-carbon-carbon bond formation

-functional group interconversion

-control of stereochemistry

-control of regiochemistry

-they are solvents for relatively non-polar compounds

-starting material for the synthesis of many compounds

Vinyl halides: ie vinyl chloride, the starting material of PVC (CDs, pipes, rods, etc)

Phenyl halides: polychlorinated biphenyls (PCBs) were banned in '79 owing to their toxicity and tendency to accumulate in the food chain

leaving group: a leaving group is a substituent that can leave as a relatively stabl entity

-it can leave as an anion of a neutral species (charges don't disappear!)

*** bases make great nucleophiles but terrible leaving groups!***

-try protonating hydroxide to get a better leaving group

Rate = k[CH₃Cl][OH^-]

This reaction is first order with respect to both substrate and nucleophile concentrations, and therefore is second order overall.

2nd order (bimolecular) Nucleophilic Substitution

SN2 Reactions!

Yay!

-one step process

-transition state contains leaving group, substrate, and nucleophile

-this is a highly energetic and unstable intermediate

-SN2 reactions lower the free energy in the system (negative free energy change)

exergonic reaction: negative Gibbs free energy change (products favored)

endergonic reaction: positive... products not favored

*****with a high Keq, the reaction goes to completion (Keq = -Gibbs/RT)

-the transition state will be of higher energy than the reactants (ie. a bell curve)

****ie. exergonic SN2 reactions require energy of activation

-in highly energonic reaction of the same type the energy barrier iwll be even higher (activation energy is very large)

**there is a direct relationship b/w deltaG++ (activation energy) and teh temperature of a reaction

-the higher the temperature, the faster the rate:

k= k₀e^{(-detaG++/RT)}

Near room temperature, a 10C increase in temperature causes a doubling of rate

-higher temperatures cause more molecules to collide with enough energy to reach the transition state and react

A reaction with a deltaG++ above 84KJmol^-1 will require heating to proceed at a reasonable rate

**backside attack of nucleophile results in an inversion of configuration

**in cyclic systems a cis compound can react and become a trans product

SN1 means: substituation, nucleophilic, 1st order

-***the rate depends on the concentration of the alkyl halide

-only the alkyl halide(substrate) (and not the nucleophile) is involved in the transition state of the step that controls the rate (the rate determining step)

-in multistep reactions, the rate of the slowest step will be the rate of the entire reaction

-this is called the rate determining step

-the rate determining step (slow one) is the one that requires the formation of unstable ionic products (ie a carbocation)

-polar solution (ie water) will help to stabilize the ionic products

-the rate determining step will have a much higher deltaG++ than the other steps... but in each step there is a blip

-when the leaving group leaves from a stereogenic center of an optically active compound in an SN1 reaction, recemization will occur

-this is because an achiral carbocation is formed

racemization: transformation of an optically active compound to a racemic mixture

**equal opportunity of attack by the nucleophile leads to equal number of back or front flips

-a molecule of solvent is the nucleophile in a substitution reaction

-if the solvent is water the reaction is a hydrolysis (halide deattaches and hydroxyl group attaches)

structure

In SN2 reactions alkyl halides show the following general order of reactivity:

methyl>primary>secondary>>tertiary (unreactive)

steric hindrance= teh spatial arrangement of the atoms or groups at or near a reacting site hinders or retards a reaction

 -in tertiary and neopentyl halides, the reacting carbon is too sterically hindered to react

*****generally only tertiary halides undergo SN1 reactions because only they can form relatively stabilized carbocations

SN1

-rate does not depend on the identity or concentration of nucleophile (b/c it sits around and waits)

SN2

-rate is directly proportional to the concentrationof nucelophile

-stronger nucleophiles react faster

-a negatively charged nucleophile is always more reactive than its neutral conjugate acid

-when comparing nucleophiles with the same nucleophilic atom, nucleophiliciteis parallel basicities:

RO^->HO^->>RCO₂^->ROH>H₂0

-methoxide is a much better nucleophile than methanol

***nucleophilicity and basicity are not the same

Polar Protic Solvents

-polar solvents have a hydrogen attached to strongly electronegative atoms

-they solvate nucleophiles and make them less reactive

ie. halide ions are solvated by water 

-larger nuclophilic atoms are less solvated and therefore more reactive in polar protic solvents..... I^->Br^->Cl^->F^-

-larger nucleophiles are also more polarizable and can donate more electron density

-relative nucleophilicity in polar solvents: (Remeber, this is measured by relative rates of reaction, unlike pKa!!! )

SH^->CN^->I^->OH^->N3^->Br^->CH₃CO₂^->CL^->F^->H₂0

Polar Aprotic Solvents

-polar aprotic solvents do not have a hydrogen atached to an electronegative atom

-they solvate cations well but leave anions unsolvated because positive centers in the colvent are sterically hindered (ie. in the middle)

-polar aprotic solvents lead to generation of "naked" and very reactive nuclophiles

-trends for nucleophilicity are the same as for basicity: F- Cl- Br- I-

**they are excellent solvents for Sn2 reactions

-polar protic solvents are excellent solvents for SN1 reactions

-polar protic solvents stabilize the carbocation-like transition state leading to the carbocation thus lowering deltaG++

***water-ethano and water-methanol mixtures are most common

********

In an SN1 reaction, the transition state of the rate-determining step has a charge separation. A polar solvent will stabilize this transition state. Increasing the percentage of water will increase the polarity of the solvent therefore the rate would increase.

**********

The nature of the leaving group

-the best leaving groups are Weak Bases which are relavitely stable (won't want to bounce back)

-the leaving group can be an anion or a neutral molecule

-leaving group ability of halides:

I->Br->Cl->>F-

-the trend is opposite to basicity:

F->>Cl->Br->I-

**carbon-halogen bonds get weaker, longer, and less polar in going from F to I

How can you turn a poor leaving group into a good one?

-PROTONATION!!

-make the leaving group (ie OH-) a weak base (ie H20)

-in both types of reaction alkyl iodides react the fastest because of superior leaving group ability!

SN1

substrate: tertiary (requires formation of a relatively stable carbocation)

Nucleophile: weak lewis base, neutral molecule, nucleophile may be the solvent (solvolysis)

Solvent: polar protic (ie. alcohols, water)

SN2

Substrate: Methyl>primary>secondary (requires unhindered substrate)

Nucleophile: Strong lewis base, rate favored by high concentration of nucleophile

Solvent: Polar aprotic (DMF,DMSO)

-generally the reaction is exothermic because one pi and one sigma bond are converted to two sigma bonds

-common addition reactions are hydrohalogenation, hydrogenation, hydration, and halogenation

-addition produces vicinal dihalides (two halides on neighbouring carbons) 

-alkanes do not react with bromine in the dark

-geminal dihalids have the two halides on the same carbon

-another useful experiment: identify alkene and alkyne compounds with a bromine solution

qualitatively: the red-brown color of Br2 will pale or disappear instantly in the presence of alkenes or alkynes

Quantitatively: 1 mol of Br2 will be needed to add to 1 double bond

-a component of cell membranes, myelin sheath, and brain and nerve tissue. It is used to make bile salts in liver, vitamin D in skin, and steroid hormones in adrenal gland.

-get it from meats, milk, egg, fish, or body makes it (liver)

-have squaline, and one carbon is oxidized at beginning, which causes a chain reaction of carbocation formation at the double bonds as they move over to satisfy electron demand

Stereochemistry of Halogen Addition

**Halogen Addition is ANTI addition..

-symmetric alkenes do not produce stereoisomers (ie. they are still non chiral)

-however cis-alkenes will become trans (enantiomer) around 95% of the time

THE MECHANISM

-The halogen molecule is induced to polarize, the positive end is attracted to the electron rich double bond, and a cyclic bromonium ion intermediate is formed (temporary)

-the bromide ion that is left atacks a carbon from the back of the cyclic bromonium. This is sterically more sensible.

-this produces the enantiomer vic-dibromide

-

-a reaction is stereospecific if a stereoisomeric form of the starting material reacts to give a specific stereoisomeric form of the product

*ie cis and trans 2-butene react to give different non-isomeric products

***if a trans stereoisomer undergoes an anti addition a meso product is formed

***if a cis stereoisomer undergoes an anti addition, enantiomers (2 products... racemic) are formed

-addition of halogen to alkynes can occur once or twice depending on how many equivalents of the halogen are added

-addition of one equivalent usually proceeds to give the trans dihalide

How would you make tetrachloroethane?

-

-H2 adds to same side of double bonds... does not form trans

-hydrogen adds to alkenes in the presence of metal catalysts

-heterogeneous catalysitsL finely divided insoluble platinum, palladium, or nickel catalysts

-homogeneous catalysts: (typically rhodium or ruthenium based) is soluble in the reaction medium

-this process is called a reduction or hydrogenation

-an unsaturated compound becomes a saturated compound

-the catalyst provides a new reaction pathway with lower deltaG++ values

Heterogeneous Catalysis

-in the heterogeneous catalysis the hydrogen and alkene adsorb to the catalyst curface and then a stepwise formation of C-H bonds occurs

-both hydrogens add tot he same face of the alkene (a syn addition)

-addition to opposite faces of the double bond is called anti addition

-**catalytic cydrogenation is a syn addition

Hydrogenation of Alkynes

-reaction of hydrogen using regular metal catalysts results in formation of the alkane

-special catalysts are needed to stop the reaction from going further

-An internal alkyne will yield a cis double bond

**Ni2B (aka P-2) is a special catalyst that only leads to the alkene product

-Most trans fats consumed today are industrially created through partial hydrogenation of plant oils and animal fats - a chemical process developed in the 1900s and first commercialized as Crisco in 1909

*hydrogenation produces saturated fat, while partial hydrogenation produces trans fat

-if the list includes hydrogenated oils, you know the food contains trans fat..

-a chain of around 5 carbons or more is insoluble in water

-monosaturated fatty acids have a double bond in the middle

(fatty acids are carbon chains with a mehyl end and a carboxylic acid end)

-polyunsaturated fatty acids are not conjugated, but rather isolated

-the middle on is always saturated, and they get closer and closer to methyl end

-omega-6 fatty acids have the first double bond on the 6th carbon... and they go to AT LEAST the middle... or further

-omega-3 begin at C3

-more saturation = more solid

-more unsaturated = more fluid

-partial hydrogenation of isolated cis bonds creates trans bond

-cis structure of phospholipid tails is essential for fluidity of membrane

triglycerides are a body's way of storing fatty acids

-they are ester groups attached to fatty acids and ester groups are all connected 

CORONARY DISEASE AND HEART ATTACK!

THE MECHANISM

-the pi electrons of the double bond are loosely held and are a source of electron density (ie. they are nucleophilic)

-alkenes react with electrophiles such as H+ from a hydrogen halide to form a carbocation, thus emptying the p orbital

-the carbocation produced is an electrophile

-it can ract with a nucleophile such as a halide

-it is highly reactive, or very unstable

-it has a trigonal planar geometry and can be approached from two directions, causing the formation of stereoisomeric products

-the stability of different carbocations formed in one reaction can affect the distribution of products (a secondary carbocation is more stable than a primary one)

-the more stable carbocation will form the major product

-addition of HX to an alkene proceeds so that the hydrogen atom adds to the carbon that already has the most hydrogen atoms

-the stability of carbocations decreases in the following order: tertiary>>secondary>>primary

Regioselective Reaction: When a reaction that can potentially yield two or more constitutional isomers actually produces only one or a predominance of one isomer

"HAH, you are regioselective)

-addition of HBr to butene yields chiral products

-since the intermediate carbocation is planar, enantiomeric products are formed

-this results in a racemic mixture

Addition of Hydrogen Halides to Alkynes

-addition of hydrogen halides occurs once or twice depending on how many molar equivalent of hydrogen halide are added

-the reaction of alkenes with dilute aquesous acid leads to Markovnikov addition of water

-hydration is 3 steps

-acid is a catalyst (is H30+) and it is regenerated at the end

-see slide for mechanism

1)Substrate

primary = only SN2

secondary = both

tertiatry = only SN1

2)Nucleophile

strong = SN2

Moerate = both

Weak = SN1

3)Leaving Group

bad = neither

good = both (but more SN2)

excellent = SN1

4)Solvent

Polar Aprotic = SN2

*quality of leaving groups and nucleophile is determined by whether or not the molecule has/will have a negative charge. If it doesn't/won't, it is a weak nucleophile/good leaving group respectively.

 -if it does have a charge, but it can be stabilized, or is attached to a halide, then it is a good leaving group or moderate nucleophile.

-if it is an unstable charge, then it is an excellent nucleophile or bad leaving group.

***There are two kinds of systems that you should learn to recognize: and LG in a benzylic position and an LG in an allylic position. Compounds like this will be resonance stabilized when the LG leaves.