organo halides halogen derivatives of hydrocarbons

Halogen derivatives of hydrocarbons:

Bonding system and physical properties. Factors affecting theC-Hlg bond strength of the response relationship skills.Halides with reduced, normal and increased reactivity. Keymechanisms and application of nucleophilic substitution (SN1and SN2). Factors affecting nucleophilic substitution.

Elimination reactions: - and -elimination, basic mechanismof -elimination (E1, E2 and E1cB). Substitution and eliminationshare of influence. Reaction of halogen compounds withmetals. Preparation of aliphatic and aromatic halogencompounds.

ORGANO HALIDES

Classification of C-Hlg compounds

According to Hlg qualityNumbers of Hlg (di-, tri-, tetra- etc.)

in case of dihalides:

Type of carbon chain: • aliphatic (saturated, unsaturated)• aromatic

The order of C (primary, secondary, or tertiary according to the classification of the carbon that bears the functional group)

n 1

Particular importance of the hybrid form of the - and -carbon reactivity

n 2

• trivial names: eg. chloroform, iodoform, fluothane

Nomenclature

• substitution nomenclature (substitutive nomenclature) - halogen name as a prefix only!

• functional group nomenclature (functional class nomenclature): hydrocarbon group + halide (fluoride, chloride, bromide, iodide) Suffix - assuming that no higher priority functional group

The IUPAC rules permit alkyl halides to be named in two different ways, called functional

class nomenclature and substitutive nomenclature.

In functional class nomenclature the alkyl group and the halide ( fluoride, chloride, bromide, or iodide) are

designated as separate words. The alkyl group is named on the basis of its longest continuous

chain beginning at the carbon to which the halogen is attached.

Substitutive nomenclature of alkyl halides treats the halogen as a halo- ( fluoro-, chloro-, bromo-, or iodo-)

substituent on an alkane chain. The carbon chain is numbered in the direction that gives the substituted carbon the

lower locant.

When the carbon chain bears both a halogen and an alkyl substituent, the two substituents are considered of equal

rank, and the chain is numbered so as to give the lower number to the substituent nearer the end of the chain.

Substitutive names are preferred, but functional class names are sometimes more convenient or more familiar and

are frequently encountered in organic chemistry.

IUPAC NOMENCLATURE OF ALKYL HALIDES

Francis A. Carey: Organic Chemistry (4th Edition), ISBN 0-07-290501-8; The McGraw-Hill Companies, Inc., 2000, p. 127

Substitutive nomenclature of alkyl halides

John McMurry: Organic Chemistry (7th Edition), ISBN-10: 0840054440 ISBN-13: 9780840054449, Brooks/Cole, 2012, p. 333

Bonding system of C-Hlg compounds

Typically EN(Hlg) > EN(C) polarized hetero nuclear -bond, partial positive charge on carbon atom(-I effect)

BUT! If the pillar C is a sp2 or sp hybridized +M effect also occurs. Result: shorter, stronger bonds

Carbon–halogen bonds are polar covalent bonds, and carbon bears a partial positive charge in alkyl halides. The presence of this polar bond makes alkyl halides polar molecules.

Electronegativity (EN): A measure of the ability of an atom to attract the electrons in a covalent bond toward itself. Fluorine is the most electronegative element.

Inductive effect: An electronic effect transmitted by successive polarization of the bonds within a molecule or an ion. OR The electron-donating or electron-withdrawing effect of a group that is transmitted through bonds is called an inductive effect.

Electronic effect: An effect on structure or reactivity that is attributed to the change in electron distribution that a substituent causes in a molecule.

Electronegativity is a chemical property that describes the tendency of an atom to attract electrons in a covalent bond towards itself.

Average C-Hlg bond energy (kJ/mol)C-F 488C-Cl 326C-Br 278C-I 210 (est.)Reason: weaker overlapping,

smaller charge separation

C-Hlg dissociation energy (kJ/mól)

homolytic heterolytic

F Br F Br

MeCH2-Hlg 448 282 920 770

PhCH2Hlg 403 229 820 657

CH2=CH-Hlg 497 320 1004 837

C-Hlg bond energy depends on: the quality of halogen, carbon hybrid status

Halogens increase in size going down the periodic table, so the lengths of the correspondingcarbon-halogen bonds increase accordingly. In addition, C―X bond strengths decrease goingdown the periodic table.

C-Hlg bond energy

C-Hlg bond distance depends on: the quality of halogen, carbon hybrid status

C-Hlg bond distance

dC-Hlg (nm)

F Cl Br I

0.139 0.178 0.195 0.214

0.133 0.172 0.188 0.210

Longer bonds

Sho

rte

rb

on

ds

Tendencies:1. aryl/vinyl halides: stronger bonds (+M effect)2. allyl/benzyl halides: weaker bonds - greater stability of the formed radical/cation

has a lower energy3. homolytic bond cleavage requires less energy

BUT!! This is true in gas phase, in solution the solvation energy can overwrite it

Bonding system of C-Hlg compounds 2.

Expected results

• aryl/vinyl halides are less reactive than simple alkyl halides

• allyl/benzyl halides are more reactive than alkyl halides

C-Hlg dissociation energy (kJ/mól)

homolytic heterolytic

F Br F Br

MeCH2-Hlg 448 282 920 770

PhCH2Hlg 403 229 820 657

CH2=CH-Hlg 497 320 1004 837

benzyl

alkyl

vinyl

Due to the ground state polarization: dipole moment appears

Me-F: 1.81 D Me-Cl: 1.87 D Me-Br: 1.80 D

The presence of the polar bonds makes alkyl halides polar molecules.

Electrostatic potential maps ofchloromethane. The most positivelycharged regions are blue, the mostnegatively charged ones red. Theelectrostatic potential is mostnegative near chlorine inchloromethane.

Distribution of electron density in chloromethane:

The polarization of the bonds to chlorine, as well as its unshared electron pairs, contribute to the concentration of negative charge on chlorine atoms.Relatively simple notions of attractive forces between opposite charges are sufficient to account for many of the properties of chemical substances. You will find it helpful to keep the polarity of carbon–oxygen and carbon–halogen bonds in mind as we develop the properties of alcohols and alkyl halides in later sections.

Halogens are more electronegative than carbon. The C-X bond is therefore polar, withthe carbon atom bearing a slight positive and the halogen a slight negative charge.

Dipole moment

The effective dipole moment is formed by two factors: the value of charge separation (EN difference) and the bond length.

CH3-Br CH3CH2-Br CH3CH2CH2-Br

[D] 1.80 1.88 1.92

Cause: Charge separation runs through the chain.Important lessons for the future: electron-withdrawing groups reduce the electron density not only of the carbon but also decreasing around the carbon and reduce the electron density of the carbon!!!

BUT! due to the nature of elementary dipole moments the resultant vector may be zero!

Bromine is less electronegative than chlorine, yet methyl bromide and methyl chloride have very similar dipole moments. Why?Dipole moment is the product of charge and distance. Although the electron distribution in the carbon–chlorine bond is more polarized than that in the carbon–bromine bond, this effect is counterbalanced by the longer carbon–bromine bond distance.

= 0

Halogens are more electronegative than carbon. The C-X bond is therefore polar, with thecarbon atom bearing a slight positive and the halogen a slight negative charge. This polarity results in a substantial dipole moment for all the halomethanes and impliesthat the alkyl halide C-X carbon atom should behave as an electrophile in polar reactions. We’ll see that much of the chemistry of alkyl halides is indeed dominated by theirelectrophilic behavior.

Don’t forget!

Physical properties of C-Hlg compounds

The forces of attraction between neutral molecules are of three types listed here. The first two of these involve induced dipoles and are often referred to as dispersion forces, or London forces.1. Induced-dipole/induced-dipole forces2. Dipole/induced-dipole forces3. Dipole–dipole forces

Induced-dipole/induced-dipole forces are the only intermolecular attractive forcesavailable to nonpolar molecules such as alkanes. In addition to these forces, polar moleculesengage in dipole–dipole and dipole/induced-dipole attractions.

The dipole–dipole attractive force is easiest to visualize. Two molecules of a polar substance experience a mutual attraction between the positively polarized region of one molecule and the negatively polarized region of the other.

Two molecules of a polar substance areoriented so that the positively polarizedregion of one and the negatively polarizedregion of the other attract each other.

As its name implies, the dipole/induced-dipole force combines features of both the induced-dipole/induced dipole and dipole–dipole attractive forces. A polar region of one molecule alters the electron distribution in a nonpolar region of another in a direction that produces an attractive forcebetween them.

Francis A. Carey: Organic Chemistry (4th Edition), ISBN 0-07-290501-8; The McGraw-Hill Companies, Inc., 2000, p. 130.

Physical properties of C-Hlg compounds 2.

With respect to the halogen in a group of alkyl halides, the boiling point increases as one descends the periodic table; alkyl fluorides have the lowest boiling points, alkyl iodides the highest. This trend matches the order of increasing polarizability of the halogens.Polarizability is the ease with which the electron distribution around an atom is distorted by a nearby electric field and is a significant factor in determining the strength of induced-dipole/induced-dipole and dipole/induced-dipole attractions. Forces that depend on induced dipoles are strongest when the halogen is a highly polarizable iodine, and weakest when the halogen is a nonpolarizable fluorine.

When comparing the boiling points of related compounds as a function of the alkyl group, we find that the boiling point increases with the number of carbon atoms, as it does withalkanes.


Melting point (Mp) and boiling point (bp) – forces: dipole-dipole interactionMp and bp are greater than in case of the alkanes, alkenes with the same number of C’s.

R-Hlg boiling point (oC) R-H (oC)

Hlg F Cl Br

Me-Hlg -78 -24 4 -162

Et-Hlg -32 12 38 -89

Bu-Hlg 32 79 102 -1

Bp is increasing: • changes in the quality of halogen (F → I)• increase in the number of carbon atoms• increase in the number of Hlg-s (except fluorides)


Conlusion

Solubility

Properties: low water solubility (all alkyl halides are insoluble in water, H bridges are stronger than dipole-dipole interactions). Highly dissolves the less polar organic substances, fats.

good extraction agents good cleanersmodification of biological lipid-lipid systems, high narcotic effect (e.g. fluothane:

CHClBr-CF3)

Density – increasing F → I, and with the number of Hlg-s, BUT decreasing with the size of the carbon chain

d(Me-F) = 0.877 g/cm3, d(Pr-F) = 0.779 g/cm3

d(Me-Cl) = 0.991 g/cm3, d(CHCl3) = 1.489 g/cm3 (but! d(CHBr3) = 2.890 g/cm3

d(Me-Br) = 1.732 g/cm3


Because alkyl halides are insoluble in water, a mixture of an alkyl halide and waterseparates into two layers. When the alkyl halide is a fluoride or chloride, it is the upperlayer and water is the lower. The situation is reversed when the alkyl halide is a bromide oran iodide. In these cases the alkyl halide is the lower layer. Polyhalogenation increases thedensity. The compounds CH2Cl2, CHCl3, and CCl4, for example, are all more dense thanwater.

Preparation of C-Hlg compounds1. Synthesis of alkyl halides

1.1. Halogenation of alkanes

It involves substitution of a halogen atom for one of the alkane’s hydrogens.

The alkane is said to undergo fluorination, chlorination, bromination, or iodinationaccording to whether X2 is F2, Cl2, Br2, or I2, respectively. The general term ishalogenation. Chlorination and bromination are the most widely used.The reactivity of the halogens decreases in the order F2 > Cl2 > Br2 > I2.Fluorine is an extremely aggressive oxidizing agent, and its reaction with alkanes isstrongly exothermic and difficult to control. Direct fluorination of alkanes requires specialequipment and techniques, is not a reaction of general applicability.Chlorination of alkanes is less exothermic than fluorination, and bromination lessexothermic than chlorination.Iodine is unique among the halogens in that its reaction with alkanes is endothermic andalkyl iodides are never prepared by iodination of alkanes.

Disadvantages: mixture, no control! (Hlg = Cl, Br)

CHLORINATION OF METHANE

The gas-phase chlorination of methane is a reaction of industrial importance and leads to a mixture of chloromethane (CH3Cl), dichloromethane (CH2Cl2), trichloromethane (CHCl3), and tetrachloromethane (CCl4) by sequential substitution of hydrogens.

The intermediates in the chlorination of methane and other alkanes are quite different;they are neutral (“nonpolar”) species called free radicals.

Simple alkyl radicals, for example, require special procedures for their isolation and study. We will encounter them here only as reactive intermediates, formed in one step of a reaction mechanism and consumed in the next. Alkyl radicals are classified as primary, secondary, or tertiary according to the number of carbon atoms directly attached to the carbon that bears the unpaired electron.

alkyl substituents stabilize free radicals

Some of the evidence indicating that alkyl substituents stabilize free radicals comes frombond energies. The strength of a bond is measured by the energy required to break it. Acovalent bond can be broken in two ways.

In a homolytic cleavage a bond between two atomsis broken so that each of them retains one of the electrons in the bond.The more stable the radical, the lower the energy required to generate it by C-H bond homolysis.The energy required for homolytic bond cleavage is called the bond dissociationenergy (BDE).

In contrast, in a heterolytic cleavage one fragment retains both electrons.

Alkyl radicals


As the table indicates, C-H bond dissociationenergies in alkanes are approximately 375 to 435kJ/mol (90–105 kcal/mol). Homolysis of the H-CH3

bond in methane gives methyl radical and requires435 kJ/mol (104 kcal/mol). The dissociation energyof the H-CH2CH3 bond in ethane, which gives aprimary radical, is somewhat less (410 kJ/mol, or 98kcal/mol) and is consistent with the notion thatethyl radical (primary) is more stable than methyl.

The dissociation energy of the terminal C-H bond in propane is exactly the same as that of ethane. The resulting free radical is primary in both cases.

Note, however, that Table 4.3 includes two entries for propane. Thesecond entry corresponds to the cleavage of a bond to one of thehydrogens of the methylene (CH2) group. It requires slightly lessenergy to break a C-H bond in the methylene group than in themethyl group.

Since the starting material (propane) and one of the products (H) are the same in both processes, the difference inbond dissociation energies is equal to the energy difference between an n-propyl radical (primary) and an isopropylradical (secondary). The secondary radical is 13 kJ/mol (3 kcal/mol) more stable than the primary radical.

Alkyl radicals 2.

Francis A. Carey: Organic Chemistry (4th Edition), ISBN 0-07-290501-8; The McGraw-Hill Companies, Inc., 2000, p. 151-152.

The reaction itself is strongly exothermic,but energy must be put into the systemin order to get it going. This energy goesinto breaking the weakest bond in thesystem, which we see from the bonddissociation energy data in Table 4.3, isthe Cl-Cl bond with a bond dissociationenergy of 242 kJ/mol (58 kcal/mol). Thestep in which Cl-Cl bond homolysisoccurs is called the initiation step.

Each chlorine atom formed in theinitiation step has seven valenceelectrons and is very reactive. Onceformed, a chlorine atom abstracts ahydrogen atom from methane as shownin step 2. Hydrogen chloride, one of theisolated products from the overallreaction, is formed in this step.A methyl radical is also formed, whichthen attacks a molecule of Cl2 in step 3.Attack of methyl radical on Cl2 giveschloromethane, the other product of theoverall reaction, along with a chlorineatom which then cycles back to step 2,repeating the process.

Steps 2 and 3 are called the propagation steps of the reaction and, when added together, give the overall equationfor the reaction. Since one initiation step can result in a great many propagation cycles, the overall process is called afree-radical chain reaction.

MECHANISM OF METHANE CHLORINATION


The chain sequence is interrupted whenever two odd-electron species combine to give an even-electron product. Reactions of this type are called chain-terminating steps.Some commonly observed chain-terminating steps in the chlorination of methane are shown in the following equations.

Combination of a methyl radical with a chlorine atom:

Combination of two methyl radicals:

Combination of two chlorine atoms:


MECHANISM OF METHANE CHLORINATION 2.

1.2. Addition of Hlg2 or HHlg to alkenes, alkynes (radical or electrophile addition mechanism)

Problems with regioselectivity

Reactivity depends on the quality of the HHlg: HI > HBr > HCl >> HF

1.2.1. ELECTROPHILIC ADDITION OF HYDROGEN HALIDES TO ALKENES

In many addition reactions the attacking reagent is a polar molecule. Hydrogen halides are among the simplest examples of polar substances that add to alkenes.

The reactivity of the hydrogen halides reflects their ability to donate a proton. Hydrogen iodide is the strongest acid of the hydrogen halides and reacts with alkenes at the fastest rate.

An alkene can accept a proton from a hydrogen halide to form a carbocation.

Carbocations, when generated in the presence of halide anions, react with them to form alkyl halides.

This reaction is called electrophilic addition because the reaction is triggered by the attack of an electrophile (an acid) on the p electrons of the double bond. Using the two p electrons to form a bond to an electrophile generates a carbocation as a reactive intermediate; normally this is the rate-determining step.

GENERAL MECHANISM

REGIOSELECTIVITY OF HYDROGEN HALIDE ADDITION: MARKOVNIKOV’S RULE

In principle a hydrogen halide can add to an unsymmetrical alkene (an alkene in which the two carbons of the double bond are not equivalently substituted) in either of two directions. In practice, addition is so highly regioselective as to be considered regiospecific.

In 1870, Vladimir Markovnikov, a colleague of Alexander Zaitsev, noticed a pattern in the hydrogen halide addition toalkenes and assembled his observations into a simple statement. Markovnikov’s rule states that when anunsymmetrically substituted alkene reacts with a hydrogen halide, the hydrogen adds to the carbon that has thegreater number of hydrogen substituents, and the halogen adds to the carbon having fewer hydrogen substituents.The preceding general equations illustrate regioselective addition according to Markovnikov’s rule, and theequations that follow provide some examples.

When a hydrogen halide adds toan alkene, protonation of thedouble bond occurs in thedirection that gives the morestable carbocation.

The way we usually phrase it now:

Markovnikov’s rule

MECHANISTIC BASIS FOR MARKOVNIKOV’S RULE

Compare the carbocation intermediates foraddition of a hydrogen halide (HX) to anunsymmetrical alkene!

The activation energy for formation of the more stable carbocation (secondary) is less than that for formation of the less stable (primary) one. Both carbocations are rapidly captured by X- to give an alkyl halide, with the major product derived from the carbocation that is formed faster. The energy difference between a primary carbocation and a secondary carbocation is so great and their rates of formation are so different that essentially all the product is derived from the secondary carbocation.

STRUCTURE, BONDING, AND STABILITY OF CARBOCATIONS


Carbocations are classified as primary, secondary, or tertiary according to the number of carbons that are directlyattached to the positively charged carbon. They are named by appending “cation” as a separate word after the IUPACname of the appropriate alkyl group. The chain is numbered beginning with the positively charged carbon (thepositive charge is always at C-1).

Alkyl groups directly attached to the positively charged carbon stabilize a carbocation. Thus, the observed order of carbocation stability is

Because alkyl groups stabilize carbocations, we conclude that they release electrons to the positively charged carbon, dispersing the positive charge. They do this through a combination of effects.

One involves polarization of the bonds to the positively charged carbon.Electrons in a C-C bond are more polarizable than those in a C-H bond, so replacing hydrogens by alkyl groups reduces the net charge on the sp2-hybridized carbon. The electron-donating or electron-withdrawing effect of a group that is transmitted Through bonds is called an inductive effect.

The charge in ethyl cation is stabilized by polarization of the electron distribution in the bonds to the positivelycharged carbon atom. Alkyl groups release electrons betterthan hydrogen

A second effect, called hyperconjugation, is also important.

According to hyperconjugation, electrons in the C-H bond of a +C-C-H unit are more stabilizing than +C-H electrons. Thus, successive replacement of the hydrogens attached to CH3 by alkyl groups increases the opportunities forhyperconjugation, which is consistent with the observed order of increasing carbocation stability: methyl primary secondary tertiary. Finally, although we have developed this picture for hyperconjugation of a +C-C-H unit, it also applies to +C-C-C as well as many others.

Ethyl cation is stabilized by delocalization of

the electrons in the C-H bonds of the methylgroup into the vacant 2p orbital of thepositively charged carbon.

1.2.2. FREE-RADICAL ADDITION OF HYDROGEN BROMIDE TO ALKENES

When the addition ofhydrogen bromide toalkenes was performedin the presence of anadded peroxide, only1-bromobutane wasformed.

Peroxides are initiators;they are notincorporated into theproduct but act as asource of radicalsnecessary to get thechain reaction started.


Don’t forget!

anti-Markovnikov addition

Markovnikov addition

The regioselectivity of addition of hydrogen bromide to alkenes under normal (ionic addition) conditions is controlled by the tendency of a proton to add to the double bond so as to produce the more stable carbocation.

ionic addition

Under free-radical conditions the regioselectivity is governed by addition of a bromine atom to give the more stable alkyl radical.

free-radical addition

Free-radical addition of hydrogen bromide to the double bond can also be initiated photochemically,either with or without added peroxides.

1.2.3. ADDITION OF HALOGENS TO ALKENES

Halogens react with alkenes by electrophilic addition.

The products of these reactions are called vicinal dihalides. Two substituents, in this case the halogens, are vicinal if they are attached to adjacent carbons. The word is derived from the Latin vicinalis, which means “neighboring.” The halogen is either chlorine (Cl2) or bromine (Br2), and addition takes place rapidly at room temperature and below in avariety of solvents, including acetic acid, carbon tetrachloride, chloroform, and dichloromethane.

Mechanism of electrophilicaddition of bromine toethylene.


The reaction of chlorine and bromine with cycloalkenes illustrates an important stereochemical feature of halogen addition: Anti addition is observed; the two bromine atoms of Br2 or the two chlorines of Cl2 add to opposite faces of the double bond.

STEREOCHEMISTRY OF HALOGEN ADDITION

Anti addition!

The stereochemistry of addition is anti.

1.2.4. ADDITION OF HYDROGEN HALIDES TO ALKYNES

Hydrogen halides, for example, add to alkynes to form alkenyl halides.

The regioselectivity of addition follows Markovnikov’s rule. A proton adds to the carbon that has the greater number of hydrogens, and halide adds to the carbon with the fewer hydrogens.

In the presence of excess hydrogen halide, geminal dihalides are formed by sequential addition of two molecules of hydrogen halide to the carbon–carbon triple bond.

The hydrogen halide adds to the initially formed alkenyl halide in accordance with Markovnikov’s rule. Overall, both protons become bonded to the same carbon and both halogens to the adjacent carbon.


1.2.5. ADDITION OF HALOGENS TO ALKYNES

Alkynes react with chlorine and bromine to yield tetrahaloalkanes. Two molecules of the halogen add to the triple bond.

A dihaloalkene is an intermediate and is the isolated product when the alkyne and the halogen are present in equimolar amounts. The stereochemistry of addition is anti.


BUT! In case of tertiary alcohols even with HHlg can take place the

substitution.

Reason: high stability of tertiary cation

Typically: Hlg = Cl, Br

Reagents: inorganic acid chlorides (SOHlg2, SO2Hlg2, POHlg3, PHlg3,

PHlg5), ClSO2OH, SF4

1.3. Substitution of hydroxyl groups of alcohols with halogens

sulfuryl chloride

thionyl chloride

The mechanism of formation of tert-butyl chloride from tert-butyl alcohol and hydrogen chloride.

2. SYNTHESIS OF BENZYL HALIDES

High regioselectivity(reason: stability of benzyl

radical)

Increased reactivity (reason: stability of

benzyl cation)

1.4. Transformation of alkyl halides into each other

cc. HHlg effective reagent, reason: stability of benzyl

cation

presipitates

Finkelstein reaction

presipitates

The positive charge in benzyl cation is shared by the carbonsortho and para to the benzylic carbon.

Electron delocalization stabilizes benzyl radical. The unpaired electron is shared by the benzylic carbon and by the ring carbons that are ortho and para to it.

Resonance forms

3. SYNTHESIS OF ARYL HALIDES

3.1. Halogenation of aromatic compound (SE mechanism)

Problems:1. Hlg = Cl, Br can be used 2. Direction, if G is strongly electron

withdrawing group the reactivity is decreased

3.2. Substitution of aromatic diazonium salts

Advantages: preparation of aromatic nitro compounds generally is easy, the position of halogen is given, any halogen atom can build in.

HBF4: Tetrafluoroboric acid

General: Present case:

Chemical properties of C-Hlg compounds

Basicity: thermodynamic affinity toward H+

Nucleophilicity: affinity toward positively polarized C atom or hetero atom (P, S, etc.)

alkenesubstitutedcompound

(cleave the H+)

Nucleophilic substitution 2.Reaction with O-nucleophiles Williamson’s ether synthesis

Note: to prepare an alcohol through an ester within 2 steps

is more efficient (no chance for concurrent

elimination reaction)

Reaction with S-nucleophilesAmbident Nu:-

The negative chargecan appeare on bothheteroatom

Solvolysis: the solvent is itself the nucleophile in the SN

process (weaker nucleophile but it is present in high excess!)

hydrogen(sulfide)

:B can be the excess of the amine

Since it can provide the mixture of products, this process is less applied (see later)

Another example for ambident nucleophile, the product ratio strongly depends on the reaction conditions

To create a C-C bond !! Importance : prolong a chain, built in a new carbon chain

Z1,Z2 = electron withdrawing group, e.g. COOR, CN (malonic ester or

acetoacetate synthesis)

Nucleophilic substitution 3.Reaction with N-nucleophiles

Gabriel’s synthesis

(POTASSIUM PHTALIMIDE)

Reaction with C-nucleophiles

Equilibrium is a problem since a mixture will be formed.

reason: similar reactivity, similar nucleophilicityThis reaction can be used only if the solubility of the product is different from the starting material.

soluble!

insolublesoluble!

insoluble! Finkelstein reaction

Mechanisms of the nucleophilic substitution reaction on aliphatic (sp3) carbon

MeI + MeSH

sp2-kind C

✓ Kinetic is second order: r = d[R-Hlg]/dt = k [R-Hlg] [Nu]✓ Bimolecular process (2) ✓ Concertic (synchronous) process (bond cleavage and formation occurs in the same time!): one step

A single-step process in which both the alkyl halide and the nucleophile are involved at the transition state. Cleavage ofthe bond between carbon and the leaving group is assisted by formation of a bond between carbon and the nucleophile.In effect, the nucleophile “pushes off” the leaving group from its point of attachment to carbon.

Nucleophilic substitution 4.Reaction with Hlg-nucleophiles

1. SN2 (substitution nucleophilic bimolecular) mechanism

Me2S + HI

Only one transtion state!

Result: stereochemically only one product can form

Attack from backside In case of a chiral non-racemic substratethe configuration change to the opposite (Walden inversion)

Substitution by the SN2 mechanism is stereospecific and proceeds with inversion of configuration at thecarbon that bears the leaving group. There is a stereoelectronic requirement for the nucleophile toapproach carbon from the side opposite the bond to the leaving group. Organic chemists often speak ofthis as a Walden inversion, after the German chemist Paul Walden, who described the earliestexperiments in this area in the 1890s.

The nucleophile attacks the substrate from the side opposite the bond to the leaving group. This iscalled “back-side displacement,” or substitution with inversion of configuration.

STEREOCHEMISTRY OF SN2 REACTIONS

stereochemical pathway forsubstitution of a leaving group (red)by a nucleophile (blue).

Hybrid orbital description of the bondingchanges that take place at carbon duringnucleophilic substitution by the SN2 mechanism


slow, ratedetermining step

fast step

✓ Kinetic is first order: r = d[R-Hlg]/dt = k [R-Hlg]✓ unimolecular process (1)✓ Two steps process

1. SN1 (substitution nucleophilic unimolecular) mechanism of nucleophilic substitution

The first step, a unimoleculardissociation of the alkyl halide toform a carbocation as the keyintermediate, is rate-determining.

The SN1 mechanism is an ionization mechanism. The nucleophile does not participate in the reaction until the rate-determining step has taken place.

Energy diagram illustrating the SN1mechanism for hydrolysis of tertbutylbromide.

The SN1 mechanism for hydrolysis of tertbutyl bromide.


Stereochemistry of SN1 reacionretention

inversion

Total process: 50% retention + 50% inversion➢ In case of a chiral, enantiopure starting material the product is a racemic mixture ➢ racemization occurs

Carbenium ion intermediate

sp2 carbon atom

Two stereochemical possibilities present themselves.The nucleophile simply assumes the position occupied by the leaving group. It attacks the substrate at the same face from which the leaving group departs. This is called “front-side displacement,” or substitution with retention of configuration.In a second possibility the nucleophile attacks the substrate from the side opposite the bond to the leaving group. This is called “back-side displacement,” or substitution with inversion of configuration.

stereochemical pathway forsubstitution of a leaving group (red)by a nucleophile (blue).


Factors that can influence the nucleophilic substitution

1. Leaving group (quality of halogen ): I > Br > Cl > F

2. Alkyl (R) group

3. Nucleophilicity (nucleophile power)

4. Solvent effect

5. Electrophilic catalyst (e. g. Ag ions can modify the mechanism of the reaction)

6. Neighbour groups (groups in position to the leaving group can take part in the reaction)

1. RELATIVE REACTIVITY OF HALIDE LEAVING GROUPS

Among alkyl halides, alkyl iodides undergo nucleophilic substitution at the fastest rate,alkyl fluorides the slowest.

The order of alkyl halide reactivity in nucleophilic substitutions is the same as their order in

eliminations. Iodine has the weakest bond to carbon, and iodide is the best leaving group.Alkyl iodides are several times more reactive than alkyl bromides and from 50 to 100 times more

reactive than alkyl chlorides. Fluorine has the strongest bond to carbon, and fluoride is thepoorest leaving group. Alkyl fluorides are rarely used as substrates in nucleophilic substitutionbecause they are several thousand times less reactive than alkyl chlorides.


2. STERIC EFFECTS IN SN2 REACTIONS

There are very large differences in the rates at which the various kinds of alkyl halides—methyl, primary, secondary, or tertiary—undergo nucleophilic substitution.

In general, SN2 reactions exhibit the following dependence of rate on substrate structure:

The large rate difference between methyl, ethyl, isopropyl, and tert-butyl bromides reflects the steric hindrance eachoffers to nucleophilic attack. The nucleophile must approach the alkyl halide from the side opposite the bond to theleaving group, and this approach is hindered by alkyl substituents on the carbon that is being attacked. The threehydrogens of methyl bromide offer little resistance to approach of the nucleophile, and a rapid reaction occurs. Replacingone of the hydrogens by a methyl group somewhat shields the carbon from attack by the nucleophile and causes ethylbromide to be less reactive than methyl bromide. Replacing all three hydrogen substituents by methyl groups almostcompletely blocks back-side approach to the tertiary carbon of (CH3)3CBr and shuts down bimolecular nucleophilicsubstitution.Francis A. Carey: Organic Chemistry (4th Edition), ISBN 0-07-290501-8; The McGraw-Hill Companies, Inc., 2000, p. 310-312.

Alkyl groups at the carbon atom adjacent to the point of nucleophilic attack also decrease the rate of the SN2 reaction. Compare the rates of nucleophilic substitution in the series of primary alkyl bromides shown in Table. Taking ethyl bromide as the standard and successively replacing its C-2 hydrogens by methyl groups, we see that each additional methyl group decreases the rate of displacement of bromide by iodide.The effect is slightly smaller than for alkyl groups that are attached directly to the carbon that bears the leaving group, but it is still substantial. When C-2 is completely substituted by methyl groups, as it is in neopentyl bromide [(CH3)3CCH2Br], we see the unusual case of a primary alkyl halide that is practically inert to substitution by the SN2 mechanism because of steric hindrance.

The relative rate order in SN1 reactions is exactly the opposite of that seen in SN2 reactions:

The steric crowding that influences reaction rates in SN2 processes plays no role in SN1 reactions. The order of alkyl halide reactivity in SN1 reactions is the same as the order of carbocation stability: the more stable the carbocation, the more reactive the alkyl halide.

An electronic effect, specifically, the stabilization of the carbocation intermediate by alkyl substituents, is the decisive factor.

Nucleophilic strength, or nucleophilicity, is a measure of how fast a Lewis base displaces a leaving group from a suitable substrate.

3. NUCLEOPHILES AND NUCLEOPHILICITY

The Lewis base that acts as the nucleophile often is, but need not always be, an anion.Neutral Lewis bases can also serve as nucleophiles. Common examples of substitutionsinvolving neutral nucleophiles include solvolysis reactions. Solvolysis reactions are substitutions in which the nucleophile is the solvent in which the reaction is carried out.Solvolysis in water converts an alkyl halide to an alcohol.

As long as the nucleophilic atom is the same, the more basic the nucleophile, the more reactive it is. An alkoxide ion (RO-) is more basic and more nucleophilic than a carboxylate ion (RCO2

- ).


Outcome: elimination is the concurrent process of the substitution

Three possible mechanisms exist according to how occurs the cleavage/formation of bonds (3 bonds!) in time during the elimination (E1, E2, E1cb)

Features: 1. total synchronous process, one TS, continuous e-flow, no large charge on the carbons.

2. Second order kinetic, bimolecular reaction (2) r = - d[RHlg]dt = k[RHlg][Nu]

G

R-Hlg + Nualkene + HNu

‡

Nucleophilic substitution (SN)

C-H acidity, Nucleophilicelimination (EN)

Basicity: thermodynamic affinity toward H+

Nucleophilicity: affinity toward positively polarized C atom or hetero atom (P, S, etc.)

Nucleophilic elimination (E)

acidic hydrogen

1. E2 mechanism

alkenesubstituted compound

TS

Beta () elimination reactions are also known as 1,2 eliminations

MECHANISM OF THE DEHYDROHALOGENATION OF ALKYL HALIDES: THE E2 MECHANISM

1. The reaction exhibits second-order kinetics; it is first-order in alkyl halide and first order in base.

Doubling the concentration of either the alkyl halide or the base doubles the reaction rate. Doubling the concentration of both reactants increases the rate by a factor of 4.

2. The rate of elimination depends on the halogen, the reactivity of alkyl halides increasing with decreasing strength of the carbon–halogen bond.

Iodide is the best leaving group in a dehydrohalogenation reaction, fluoride the poorest leaving group.

In the 1920s, Sir Christopher Ingold proposed a mechanism for dehydrohalogenation that is still accepted as a valid description of how these reactions occur. Some of the information on which Ingold based his mechanism included these facts:


Ingold proposed a concerted (one-step) mechanism for dehydrohalogenation and gave it the mechanistic symbol E2, standing for elimination bimolecular.

are all taking place at the same transition state. The carbon–hydrogen and carbon–halogen bonds are in the process of being broken, the base is becoming bonded to the hydrogen, a bond is being formed, and the hybridization of carbon is changing from sp3 to sp2.

In the E2 mechanism the three key elements

Potential energy diagram forconcerted (one step) E2 elimination of an alkyl halide.

The regioselectivity of elimination is accommodated in the E2 mechanism by noting that a partial doublebond develops at the transition state. Since alkyl groups stabilize double bonds, they also stabilize apartially formed bond in the transition state. The more stable alkene therefore requires a lower energyof activation for its formation and predominates in the product mixture because it is formed faster thana less stable one.

The most important factors governing alkene stability are:1. Degree of substitution (alkyl substituents stabilize a double bond)2. Van der Waals strain (destabilizing when alkyl groups are cis to each other)

Degree of substitution. We classify double bonds as monosubstituted, disubstituted, trisubstituted, ortetrasubstituted according to the number of carbon atoms that are directly attached to the C=Cstructural unit.

In general, alkenes with more highly substituted double bonds are more stable than isomers with less substituted double bonds.

Like the sp2-hybridized carbons of carbocations and free radicals, the sp2-hybridized carbons of double bonds are electron attracting, and alkenes are stabilized bysubstituents that release electrons to these carbons. As we saw in the preceding section, alkyl groups are better electron-releasing substituents than hydrogen and are, therefore, better able to stabilize an alkene.

van der Waals strain. Alkenes are more stable when large substituents are trans to each other than when they are cis.

Ball- and spoke and space-fillingmodels of cis- and trans-2-butene.The space-filling model shows theserious van der Waals strainbetween two of the hydrogens incis-2-butene. The molecule adjustsby expanding those bond anglesthat increase the separationbetween the crowded atoms. Thecombination of angle strain and vander Waals strain makes cis-2 buteneless stable than trans-2-butene.

The difference in stability between stereoisomeric alkenes is even more pronounced with larger alkyl groups on the double bond.

more

more stable isomer

During the reaction: 2 sp3 AO ( bond)→ 2 pz (p bond).

Condition for minimum energy investment: through the

whole process maximum overlaping atoms must be

oriented in the same plane (C-Hlg / C-C / C-H and Nu…H)

Additional criteria: minimum change in the location of

atoms antiperiplanar position for Hlg and H atoms during

the elimination (anti-elimination) -DIASTEREOSELECTIVITY

A further aspect: elimination from a non-symmetrical alkyl halides that

contains different-order - and ’-carbon atoms Zaitsev’s rule: the

hydrogen is cleaved out from that carbon which results an alkene having

greater thermodynamic stability (more alkyl groups bearing)

Zajtsev’s

product

(favored)

Hofmann’s

product

’

Trans diaxial elimination in case ofcyclohexyl derivatives

2 antiperiplanar H, the product ratio is controlled by the Zajcev’s rule (reason:

the more substituted alkene has greaterthermodynamic stability)

1 antiperiplanar H

Neomenthyl chloride 2-menthene (25%)

3-menthene (75%)

menthyl chloride 2-menthene (100%)

’

ANTI ELIMINATION IN E2 REACTIONS: STEREOELECTRONIC EFFECTS 1.


Although both stereoisomers yield 4-tert-butylcyclohexene as the only alkene, they do so at quite different rates. The cis isomer reacts over 500 times faster than the trans.

The rates of elimination of the cis and trans isomers of 4-tert-butylcyclohexyl bromide.



The difference in reaction rate results from different degrees of bond development in the E2transition state. Since overlap of p orbitals requires their axes to be parallel, bond formation is bestachieved when the four atoms of the H−C−C−X unit lie in the same plane at the transition state. Thetwo conformations that permit this relationship are termed syn periplanar and anti periplanar.

Because adjacent bonds are eclipsed when the H−C−C−X unit is syn periplanar, a transition statehaving this geometry is less stable than one that has an anti periplanar relationship between theproton and the leaving group.

The bromine is axial in the most stable conformation of cis-4-tert-butylcyclohexyl bromide, but it isequatorial in the trans stereoisomer. An axial bromine is anti periplanar with respect to the axialhydrogens at C-2 and C-6, and so the proper geometry between the proton and the leaving group isalready present in the cis bromide, which undergoes E2 elimination rapidly. The less reactivestereoisomer, the trans bromide, has an equatorial bromine in its most stable conformation. Anequatorial bromine is not anti periplanar with respect to any of the hydrogens that are to it. Therelationship between an equatorial leaving group and all the C-2 and C-6 hydrogens is gauche. Inorder to undergo E2 elimination, the trans bromide must adopt a geometry in which the ring isstrained. The transition state for its elimination is therefore higher in energy, and reaction isslower.


2. E1 mechanism

slow, rate determining

steps

Fast steps (deprotonation)

G‡

‡1 ‡2

Alkene + HNuR-Hlg + Nu

R

two steps process, carbocation (carbenium ion) intermediate2. First order kinetic, monomolecular process (1), r = - d[RHlg]dt = k[RHlg] 3. E1 is the concurrent reaction of SN1, the product ratio is mostly independent

from the leaving group and Nu – generally Zajcev’s rule controls

3. E1cB mechanism

Features: 1. two steps process, carbanion intermediate.2. First order kinetic, rate determining step is :Hlg cleavage, monomolecular (1)

1. step 2. step

Relatively rare. In the presence of electron withdrawing groups with –M effect (Z= NO2, ArSO2, CN, COOR, SMe2+, etc.) and poor leaving groups, Hoffman product is favored

Conjugated baseacid

3. -elimination – formation of a carbene Rare, special reaction

Carbene: e- deficient (6 e-!) reactive intermediates without charge – looking for Nu reagents

4. Reaction with metals, reductive dehalogenationHalogene-metal exchange reaction – SET mechanism („single electron transfer”)

carbene Dichlorocarbene

Requirements: lack of the hydrogene or carbon. (in the presence of hydrogene(s): elimination reaction)

Wurtzreaction

Wurtz-Fittigreaction

or

cycloalkeneGrignard reagent

In case of some metals (Mg, Zn) insertation reaction R-M-Hlg

(see later)

vic.- dihalide alkene

organometallic compound

Substitution reaction of aryl halides (SNAr)Decreased reactivity due to the halogen +M effect

No chance for SN1 or SN2 reaction! Different mechanism under harsh reaction condition

Mechanisms: 1. Elimination-addition mechanism

2. Addition-elimination mechanism Electron withdrawinggroups in position 2,4,6 andsubstituents that can takepart in resonance (-Meffect)!!

The best leaving group is: FThe unusually high reactivity of arylfluorides arises because fluorine isthe most electronegative of thehalogens, and its greater ability toattract electrons increases the rate offormation of the cyclohexadienylanion intermediate in the first step ofthe mechanism.

Aryne or benzynes are highly reactive species derivedfrom an aromatic ring by removal of two orthosubstituents

Meisenheimer’s complex

Resonance structures of intermediates

Aryne or benzynes

Fundamentals of chemisty of organometallic compounds. Bond system, the concept of "umpolung."

Carbanions, such as C-nucleophiles and bases. Their importancein C-C bond building. Grignard compounds and their use. Organometallic compounds: production

and conversion into each other, transmetalation.

Bond system of organometallic compoundsOrganometallic compounds: direct carbon-metal bonds (typically s and d-field + a few from p-field from the periodic table)

Since ENMetal < ENC polarised heteronuclear bond, charge excess on the carbon. The covalent/ionic property depends on the quality of the metal.

Reactivity depends on the polarity of the C-M bond!

Organometallic Compounds = carbanion equivalents!!

For otherheteroatoms :

The C-M bond polarization opposite to the other C-X heteronuclear bond polarization "umpolung" (through polarization)

Fundamental reactions based on bonding systems /electron shifts attack of electrophiles, electron-deficient reagents

• proton as electron-deficient reagents (Organometallic compounds = base)

• attack of any electrophile (E) C-E bond formation.

Primary importance: reaction with C electrophiles C-C bond formation!!!

generally disadvantageous

The synthetic use of organometallic compounds is rapidly expanding, it is the organic chemistry of today!!!

Conditions for reactions carried out with organometallic compounds

1. Reagents, solvents with active hydrogen (e.g. alcohols, acids) can not be used

inert, dry solvents are necessary, reagents also can not having any acidic H!!

2. Carbon dioxide as electrophile inert atmosphere (N2, Ar) during the reaction

3. Oxygen reactive molecule inert atmosphere; in air spontaneous ignition can occur

include ethers (Et2O, THF, dioxane),

alkanes (cycloalkanes (hexane, cyclohexane)

Structure and chemistry of Grignard compounds Victor GrignardNobel award: 1912

"for the discovery of the so-called Grignard reagent,

which in recent years has greatly advanced the progress of organic

chemistry"

Preparation: Mg insertion into C-Hlg bond!

BUT! The structure of Grignard compound is more difficult! The characteristic features of organometallic compounds: formation of associates – oligomers, polymers

More stable with ether type solvents…

The ether solvent is built into the associates, stabilizing effect!

PhMgBr.2Et2OGrignard reagent is a carbanion equivalent (base or C-nucleophile)

1. Grignard reagent as baseApplication for: • "active" hydrogen determination • reductive dehalogenation under mild

conditions

In case of CH acids: production of a new metal-organic compounds

E. g.Generally a side reaction!!

2. Grignard reagent as C nucleophile – mostly towards electrophilic C2.1. Reaction with sp3 C-electrophiles – SN reaction!!

A very effective C-C bond formation, if R1 = benzyl, allyl

Formally SN (C-O bond cleaveage by Nu attack), in practice AdN

Ethylene oxide Primary alcohol

acetale aldehyde

2.2. Reaction with C-electrophiles having sp2 C – AdN reaction!!

✓ R1 = R2 = H (formaldehyde) → 1o alcohol✓ R1 = alkil/aril; R2 = H (aldehyde) → 2o alcohol✓ R1 = R2 = alkil/aril (ketone) → 3o alcohol

Reactive intermediate

Aldehydes and ketones are NOT synthethised in this way!

2.3. Reaction with C-electrophiles having sp C – AdN reaction

secondary or tertiaryalcohol

secondary amine

carboxylic acid

2.3. Reaction with C-electrophiles having sp C – AdN reaction

Preparation of organometallic compounds

Generally from R-Hlg, Hlg-metal exchange (reductive substitution)

BuLi

In some cases metal-metal exchange (transmetalation)

M1 always more electropositive!

With more powerful CH acids hydrogen-metal exchange (metalation)

R H R1 M+ R M R1 H+

organo halides halogen derivatives of hydrocarbons

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