forms", you should focus on those which most clearly follow the guidelines given above.

"Pushing Electrons;" Representing Reaction Mechanisms

The mechanism of a reaction is a step-by-step description of how that reaction is thought to occur. In microscopic detail, chemical reactions involve multiple steps, including encounter equilibria, bondmaking and bond-breaking, diffusion steps and re-hybridization ("heavy atom rearrangement"). In undergraduate organic chemistry, mechanisms are generally simplified to include only bond-making and breaking steps and "curved arrows" are generally utilized to indicate the flow of electrons within these steps. Although these simplified mechanisms are only approximations, they are useful since they allow a clearer understanding of how a given reaction proceeds, and allow reactions to be organized by mechanisms, making the study of organic chemistry simpler and more logical. The process of "pushing electrons" using curved arrows requires a few simple conventions: Movement of a pair of electrons is shown using an arrow with a standard double-barbed arrowhead. Movement of a single electron (a radical reactions) is shown using an arrow with only a single barb. The arrow is drawn from the middle of the electron pair (or single electron) which is moving, to the atom accepting the electron(s).

Thus, homolytic cleavage of a carbon-bromine bond (a radical process) is shown below in (a) and the heterolytic cleavage is shown in (b).

The heterolytic cleavage (b) leads to the formation of a pair of ions, which is indicated in the mechanism by the positive and negative charges. Two examples of this type of heterolytic cleavage reaction which are discussed in elementary organic chemistry are the E1 and SN1 reaction mechanisms. Both of these reactions are unimolecular (the "1") meaning that only one of the reactant molecules is present in the rate-limiting transition state. The prefixes on these general mechanisms refer to elimination ("E") and substitution, nucleophilic ("SN"). Treating the SN1 reaction first, the rate of reaction of 2-methyl-2-propanol with HCl to give 2-chloro2-methylpropane has been found to be independent of the concentration of chloride anion in the reaction mixture, suggesting that only the alcohol is present in the rate-limiting transition state and that reaction with chloride anion is fast. Thus, the rate-limiting step most likely involves acidcatalyzed loss of the hydroxyl group to give an intermediate carbocation (the rate-limiting step is the slowest step in a given reaction sequence). Reaction of the carbocation with chloride anion is then very fast, to give the final product. The major bond-making and bond-breaking steps in this process can be represented by the mechanism shown below.

The protonation step is a rapid equilibrium process (described by the Ka for the protonated alcohol). The slow, or rate-limiting step is the breaking of the carbon-oxygen bond, and the fast step is the addition of chloride anion. Chloride anion concentration does not affect the rate of the reaction since the step involving the nucleophilic attack occurs after the rate-limiting step. An example of a unimolecular elimination reaction (E1) is shown in the scheme below.

In this reaction, 2-chloro-2-methylpropane reacts with a base to lose HCl and form the alkene, 2methylpropene. Again, the rate of this reaction is found to be independent of the concentration of the base that is used, requiring that the only reactant in the rate-limiting transition state is the alkyl halide and that loss of the proton from the carbocation is very fast. In the mechanistic representation of this reaction, the chlorine is shown to depart with a pair of electrons to give the carbocation and chloride anion. To show the process of elimination, the electron pair from the base is shown removing the hydrogen from the carbon adjacent to the carbocation. Concurrent with this, the electron pair from the carbon-hydrogen bond is shown moving into the space between the carbocation and the carbon, to form a carbon-carbon double bond; again, this process must be fast relative to the spontaneous loss of chlorine from the starting material in order for the reaction to be independent of the concentration of the base. Implied in the mechanism, although not generally discussed, is the re-hybridization of the CH2 group and the overlap of the adjacent p-orbitals to form the alkene -system. There are also major changes in the solvation of the (neutral) starting material as it forms ions, and further changes as the neutral alkene is produced. While these steps are generally ignored, examples exist where these types of processes are partially, or largely, rate-limiting. Both of the examples described above are multiple step reactions involving a high-energy intermediate (the carbocation). These types of reactions are said to occur stepwise, and generally one step in the sequence is slow and is rate-limiting. In a concerted process, all of the reactant molecules are present together in the rate-limiting transition state and all of the bond-making and bond-breaking steps occur simultaneously. Two examples of these types of concerted processes are the SN2 and the E2 reaction mechanisms. An example of an SN2 process is shown below:

The rate of the reaction of 2-chloropropane with hydroxide anion is dependent on both the concentration of the alkyl halide and on the concentration of hydroxide anion (the reaction is bimolecular; the "2" in SN2). This means that both of these must be present together in the ratelimiting transition state. The process of substitution within this transition state can be shown using curved arrows as shown above. The electron pair on hydroxide anion is shown to attack to carbon bearing the chlorine (the leaving group) at the same time that the carbon-chlorine bond is breaking. In one simultaneous, coupled, movement the bond from the oxygen to the carbon has formed, the bond from the carbon to the chlorine has undergone heterolytic cleavage, and the central carbon has undergone stereochemical inversion (S-2-chlorobutane has formed R-2-butanol). A concerted reaction such as this does not have a "high energy" intermediate (such as the carbocation, described for the SN1 process), but occurs in a single step through a concerted transition state.

The second common example of a concerted bimolecular process is the E2 elimination.

In an E2 elimination reaction, the rate is dependent on the concentration of the alkyl halide and on the concentration of the base. Again, both of these must be together in the rate-limiting transition step, and the electron flow in this transition state is typically drawn as shown above. In a coupled, concerted process, the electron pair on the base removes the proton from the -carbon at the same time as the electron pair is moving into the space between the carbons at the same time as the carbon-chlorine bond is breaking. Again, there is no intermediate, only the concerted transition state. The reaction mechanisms shown in the animations include examples of concerted bimolecular processes, along with examples of highly complex multiple step reactions. For all of these examples, however, the mechanism can be simplified and shown as a discrete set of electron movements using the curved arrow approach. In those examples where the rate-limiting transition state is wellcharacterized, it is shown as part of the animation. For a more detailed discussion of each of the reactions in this section, please see the discussion in your text.

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Classifying Mechanisms
There are really only a few fundamental mechanistic processes in organic chemistry. Here they are, complete with the curly arrows to show the general bonding changes, for each of the mechanistic classes. Other "more" complex mechanisms are typically composites of this fundamental set. Remember, most of these "classes" can be subdivided depending on the exact order of events (e.g. SN1 or SN2) Links are provided to key descriptions of each mechanism from the chapter pages.

Mechanism

Mechanism

Chapter Ch 4 & 8

Ch 5

Ch 6 & 9

Ch 12

Ch 17

Ch 20

Mehanizmi pojedinih reakcija s detaljima

Free Radical Halogenation

Free Radical Halogenation occurs when either bromine or chlorine is added to an alkane in the presence of light (hv.) Free radical halogenation with flourine or iodine is rarely used because flourine is so reactive that it is not very selective, and the addition of Iodine is so endothermic to be effective as a synthesis of alkyl halides. The reaction begins with an initiation step: the separation of the halide into its radicals by the addition of ultra-violet light. Note the use of a single headed arrow to show the movement of only one electron. Initiation Step:

This step is immediately followed by the Propogation Steps: First the formation of the Tertiary Radical: Propogation Steps:

And then the reaction of the radical with another molecule of Cl2:

Termination steps for free radical reactions are when the radicals collide. This stops the chain reaction because it does not reform the halide radical. Termination Steps:

In this reaction, the halide radical will attack primarily in the place that will yield the most substituted alkyl radical. This is because more highly substituted radicals are more stable. It also prefers the allylic position, the position next to a double bond, and the benzyllic position, the first carbon in a side-chain off a benzene ring because both allow resonance of the radical over one or more carbons, effectively stabilizing it. Free-radical bromination takes place by the exact same mechanism; however, bromine chooses highly substituted carbons more selectively.

Free radicals- halogenation of cycloalkanes

Free Radicals- allylic bromination

Nucleophillic Substition

The Sn2 Reaction--Nucleophillic Bimolecular Substition

Nucleophillic substitution generally has the following form:

But why in the world would a nucleophile want to attack a carbon. The answer lies in that opposite charges attract. A nucleophile is a species that is attracted to positive charges, and oftentimes may even have a full negative charge. Since the leaving group invariably draws electrons from the carbon that it is attached to, it gives the carbon a partially positive charge ( +), making it an attractive candidate for nuclophilic substitution.

The Sn2 Reaction involves displacement of a leaving group (usually a halide or a tosylate), by a nucleophile. For steric reasons, the fastest reactions occur with methyl and primary halides, but sometimes do go with secondary halides (although it is usually accompanied by elimination), and will not react at all with tertiary halides. In the following example, the hydroxide ion is acting as the nucleophile and bromine is the leaving group:

It was found, however, that inversion of configuration occurs. Therefore the following mechanism was proposed--the backside attack of the nucleophile, with the leaving group leaving in a concerted step. This backside attack causes the inversion of stereochemistry shown thus:

This mechanism was consistent with the fact that when the concentration of either the bromomethane or the hydroxide ion concentration was doubled the reaction rate was doubled as well, as defined by the rate equation (rate = kr[CH3Br][-OH].) This is because both are involved in the rate-determining step. As we can see from the reaction diagram, the transition state ( ), is where the

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hydroxide ion has begun to bond and the halide has started to leave.

Stereochemistry of the S 2 Reaction

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Hydroxide anion is a strong nucleophile and will react with primary and secondary alkyl halides by an SN2 mechanism to yield alcohols. In this example, hydroxide anion displaces chloride from S-2-chlorobutane to give R2-butanol. The stereochemical inversion occurs because the central carbon goes planar in the SN2 transition state, and then physically inverts as products are formed. Since the chlorine in the starting material, and the hydroxyl group in the product, are both the "highest priority" atoms around the stereocenter, the absolute stereochemistry simply changes from S to R.

PRIMJERI: S 2 Reaction between Acetylide Anion and Chloromethane

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> Williamson Ether Synthesis

The first step of the Williamson Ether Synthesis is the reaction of a metal with an alcohol to form an alkoxide ion plus hydrogen gas.

Alkoxide ion is a powerful nucleophile, and reacts well in an Sn2 reaction.

The alkyl halide must be primary so that the backside attack is not sterically hindered. When it is not primary, elimination usually results

Organohalides- preparation from ROH and HX

Organohalides- preparation from ROH and PBr3

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ADICIJE
Themes > Science > Chemistry > Organic Chemistry > Common Reaction Mechanisms > Electrophilic Addition to Alkenes Electrophillic addition to alkenes generally takes the following form:

E+ = Electrophile Nuc: = Nucleophile General Mechanism: The first step requires a powerful electrophile to attract the pi bond electrons, which then forms a carbocation. A nucleophile quickly adds to the carbocation to form the monosubstituted product. Types of Electrophilic Addition: Hydroxylation Hydrogenation Halogenation Oxidative Cleavage Hydration Epoxidation Cyclopropanation Halohydrin Formation

Orientation of Addition: Electrophilic Addition adds to give the Markovnikov Product, with the nucleophile added to the more highly substituted carbon. This is because the carbocation intermediate is significantly stabilized by alkyl substituents. Example of Electrophilic Addition HBr to Alkenes:

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The Addition of HBr to an Alkene

The addition of HBr to an alkene is a two-step process: in the first step the alkene is protonated to generate a carbocation. The regiochemistry of this protonation is such that the most stable carbocation is always formed (Markovnikov's Rule). The planar carbocation can add bromide anion from either face, and in the second step, the anion attacks to form the alkyl bromide.

Addition of HCl to 2-Methylpropene

The addition of HCl to an alkene is a two-step process: in the first step the alkene is protonated to generate a carbocation. The regiochemistry of this protonation is such that the most stable carbocation is always formed (Markovnikov's Rule). In this example, protonation on the tertiary carbon would generate a primary carbocation, while protonation on the primary carbon (the CH2) would generate a more stable tertiary carbocation. The planar carbocation can add chloride anion from either face, and in the second step, chloride anion attacks to form the tertiary alkyl chloride. As with any reaction involving carbocation intermediates, if the initially formed carbocation is not the most stable "potential" carbocation in the molecule, rearrangement will most likely occur to
give the most stable carbocation intermediate.

Addition of Bromine - Formation of a Bromonium Ion Addition of Br to an Alkene

2

Strong electrophiles, such as Br+ can add directly to the alkene system to form short-lived

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cyclic addition products. In this example, Br+, formed from the dissociation of Br2, adds to the system of trans-2-butene to give the cyclic bromonium ion. A bromonium ion is strongly electrophilic and can add nucleophiles at one of the alkene carbons. Due to the bulk of the bromonium ion, this attack invariably occurs from the opposite face, generating transaddition products. In this example, bromide anion attacks the bromonium ion to give the trans-dibromide.

Themes > Science > Chemistry > Organic Chemistry > Common Reaction Mechanisms > Hydroboration of Alkenes Hydroboration of Alkenes generally takes the following form:

General Mechanism: The first step involves attack of the double bond on BH3 forming a 4-membered ring transition state. It is because of this transition state that hydroboration forms the Anti-markovnikov product. The steric bulk of the Borane is enough to force it to add to the less stercally hindered side. Peroxide then resolves it into the alcohol. Orientation of Addition: Hydroboration adds to give the Anti-Markovnikov Product, with the alcohol on the less highly substituted carbon. This is due to the steric bulk of the borane. Example of Hydroboration to Alkenes:

Addition of BH to an Alkene
3

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The addition of BH3 to an alkene occurs through a concerted transition state in which the hydrogen and the boron add to the same face of the alkene system to give an alkyl borane with cis-stereochemistry (a syn-addition). In a common second step, the alkyl borane can be oxidized by alkaline hydrogen peroxide to generate an alcohol. Since the hydroxyl group directly replaces the boron, the alcohol formed also represents a syn-addition. Further, the regiochemistry of the addition of the hydrogen and the boron is generally to place the hydrogen on the carbon which would form the most stable carbocation, making the overall addition of the hydroxyl group antiMarkovnikov. This regiochemistry may be the result of a polar, concerted transition state (forming the most stable partially positive carbon), or simply a result of steric bulk.

Reaction of Dichlorocarbene with an Alkene

In the presence of a strong base, chloroform undergoes a 1,1-elimination of HCl to generate the powerful electrophile, dichlorocarbene. You should note that dichlorocarbene is neutral, but since the carbon is surrounded by only six electrons, it is a powerful electrophile. The direct addition of this electrophile to an alkene s ystem results in the formation of a dichlorocyclopropane derivative.

Hydrogenation
Addition of hydrogen to a carbon-carbon double bond is called hydrogenation. The overall effect of such an addition is the reductive removal of the double bond functional group. Regioselectivity is not an issue, since the same group (a hydrogen atom) is bonded to each of the double bond carbons. The simplest source of two hydrogen atoms is molecular hydrogen (H2), but mixing alkenes with hydrogen does not result in any discernible reaction. Although the overall hydrogenation reaction is exothermic, a high activation energy prevents it from taking place under normal conditions. This restriction may be circumvented by the use of a catalyst, as shown in the following diagram.

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Primjer (prvi primjer je obavezan, a onaj s diimidom za Vau informaciju):

Oxidations (i) Hydroxylation

Dihydroxylated products (glycols) are obtained by reaction with aqueous potassium permanganate (pH > 8) or osmium tetroxide in pyridine solution. Both reactions appear to proceed by the same mechanism (shown below); the metallocyclic intermediate may be isolated in the osmium reaction. In basic solution the purple permanganate anion is reduced to the green manganate ion, providing a nice color test for the double bond functional group. From the mechanism shown here we would expect syn-stereoselectivity in the bonding to oxygen, and regioselectivity is not an issue.

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i) Epoxidation
Some oxidation reactions of alkenes give cyclic ethers in which both carbons of a double bond become bonded to the same oxygen atom. These products are called epoxides or oxiranes. An important method for preparing epoxides is by reaction with peracids, RCO3H. The oxygen-oxygen bond of such peroxide derivatives is not only weak (ca. 35 kcal/mole), but in this case is polarized so that the acyloxy group is negative and the hydroxyl group is positive (recall that the acidity of water is about ten powers of ten weaker than that of a carboxylic acid). If we assume electrophilic character for the OH moiety, the following equation may be written.

Epoxides may be cleaved by aqueous acid to give glycols that are often diastereomeric with those prepared by the syn-hydroxylation reaction described above. Proton transfer from the acid catalyst generates the conjugate acid of the epoxide, which is attacked by nucleophiles such as water in the same way that the cyclic bromonium ion described above undergoes reaction. The result is anti-hydroxylation of the double bond, in contrast to the synstereoselectivity of the earlier method. In the following equation this procedure is illustrated for a cis-disubstituted epoxide, which, of course, could be prepared from the corresponding cis-alkene. This hydration of an epoxide does not change the oxidation state of any atoms or groups.

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(iii) Oxidative Cleavage of Double Bonds

Ozonolysis In determining the structural formula of an alkene, it is often necessary to find the location of the double bond within a given carbon framework. One way of accomplishing this would be to selectively break the double bond and mark the carbon atoms that originally formed that bond. For example, there are three isomeric alkenes that all give 2-methylbutane on catalytic hydrogenation. These are 2-methyl-2-butene (compound A), 3-methyl-1-butene (compound B) and 2-methyl-1-butene (compound C), shown in the following diagram. If the double bond is cleaved and the fragments marked at the cleavage sites, the location of the double bond is clearly determined for each case. A reaction that accomplishes this useful transformation is known. It is called ozonolysis, and its application to each of these examples may be seen by clicking the "Show Reaction" button.

Mechanism

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Addition Reactions of Conjugated Dienes

Adition of bromine to conjugated dienes, often give unexpected products. The addition of bromine to 1,3-butadiene is an example. Thus, if one molar equivalent of 1,3-butadiene is treated with one equivalent of bromine, a roughly 50:50 mixture of 3,4-dibromo-1-butene (the expected product) and 1,4-dibromo-2butene (chiefly the E-isomer) is obtained. The latter compound is remarkable in that the remaining double bond is found in a location where there was no double bond in the reactant. This interesting relocation requires an explanation. CH2=CH-CH=CH2 + Br2 BrCH2CHBr-CH=CH2 + BrCH2CH=CHCH 2Br 3,4-dibromo-1-butene 1,4-dibromo-2-butene

The expected addition product from reactions of this kind is the result of 1,2-addition, i.e. bonding to the adjacent carbons of a double bond. The unexpected product comes from 1,4addition, i.e. bonding at the terminal carbon atoms of a conjugated diene with a shift of the remaining double bond to the 2,3-location. These numbers refer to the four carbons of the conjugated diene and are not IUPAC nomenclature numbers. Product compositions are often temperature dependent, as the addition of HBr to 1,3-butadiene demonstrates CH2=CH-CH=CH2 + HBr CH3CHBr-CH=CH2 + CH3CH=CHCH2Br 21

reaction temperature 0 C 40 C

1,2 addition yield 70% 15%

1,4 addition yield 30% 85%

Bonding of an electrophilic atom or group to one of the end carbon atoms of a conjugated diene (#1) generates an allyl cation intermediate. Such cations are stabilized by charge delocalization, and it is this delocalization that accounts for the 1,4-addition product produced in such addition reactions. As shown in the diagram, the positive charge is distributed over carbons #2 and #4 so it is at these sites that the nucleophilic component bonds. Note that resonance stabilization of the allyl cation is greater than comparable stabilization of 1,3-butadiene, because charge is delocalized in the former, but created and separated in the latter.

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Free Radical Reactions of Alkenes 1. Addition of Radicals to Alkenes

Protons and other electrophiles are not the only reactive species that initiate addition reactions to carboncarbon double bonds. Curiously, this first became evident as a result of conflicting reports concerning the regioselectivity of HBr additions. As noted earlier, the acid-induced addition of HBr to 1-butene gave predominantly 2-bromobutane, the Markovnikov Rule product. However, in some early experiments in which peroxide contaminated reactants were used, 1-bromobutane was the chief product. Further study showed that an alternative radical chain-reaction, initiated by peroxides, was responsible for the antiMarkovnikov product. This is shown by the following equations.

The weak OO bond of a peroxide initiator is broken homolytically by thermal or hight energy. The resulting alkoxy radical then abstracts a hydrogen atom from HBr in a strongly exothermic reaction. Once a bromine atom is formed it adds to the -bond of the alkene in the first step of a chain reaction. This addition is regioselective, giving the more stable carbon radical as an intermediate. The second step is carbon radical abstraction of another hydrogen from HBr, generating the anti-Markovnikov alkyl bromide and a new bromine atom. Each of the steps in this chain reaction is exothermic, so once started the process continues until radicals are lost to termination events.

ELIMINATION
Themes > Science > Chemistry > Organic Chemistry > Common Reaction Mechanisms > Second Order Elimination: The E2 Mechanism

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Secondary Elimination generally follows the following form:

General Mechanism: A base attacks a Hydrogen neighboring the leaving group, pushing the electrons into the double bond as the leaving group leaves. Rate Equation: Rate = kr[R-X][B] Points to Watch: Solvent Effects: Substrate Effects: Solvent polarity is unimportant. Can work in a wide variety of solvents Highly substituted substrates work best 3 deg > 2 deg. Primary and methyl halides don't react. Must occur with antiperiplanar stereochemistry. Base strength is important because the base is involved in the rate-determining step Since E2 does not go by carbocation intermediate, no rearangements can occur. Good leaving group required (ie. halide, tosylate, etc)

Stereochemistry:

Effect of Base:

Rearangements: Leaving Group

Mechanism of the E2 Elimination Reaction

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In the presence of polar, non-protic solvents (i.e., DMSO or DMF), alkyl halides undergo reaction with bases to generate alkenes by an E2 mechanism. In the E2 reaction, the proton removed by the base must be anti- to the leaving group, and they must also be periplanar (the hydrogen, the leaving group and the two carbons must all be in the same plane). In the E2 reaction, both the alkyl halide and the base are present in the rate-limiting transition state, making the reaction bimolecular and concerted .

Dehydration of an Alcohol with POCl

Alcohol anions react with POCl3 in pyridine to give dichlorophosphate esters . The dichlorophosphoryl group is a "good leaving group" and these esters undergo further reaction with pyridine to generate alkenes by an E2 mechanism. In the E2 reaction, the proton removed by the base must be anti- to the leaving group, and they must also be periplanar (the hydrogen, the leaving group and the two carbons must all be in the same plane). In the E2 reaction in this example, both the dichlorophosphate ester and pyridine are present in the rate-limiting transition state, making the reaction bimolecular and concerted .

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Themes > Science > Chemistry > Organic Chemistry > Common Reaction Mechanisms > First Order Elimination: The E1 Mechanism First Order Elimination generally follows the following form:

General Mechanism: The first step requires the loss of the leaving group, forming a carbocation intermediate. A base then attacks a neighboring hydrogen forming the double bond. Rate Equation: Rate = kr[R-X] Points to Watch:

Solvent Effects: Substrate Effects:

Solvent polarity is unimportant. Works best in a good ionizing solvent Highly substituted substrates work best 3 deg > 2 deg. Primary and methyl halides don't react.

Stereochemistry No special stereochemistry required : Effect of Base: Base strength is unimportant because the base is not involved in the rate-determining step Since E1 goes by carbocation intermediate, rearangements can occur. Good leaving group required (ie. halide, tosylate, etc)

Rearangements:

Leaving Group

Mechanism of the E1 Elimination Reaction

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In the presence of polar solvents (i.e., alcohols or water), tertiary alkyl halides undergo reaction with bases to generate alkenes by an E1 mechanism. In the E1 reaction, the rate-limiting step is the spontaneous ionization of the alkyl halide to give the tertiary carbocation which is then deprotonated by the base in a fast, second step. In the E1 reaction, only the alkyl halide is present in the rate-limiting transition state, making the reaction unimolecular and stepwise. As with any reaction involving carbocation intermediates, if the initially formed carbocation is not the most stable "potential" carbocation in the molecule, rearrangement will most likely occur to give the most stable carbocation intermediate.

Alcohol Dehydrations
Alcohol Dehydrations generally take the following form:

General Mechanism: First step involves the protonation of the alcohol by an acid, followed by loss of water to give a carbocation. Elimination occurs when the acid conjugate base plucks off a hydrogen. Alcohol dehydrations always go by E1 mechanism.

Points to Watch: Because the intermediate involves carbocation, rearangements can occur Example of Alcohol Dehydrations:

Nucleophilic Addition to Carbonyl Groups

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Nucleophilic Addition to Carbonyl Groups generally takes the following form:

General Mechanism: The nucleophile attacks the partially positive carbonyl group, chasing the electrons onto the Oxygen. Subsequent protonation yields the alcohol. Variety of Nucleophiles: Primjeri: Grignard Reagents Alcohols Amines Alkyl Lithium Reagents Acetylide Ions

Hydration
It has been demonstrated (above) that water adds rapidly to the carbonyl function of aldehydes and ketones. In most cases the resulting hydrate (a geminal-diol) is unstable relative to the reactants and cannot be isolated. Exceptions to this rule exist, one being formaldehyde (a gas in its pure monomeric state). Here the weaker pi-component of the carbonyl double bond, relative to other aldehydes or ketones, and the small size of the hydrogen substituents favor addition. Thus, a solution of formaldehyde in water (formalin) is almost exclusively the hydrate, or polymers of the hydrate.

Acid-Catalyzed Hydration of a Carbonyl

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The oxygen of a carbonyl group undergoes equilibrium protonation in strong acid to give an oxonium ion which greatly increases the electrophilicity of the carbonyl carbon, allowing weak nucleophiles to add to form "tetrahedral addition intermediates" . In this example, equilibrium protonation of the carbonyl oxygen occurs, followed by attack of the solvent (water) on the carbonyl carbon of a ketone or aldehyde. The resulting addition intermediate rapidly loses a proton to form the geminal-diol, also known as a ketone or aldehyde hydrate.

Base-Catalyzed Hydration of a Carbonyl

The carbonyl carbon is electrophilic and reacts with nucleophiles to form "tetrahedral addition intermediates". In this example, hydroxide anion attacks the carbonyl carbon of a ketone or aldehyde to form an anionic addition intermediate, which undergoes protonation to form the geminal-diol, also known as a ketone or aldehyde hydrate.

Hemiacetal/Acetal Formation
Similar acid catalysed hydration a reversible additions of alcohols to aldehydes and ketones take place. The equally unstable addition products are called hemiacetals. Acetals are geminal-diether derivatives of aldehydes or ketones, formed by reaction with two equivalents of an alcohol and elimination of water. Ketone derivatives of this kind were once called ketals, but modern usage has dropped that term. The following equation shows the overall stoichiometric change in acetal formation, but a dashed arrow is used because this conversion does not occur on simple mixing of the reactants.

In order to achieve effective acetal formation two additional features must be implemented. 29

First, an acid catalyst must be used; and second, the water produced with the acetal must be removed from the reaction. The latter is important, since acetal formation is reversible. Indeed, once pure acetals are obtained they may be hydrolyzed back to their starting components by treatment with aqueous acid. The mechanism shown here applies to both acetal formation and acetal hydrolysis by the principle of microscopic reversibility .
Primjeri

Formation of Imines and Related Compounds

The reaction of aldehydes and ketones with ammonia or 1-amines forms imine derivatives, also known as Schiff bases, (compounds having a C=N function). This reaction plays an important role in the synthesis of 2-amines, as discussed earlier. Water is eliminated in the reaction, which is acid-catalyzed and reversible in the same sense as acetal formation.

R2C=O + R'NH2

R'NH(R2)COH

R2C=NR' + H2O

An addition-elimination mechanism for this reaction was proposed, and an animation showing this mechanism is activated by the button. Imines are sometimes difficult to isolate and purify due to their sensitivity to hydrolysis. 30

Consequently, other reagents of the type YNH2 have been studied, and found to give stable products (R2C=NY) useful in characterizing the aldehydes and ketones from which they are prepared

Mechanism of Imine Formation

The addition of amines to ketones and aldehydes proceeds through several concurrent mechanisms, depending on the pH and the nature of the reactants. In this example, free amine attacks the carbon of a carbonyl group to give a Zwitterionic addition intermediate (one positive and one negative charge). This rapidly loses a proton from the nitrogen to give the anionic addition intermediate, which is protonated to give the neutral carbinolamine. Protonation of the carbinolamine on oxygen converts the hydroxyl group into a "good leaving group", which departs, leaving the imonium cation. Equilibrium deprotonation of this gives the neutral imine as final product

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Enamine Formation
The previous reactions have all involved reagents of the type: YNH2, i.e. reactions with a 1-amino group. Most aldehydes and ketones also react with 2-amines to give products known as enamines. Two examples of these reactions are presented in the following diagram. It should be noted that, like acetal formation, these are acid-catalyzed reversible reactions in which water is lost. Consequently, enamines are easily converted back to their carbonyl precursors by acid-catalyzed hydrolysis. A mechanism for enamine formation may be seen by pressing the "Show Mechanism" button.

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Cyanohydrin Formation
The last example of reversible addition is that of hydrogen cyanide (HCN), which adds to aldehydes and many ketone to give products called cyanohydrins. RCH=O + HCN RCH(OH)CN (a cyanohydrin)

Since hydrogen cyanide itself is an acid (pKa = 9.25), the addition is not acid-catalyzed. In fact, for best results cyanide anion, CN(-) must be present, which means that catalytic base must be added. Cyanohydrin formation is weakly exothermic, and is favored for aldehydes, and unhindered cyclic and methyl ketones. Two examples of such reactions are shown below.

The cyanohydrin from benzaldehyde is named mandelonitrile. The reversibility of cyanohydrin formation is put to use by the millipede Apheloria corrugata in a remarkable defense mechanism. This arthropod releases mandelonitrile from an inner storage gland into an outer chamber, where it is enzymatically broken down into benzaldehyde and hydrogen cyanide before being sprayed at an enemy.

Reduction by Complex Metal Hydrides

Addition of a hydride anion to an aldehyde or ketone would produce an alkoxide anion, which on protonation should yield the corresponding alcohol. Aldehydes would give 1-alcohols (as shown) and ketones would give 2-alcohols. RCH=O + H:() Primjeri: RCH2O() + H3O() RCH2OH

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Addition of Organometallic Reagents

The two most commonly used compounds of this kind are alkyl lithium reagents and Grignard reagents. They are prepared from alkyl and aryl halides, as discussed earlier. These reagents are powerful nucleophiles and very strong bases (pKa's of saturated hydrocarbons range from 42 to 50), so they bond readily to carbonyl carbon atoms, giving alkoxide salts of lithium or magnesium. Because of their ring strain, epoxides undergo many carbonyl-like reactions, as noted previously. Reactions of this kind are among the most important synthetic methods available to chemists, because they permit simple starting compounds to be joined to form more complex structures. Examples are shown in the following diagram.

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Example of Nucleophilic Addition to Carbonyl Groups:

Other Carbonyl Group Reactions A. Reduction

Wolff-Kishner Reduction Reaction of an aldehyde or ketone with excess hydrazine generates a hydrazone derivative, which on heating with base gives the corresponding hydrocarbon. A high-boiling hydroxylic solvent, such as diethylene glycol, is commonly used to achieve the temperatures needed. 35

The following diagram shows how this reduction may be used to convert cyclopentanone to cyclopentane. A second example, in which an aldehyde is similarly reduced to a methyl group, also illustrates again the use of an acetal protective group. The mechanism of this useful transformation involves tautomerization of the initially formed hydrazone to an azo isomer, and will be displayed on pressing the "Show Mechanism" button. The strongly basic conditions used in this reaction preclude its application to base sensitive compounds.

Fischer Esterification

The oxygen of a carbonyl group undergoes equilibrium protonation in strong acid to give an oxonium ion, which greatly increases the electrophilicity of the carbonyl carbon, allowing weak nucleophiles to add to form

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"tetrahedral addition intermediates" . In this example, equilibrium protonation of the carbonyl oxygen occurs, followed by attack of the solvent (alcohol) on the carbonyl carbon of a carboxylic acid. The resulting addition

intermediate rapidly loses a proton to form the neutral intermediate. Equilibrium protonation of this intermediate on one of the hydroxyl groups converts that hydroxyl group into a "good leaving group". Loss of water forms an intermediate oxonium ion which rapidly loses a proton to give the final product, a carboxylic acid ester. Note that all of these steps are in equilibrium, and the position of the equilibrium (ester hydrolysis or ester formation) is governed by the reaction conditions; i.e., excess water leads to hydrolysis, excess alcohol leads to esterification. This reaction is generally referred to as Fischer Esterification.

Hydrolysis of an Ester by Base

The carbonyl carbon is electrophilic and reacts with nucleophiles to form "tetrahedral addition intermediates" . In this example, hydroxide anion attacks the carbonyl carbon of a carboxylate ester to form an anionic addition intermediate. Collapse of this intermediate reforms the carbonyl carbon with the concurrent loss of the alkoxy group, yielding the carboxylic acid. Since the acid is formed in base, it is in equilibrium with the corresponding carboxylate anion.

Hydrolysis of an Ester by Acid

The oxygen of a carbonyl group undergoes equilibrium protonation in strong acid to give an oxonium ion, which greatly increases the electrophilicity of the carbonyl carbon, allowing weak nucleophiles to add to form "tetrahedral addition intermediates" . In this example, equilibrium protonation of the carbonyl oxygen occurs, followed by attack of the solvent (water) on the carbonyl carbon of a carboxylate ester. The resulting addition intermediate rapidly loses a proton to form the neutral intermediate. Equilibrium protonation of this intermediate on the alkoxy group converts that group into a "good leaving group". Loss of alcohol forms an intermediate oxonium ion which rapidly loses a proton to give the final product, a carboxylic acid

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Acyl Transfer Reactions

The carbonyl carbon is electrophilic and reacts with nucleophiles to form "tetrahedral addition intermediates". In this example, a generic nucleophile attacks the carbonyl carbon of an acyl compound (a carboxylic acid derivative; an acid halide, an acid anhydride, a carboxylate ester, a protonated carboxylic acid, or an amide) to form an anionic addition intermediate. Collapse of this intermediate reforms the carbonyl carbon with the concurrent loss of one of the attached groups. In this example, the nucleophile remains and the "leaving group" departs, forming a new acyl derivative (hence, "acyl transfer").

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Carbonyl Substitution

The oxygen of a carbonyl group undergoes equilibrium protonation in strong acid to give an oxonium ion, which greatly increases the acidity of hydrogens on adjacent carbons (carbons ). In this example, equilibrium protonation of the carbonyl oxygen occurs, followed by removal of an hydrogen by the solvent to give an enol intermediate. By virtue of resonance with the oxygen, the enol carbon has electron density and reacts with electrophiles (E+ in this example) to form addition compounds. The initial cation is rapidly deprotonated to give the final substitution product.

Carbonyl Condensation Reactions

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Hydrogens on carbons which are adjacent to carbonyls (carbons ) are acidic and undergo equilibrium proton transfer to give enolate anions. By virtue of resonance with the oxyanion, the enol carbon has significant electron density and reacts with weak electrophiles (a second carbonyl carbon in this example) to form substitution compounds. The initial oxyanion is rapidly protonated by the solvent to give the final carbonyl condensation product, a hydroxy carbonyl compound

The Aldol Condensation

Hydrogens on carbons which are adjacent to carbonyls (carbons ) are acidic and undergo equilibrium proton transfer to give enolate anions. By virtue of resonance with the oxyanion, the enolate carbon has significant electron density and reacts with weak electrophiles (a second mole of acetaldehyde in this example) to form substitution compounds. The initial oxyanion is rapidly protonated by the solvent to give the final carbonyl condensation product. The hydroxy carbonyl compound in this example, formed from two moles of acetaldehyde, is called "aldol", and the reaction is generally referred to as the aldol condensation.

The Claisen Condensation

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Hydrogens on carbons which are adjacent to carbonyls (carbons ) are acidic and undergo equilibrium proton transfer to give enolate anions. In this example, the carboxylic acid ester, ethyl acetate is the reactant and ethoxide anion is the base. By virtue of resonance with the oxyanion, the enolate carbon has significant electron density and reacts with weak electrophiles (a second mole of ethyl acetate in this example) to form an anionic tetrahedral addition intermediate. Collapse of this intermediate, with the expulsion of ethoxide, gives the final product, ethyl acetoacetate (ethyl 3-oxo-butanoate). This reaction is generally referred to as the Claisen condensation.

Michael Addition of a Keto Ester with an ,Unsaturated Ketone

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Hydrogens on carbons which are adjacent to two carbonyls are significantly acidic and undergo equilibrium proton transfer to give enolate anions. By virtue of resonance with the oxyanion, the enolate carbon has significant electron density and reacts with weak electrophiles (the carbon of an ,unsaturated ketone in this example) to form substitution compounds. (The position of an ,unsaturated aldehyde or ketone is electrophilic due to resonance with the adjacent carbonyl group.) The initial oxyanion collapses and the carbanion is rapidly protonated by the solvent to give the final condensation product. The addition of nucleophiles to the positions of ,unsaturated carbonyl compounds is generally referred to as a Michael
addition

Nucleophilic substitution- Aldehydes to carboxylic acids and alcohols- Cannizzaro reaction

Cyclisation- carbanion based- Dieckmann cyclisation

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Robinson annelation
Enols and Enolates- Robinson ring annelation

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Hofmann Rearrangement
Mechanism of the Hofmann Rearrangement

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The Hofmann Rearrangement of amides to give amines follows a complex mechanism including an alkyl group migration and the decarboxylation of a carbamic acid. The sequence begins with deprotonation of the amide nitrogen by base to give an anion, which reacts with bromine to give an N-bromo amide. Deprotonation of this intermediate forms an anion which can expel bromide anion with the concurrent migration of the alkyl group from the carbonyl carbon to the nitrogen, yielding an alkyl isocyanate. Addition of hydroxide anion to the isocyanate carbon gives (after proton equilibration) the carbamic acid anion. This intermediate is unstable and rapidly decarboxylates, forming carbon dioxide and an amine anion. Rapid protonation of this anion gives the primary amine as the final product.

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Beckmann Rearrangement

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Baeyer-Villiger Rearrangement

Substitution Reactions of Benzene Derivatives

When substituted benzene compounds undergo electrophilic substitution reactions of the kind discussed above, two related features must be considered: I. The first is the relative reactivity of the compound compared with benzene itself. Experiments have shown that substituents on a benzene ring can influence reactivity in a profound manner. For example, a hydroxy or methoxy substituent increases the rate of electrophilic substitution about ten thousand fold, as illustrated by the case of anisole in the virtual demonstration (above). In contrast, a nitro substituent decreases the ring's reactivity by roughly a million. This activation or deactivation of the benzene ring toward electrophilic substitution may be correlated with the electron donating or electron withdrawing influence of the substituents, as measured by molecular dipole moments. In the following diagram we see that electron donating substituents (blue dipoles) activate the benzene ring toward electrophilic attack, and electron withdrawing substituents (red dipoles) deactivate the ring (make it less reactive to electrophilic attack).

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The influence a substituent exerts on the reactivity of a benzene ring may be explained by the interaction of two effects: The first is the inductive effect of the substituent. Most elements other than metals and carbon have a significantly greater electronegativity than hydrogen. Consequently, substituents in which nitrogen, oxygen and halogen atoms form sigma-bonds to the aromatic ring exert an inductive electron withdrawal, which deactivates the ring (left-hand diagram below). The second effect is the result of conjugation of a substituent function with the aromatic ring. This conjugative interaction facilitates electron pair donation or withdrawal, to or from the benzene ring, in a manner different from the inductive shift. If the atom bonded to the ring has one or more non-bonding valence shell electron pairs, as do nitrogen, oxygen and the halogens, electrons may flow into the aromatic ring by p- conjugation (resonance), as in the middle diagram. Finally, polar double and triple bonds conjugated with the benzene ring may withdraw electrons, as in the right-hand diagram. Note that in the resonance examples all the contributors are not shown. In both cases the charge distribution in the benzene ring is greatest at sites ortho and para to the substituent. In the case of the nitrogen and oxygen activating groups displayed in the top row of the previous diagram, electron donation by resonance dominates the inductive effect and these compounds show exceptional reactivity in electrophilic substitution reactions. Although halogen atoms have non-bonding valence electron pairs that participate in p- conjugation, their strong inductive effect predominates, and compounds such as chlorobenzene are less reactive than benzene. The three examples on the left of the bottom row (in the same diagram) are examples of electron withdrawal by conjugation to polar double or triple bonds, and in these cases the inductive effect further enhances the deactivation of the benzene ring. Alkyl substituents such as methyl increase the nucleophilicity of aromatic rings in the same fashion as they act on double bonds.

II. The second factor that becomes important in reactions of substituted benzenes concerns the site at which electrophilic substitution occurs. Since a mono-substituted benzene ring has two equivalent ortho-sites, two equivalent meta-sites and a unique para-site, three possible

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constitutional isomers may be formed in such a substitution. If reaction occurs equally well at all available sites, the expected statistical mixture of isomeric products would be 40% ortho, 40% meta and 20% para. Again we find that the nature of the substituent influences this product ratio in a dramatic fashion. Bromination of methoxybenzene (anisole) is very fast and gives mainly the para-bromo isomer, accompanied by 10% of the ortho-isomer and only a trace of the metaisomer. Bromination of nitrobenzene requires strong heating and produces the meta-bromo isomer as the chief product.

Some additional examples of product isomer distribution in other electrophilic substitutions are given in the table below. It is important to note here that the reaction conditions for these substitution reactions are not the same, and must be adjusted to fit the reactivity of the reactant C6H5-Y. The high reactivity of anisole, for example, requires that the first two reactions be conducted under very mild conditions (low temperature and little or no catalyst). The nitrobenzene reactant in the third example is very unreactive, so rather harsh reaction conditions must be used to accomplish that reaction.

CH3

Cl or Br

NO2

RC=O

SO3H

OH

NH2

Saetak
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Electrophilic Aromatic Substitution

In electrophilic aromatic substitution, strong electrophiles, such as Br+ directly add to the arene ring to form shortlived addition products, termed sigma-complexes . In a sigma-complex, one of the ring carbons is sp3, and a positive charge appears on the adjacent ring carbon. Because of the presence of the sp3 carbon, the ring is no longer aromatic, and has lost the aromatic stabilization energy. Removal of a proton from the sp3 carbon allows the atom to re-hybridize and to promote the electrons to a orbital, re-forming the aromatic sextet. In this example, Br+, formed from the dissociation of the Br2-FeBr3 complex, adds to the ring to give the sigma-complex. Loss of a proton gives the final product, bromobenzene. This general mechanism is applicable for a wide variety of
electrophiles, including NO+, HSO3+, R+ and RC O+.

Characteristics of Specific Substitution Reactions Halogenation: C6H6 + Cl2 & heat FeCl3 catalyst Nitration: Sulfonation: Alkylation: Friedel-Crafts Acylation: Friedel-Crafts C6H6 + HNO3 & heat H2SO4 catalyst C6H6 + H2SO4 + SO3 & heat C6H6 + R-Cl & heat AlCl3 catalyst C6H6 + RCOCl & heat AlCl3 catalyst

> C H Cl
6 5 6 5

+ HCl
2

Chlorobenzene + H2O + H2O + HCl + HCl Nitrobenzene

6 5 3

> C H NO

> C H SO H > C H -R
6 5 6 5

Benzenesulfonic acid An Arene An Aryl Ketone

> C H COR

Nucleophilic Aromatic Substitution

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In nucleophilic aromatic substitution, strong nucleophiles, such as HO- directly add to the arene ring to form shortlived addition products, termed sigma-complexes . In a sigma-complex in nucleophilic aromatic substitution, one of
the ring carbons is sp3, and a negative charge appears on the adjacent ring carbon, which is generally delocalized onto an attached electropositive group, such as a nitro group. Because of the presence of the sp3 carbon, the ring is no longer aromatic, and has lost the aromatic stabilization energy. Loss of the leaving group from the sp3 carbon

allows the atom to re-hybridize and to promote the electrons to a orbital, re-forming the aromatic sextet. In this example, HO- adds to carbon #1 of 1-chloro-2-nitrobenzene to give the sigma-complex. Loss of the chlorine gives the final product, bromobenzene. Nucleophilic aromatic substitution is limited to rings with a potential leaving group
and with one or more strongly electropositive groups.

Pericyclic Reactions
An important body of chemical reactions, differing from ionic or free radical reactions in a number of respects, has been recognized and extensively studied. Among the characteristics shared by these reactions, three in particular set them apart.: 1. They are relatively unaffected by solvent changes, the presence of radical initiators or scavenging reagents, or (with some exceptions) by electrophilic or nucleophilic catalysts. 2. They proceed by a simultaneous (concerted) series of bond breaking and bond making events in a single kinetic step, often with high stereospecificity. 3. In agreement with 1 & 2, no ionic, free radical or other discernible intermediates lie on the reaction path. Since reactions of this kind often proceed by nearly simultaneous reorganization of bonding electron pairs by way of cyclic transition states, they have been termed pericyclic reactions. The four principle classes of pericyclic reactions are termed: Cycloaddition, Electrocyclic, Sigmatropic, and Ene Reactions. A general illustration of each class will be displayed by clicking on the following diagram. The cycloaddition and ene reactions are shown in their intermolecular format. Corresponding intramolecular reactions, which create an additional ring, are well known.

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All these reactions are potentially reversible (note the gray arrows). The reverse of a cycloaddition is called cycloreversion and proceeds by a ring cleavage and conversion of two sigma-bonds to two pi-bonds. The electrocyclic reaction shown above is a ring forming process. The reverse electerocyclic ring opening reaction proceeds by converting a sigmabond to a pi-bond. As shown, the retro ene reaction cleaves an unsaturated compound into two unsaturated fragments. Finally, sigmatropic bond shifts may involve a simple migrating group, as shown in the example above, or may take place between two pi-electron systems (e.g. the Cope rearrangement). The general descriptions shown above provide a basis for reaction classification, but care must be taken to assure that a given transformation is truly concerted. Unfortunately, this is not a trivial determination, often requiring a combination of isotope labeling and stereochemical studies to arrive at a plausible conclusion. There is also a subtle distinction to be made between a synchronous reaction in which all bond-making and bond-breaking events take place in unison, and a multi-stage concerted process in which some events precede others without generating an intermediate state. Although some pericyclic reactions occur spontaneously, most require the introduction of energy in the form of heat or light, with a remarkable product dependence on the source of energy used. An appreciation of the stereoselective structural changes these reactions promote is best achieved by inspecting some individual examples.

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1. Cycloaddition Reactions
A concerted combination of two -electron systems to form a ring of atoms having two new bonds and two fewer bonds is called a cycloaddition reaction. The number of participating -electrons in each component is given in brackets preceding the name, and the reorganization of electrons may be depicted by a cycle of curved arrows - each representing the movement of a pair of electrons. These notations are illustrated in the drawing on the right. The ring-forming cycloaddition reaction is described by blue arrows, whereas the ringopening cycloreversion process is designated by red arrows. Note that the number of curved arrows needed to show the bond reorganization is half the number total in the brackets.

Diels-Alder Cycloaddition or [4 + 2] Cycloaddition

The most common cycloaddition reaction is the [4+2] cyclization known as the Diels-Alder reaction. In Diels-Alder terminology the two reactants are referred to as the diene and the dienophile. The following diagram shows two examples of [4+2] cycloaddition, and in the second equation a subsequent light induced [2+2] cycloaddition. In each case the diene reactant is colored blue, and the new -bonds in the adduct are colored red. The stereospecificity of these reactions should be evident. In the first example, the acetoxy substituents on the diene have identical E-configurations, and they remain cis to each other in the cyclic adduct. Likewise, the ester substituents on the dienophile have a transconfiguration which is maintained in the adduct. The reactants in the second equation are both monocyclic, so the cycloaddition adduct has three rings. The orientation of the quinone six-membered ring with respect to the bicycloheptane system (colored blue) is endo, which means it is oriented cis to the longest or more unsaturated bridge. The alternative configuration is called exo. Since the dienophile (quinone) has two activated double bonds, a second cycloaddition reaction is possible, provided sufficient diene is supplied. The second cycloaddition is slower than the first, so the monoadduct shown here is easily prepared in good yield. Although this [4+2] product is stable to further heating, it undergoes a [2+2] cycloaddition when exposed to sunlight. Note the loss of two carbon-carbon -bonds and the formation of two -bonds (colored red) in this transformation. Also note that the pi-subscript is often omitted from the [m+n] notation for the majority of cycloadditions involving -electron systems.

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The essential characteristics of the Diels-Alder cycloaddition reaction may be summarized as follows: (i) The reaction always creates a new six-membered ring. When intramolecular, another ring may also be formed. (ii) The diene component must be able to assume a s-cis conformation. (iii) Electron withdrawing groups on the dienophile facilitate reaction. (iv) Electron donating groups on the diene facilitate reaction. (v) Steric hindrance at the bonding sites may inhibit or prevent reaction. (vi) The reaction is stereospecific with respect to substituent configuration in both the dienophile and the diene. These features are illustrated by the following eight examples, one of which does not give a Diels-Alder cycloaddition. Try to predict the course of each reaction before disclosing the answers by pressing the "Show Products" button. The formation of a new six-membered ring should be apparent in every case where reaction occurs. Dodatni primjeri

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3. Sigmatropic Rearrangements
The [3,3] sigmatropic rearrangement of 1,5-dienes (Cope rearrangement) and allyl vinyl ethers, ( Claisen rearrangement) are among the most commonly used sigmatropic reactions. Three examples of the Cope rearrangement are shown in the following diagram. Reactions 1 and 2 (top row) demonstrate the stereospecificity of this reaction. The light blue -bond joins two allyl groups, oriented so their ends are near each other. Since each allyl segment is the locus of a [1,3] shift, the overall reaction is classified as a [3,3] rearrangement. The three pink colored curved arrows describe the redistribution of three bonding electron pairs in the course of this reversible rearrangement. The diene reactant in the third reaction is drawn in an extended conformation. This molecule must assume a coiled conformation (as above) before the [3,3] rearrangement can take place. The product of this rearrangement is an enol which immediately tautomerizes to its keto form. Such variants are termed the oxy-Cope rearrangement, and are useful because the reverse rearrangement is blocked by rapid ketonization. If the hydroxyl substituent is converted to an alkoxide salt, the activation energy of the rearrangement is lowered significantly. The degenerate or self-replicating Cope rearrangement has been a fascinating subject of research. For examples .

Two examples of the Claisen Rearrangement may be seen by clicking on the above diagram. Reaction 4. is the classic rearrangement of an allyl phenyl ether to an ortho-allyl phenol. The methyl substituent on the allyl moiety serves to demonstrate the bonding shift at that site. The initial cyclohexadienone product immediately tautomerizes to a phenol, regaining the stability of the aromatic ring. Reaction 5 is an aliphatic analog in which a vinyl group replaces the aromatic ring. In both cases three pairs of bonding electrons undergo a reorganization. By clicking on the above diagram a second time two examples of [2,3] sigmatropic rearrangements will be displayed.

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