O Chem Test 3

Zaitsev's Rule

(1875) dehydrohalogenation's preferred alkene product has the greater number of alkyl groups bonded to the (sp2) C atoms. More substituted alkene -> more stable and forms faster.

Hughes and Ingold

(1953) proposed two elimination mechanisms, E2 (elimination, bimolecular) and E1 (elimination eunimolecular), similar to SN2 and SN1. Mechanism evidence: 1. With concentrated base, elimination is first order in [R-X] and first order in base [Z-] second order overall. a. If [Z-} strength or concentration is reduced, sometimes elimination rate is independent of base concentration (first order overall) for secondary and tertiary R-X.

Nucleophile

(hydroxide ion) is stabilized more than transition state- activation energy is higher and SN2 reaction rate is slower in strongly ionizing solvents.

Nuleophilicity Trends

-A bases is a stronger nucleophile than its conjugate acid. -This decreases from left to right in the periodic table for analogous species. -This increases from top to bottom on the periodic table (paralleling solvated size and polarizability trends)

SN1 Reaction Features

-At least two and often three elementary steps (collisions); bond breaking and bond making are not simultaneous. -Reaction rate is first order in [R-X] but independent of [Z-H] (zeroeth order). -Step 1 is rate determining; steps 2 annd 3 are fast by comparison -Unimolecular transition state structure (for the slow step) -R-X overall reactivity: slowest methyl< primary < secondary < tertiary fastest - Intermediate products are ions : carbocations, oxonium ions, halides, etc -Optically active substrates -> at least partially racemized products (R-X)

Apparent Trends of Alkyl Halides

-Higher boiling points and densities- mostly due to London and dipole-dipole attractions. -F has about the same surface area as H. Higher bp mostly due to dipole-dipole -Bp differences are due to different X surface area. I>Br>Cl>F. Greater surface area = greater London attractions -More isomer branching- lower bp and density -Only fluorides and monochlorides are less dense than water. More halogen atoms per molecule = higher boiling point and density.

Factors that Influence E2 Rates

-More beta-hydrogen atoms in a substrate -> higher collision probability with base. -Weaker C-Hbeta bond -> easier to break and faster E2. Bond strength order: stronger primary C > secondary C-H > tertiary C-H weaker. These work in the same direction with alkyl substituent hyperconjugation stabilization (in the alkene-like transition state). Hyperconugation is usually dominant, however.

SN2

-One elementary step (collision)- concerted bond breaking and formation. -First order in [R-X] and first order [ Z-] (nuclephile), second order overall -Backside attack - Z- stays as far away from X as possible during collision with R-X -Complete C inversion. -Bimolecular, pentavalent transition state -Fastest for methyl and slowest for tertiary alkyl halides. -Z- forms a new sigma bond (coordinate covalent bond) to C with its own lone electron pair.

E1 Features

-Reaction rate depends on [R-X] but not [Z-H] (first order overall) -Two elementary steps (bond breaking and bond making are not simultaneous). Unimolecular transition state structure (containing only R-X and not Z-H) for rate determining step. -R-X reactivity order is the same as for SN1 - rate is determined by carbocation stability : slowest primary > secondary> tertiary fastest -Intermediate products are ions (carbocation and halide) -Rearranged products form, where possible -No deuterium isotope effect -Large element effect -Not stereospecific

E2 Features

-Second order rate law. -Only one elementary step (bond breaking and bond formation are simultaneous or concerted). Bimolecular transition state structure (containing both R-X and Z-) -No rearranged products -Large deuterium isotope effect -No hydrogen exchange occurs -Large element effect -Beta hydrogens and X are either syn- or anti-coplanar in transition state structures.

Zaitsev's Rule Explanation

1. Alkyl groups stablize alkenes thorugh hyperconjugation effects 2. Adjacent alkyl groups donate electron density to the pi bond strengthening it 3. More substituted alkyl groups have less steric interaction

Which mechanism operates E2 or E1

1. Both mechanisms are fastest for tertiary R-X. 2. More concentrated and stronger base Z- -> faster E2 vs. E1 for all R-X's. 3. E1 occurs only for secondary and tertiary R-X's (which can form stable carbocations) with low concentration weak bases (Z-H solvent, and no Z-) 4. Like SN2, E2 is not very sensitive to solvent polarity. Like SN1, E1 is faster in polar protic solvents.

R-X Analysis

1. Insoluble in H2SO4 (conc.) 2. Do not react with Br2 (cold,dark). Do not react with oxidizing agents - KMnO4/KOH (cold/dil), or CrO3 3. Sodium fusion, then AgNO3 (aq) precipitates AgX. Reaction with AgNO3 can often be done directly, reactivity: R-I > R-Br > R-Cl 4. Spectroscopic methods

Evidence Supporting SN2 Mechanism

1. Kinetic data: second order reaction rate law, steric effect 2. Product studies: stereochemistry (configuration inversion)

Deuterium Exchange

A "_______________ _____________" experient was done to see E1cB actually operates - 2-phenyl-1-bromoethane reaction with sodium ethoxide in H3CCH2OD (solvent). A phenyl group makes the benzylic H-atoms more acidic than normal which should promote E1cB. After about half of the 2-phenyl-1-bromoethane had been converted into alkene, reaction was interrupted and unreacted 2-phenyl-1-bromoethane was analyzed by mass spectrometry. It contained no deuterium. Reversible carbanion formation (E1cB step 1) can therefore be ruled out.

Fast (good) Leaving Group

A ________ ___________ ___________ (such as X-) becomes a weak Lewis base after it has left, so that products are more stable and reverse reaction is slow. These are polarizable and sustain partial bonding to a dipole positive C atom from a longer distance, stabilizing the transition state. - I is both a good nucleophile (in aqueous solution) and this. -F is a poor nucleophile (in aqueous solution) and not this.

Carbanion

A ________________ is the conjugate (very strong) base of a (very weak) carbon acid.

Isotopes

A given element's _______________ have similar (but not identical) chemical properties. They often undergo the same reactions, but different rates.

Carbocation

A high energy intermediate product formed during SN1. A group of covalently bonded atoms containing a carbon atom that has a positive formal electrical charge, and only six (shared) electrons. Properties: highly reactive Lewis acid (electrophile), cannot be easily isolated and studied. SP2 hybridized.

Primary Pathway

A less stable carbocation rearranges to a more stable carbocation. Rearrangements are fast and intramolecular (winthin the same molecule) Lewis acid/base reactions. Most commonly occurs by: a 1,2-hydride shift or a 1,2 alkyl shift. Rearrangement actually occurs simultaneously with C-X bond breaking for primary R-X i.e. is concerted with leaving group loss. A primary carbocation does not actually form.

Steric Effects

A rate difference resulting from different sized groups (near a reaction site) in one structure vs. another. This is largely responsible for SN2 reaction rate differences: faster- Methyl>primary>secondary>tertiary- slower

Isotope Effect

A reaction rate (or equilibrium position) difference caused by a different atomic isotope presence. If a particular atom is not bound as tightly in a transition state as it was in a reactant, the same reaction involving a heavier atomic isotope will be slower.

Elimination

A sigma bond is broken to each of two adjacent bonded atoms (often sp3 C's) and a double (pi) bond forms in between.

E1cB

A two step carbanion mechanism (__________, elimination, unimolecular, conjugate base) is equally consistent.

Polar

Alkyl halides are not very _______________: -Almost water insoluble = slow environmental degradation -Soluble in nonpolar organic solvents -Rarely dissolve in (polar) ionic compounds. -Smell- like dry cleaning fluid (Cl3CCH3)

Solution

All four elimination and substitution mechanisms compete in a given R-X _________________ (X=halogen of sulfonate). One mechanism can often be made to predominate over others by appropriate reaction condition choices, but outcomes cannot always be predicted.

Gas Phase

Although this phase SN1 is very slow compared to this phase SN2, the two rate can be comparable in solution. To summarize" -Strongly ionzing, H-bonding polar solvents favor SN1 over SN2. -Weakly ionizng, non H-bonding (polar aprotic) or nonpolar solvents favor SN2 over SN1. -Which mechanisms predominates can often be controlled by nucleophile, substrate, and (above all) solvent choice.

Dechlorodiphenyltrichloroethane (DDT)

An insecticide discovered in 1939. Low human toxicity- one ounce kills a human, but protects one acre from insects. A cumulative poison for species at the top of the food chain, banned in US as an agricultural pesticide (1972). It is estimated to have saved over 500 million lives (from malaria, bubonic plague, yellow fever, etc) and is still used as a last resort outside of the US.

Nucleophile

Attracted to a (positively charged) atomic nucleus: i.e. a lewis base. Electrically neutral or negatively charged ion - never a positively charged ion. Its strength does not exactly parallel base strength due to additional factors besides Lewis basicity. All strong bases are these, but some weaker bases are also these.

E2

Basic H and X 1,2-elimination, R-X reactivity: faster tertiary > secondary > primary slower. Base OH- remose a Beta-H+ (proton) from R-X. X (leaving group) takes a bonding electron pair; H leaves its bonding electron pair behind which becomes the pi-electron pair. An alkene product mixture can form from nonequivalnet Beta-H atoms. KOH is often used as a base - more soluble than NaOH in ethanol solvent. Other bases: NaOCH3, NaOCH2CH3, KoC(CH3)3. Water or alcohol solvents sometimes act as (weak) bases. This does not yield rearranged alkene products because carbocations are not involved.

R-X

Both SN2 and SN1 operate to some extent in all _______ reactions. However, one mechanism is usually much faster than others. Factors affecting SN2 vs. SN1 rates: 1. Better (faster) leaving group -> faster both mechanisms 2. Alkyl sustituents speed up SN1 (through carbocation + charge delocalization). a. Tertiary these react mainly by SN1. b. Methyl and primary these react mainly by SN2. c. secondary these probably react by SN2. 3. Highand strong Z- (nucleophile) concentration favors SN2 over SN1 for all these. 4. Polar protic (hydrogen bonding) solvent favors SN1 over SN2 for all these because it solvates ions better. 5. AgNO3 addition (which precipitates halide ions) can cause otherwise likely ionizations.)

Solvation

By contrast to SN1, bond formation to Z- releases energy almost at the same time as it is needed to break the C-X bond in the SN2 transition state-> _________________ has little stabilizing effect on SN2.

Polar Aprotic Solvent

Cannot form hydrogen bonds- has a moderately high dielectric constant. Ex. acetone, DMF -All have uncrowded O atoms (with lone pair electrons) and strongly solvate cations. -They solvate anions weakly. Dipole positive is sterically crowded and forms only weak dipole-ion attractions.

Step 1 Transition State Structure for SN1

Central C atom has carbocation character in transition state i.e. it has partial (or fractional) + charge. Electron release (from three adjacent alkyl substituents) stabilizes a transition state in a similar way as it stabilizes a full carbocation - through inductive electron release and/or hyperconjugation.

Transition State

Charge is delocalized between nucleophile and leaving group. This "soft" charge is only weakly solvated and is not stabilized much by a strongly ionizing solvent. (SN2 in gas phase)

Crossing Reactivity Curves

E.D Hughes and C. Ingold (1935) - _________ _________ _________ -> two competing mechanisms must operate: SN2 operates for methyl, primary and sometimes secondary (second order rate law) and SN1 operates sometimes for secondary and tertiary (first order).

Alternative View

E2 is similar to SN2 where the nucleophile is the beta-C atom lone pair (after H+ is removed). E2 is stereospecific.

Anti-Conformation

E2 occurs from an _______________________ whenever an alkyl halide Hbeta and X atom can achieve it. Maximum orbital overlap occurs when Hbeta and X are coplanar- allows C-Hbeta sigma electron "flow " into forming pi orbital. Br is axial on bromocyclohexane.

Bond Dipole Moments

Electronegativity difference and bond length determine ________ ___________ _____________.

Heterolytic Bond Dissociation Enthalpy

Energy (kJ) to convert one mol of alkyl bromide into one mol of carbocations and one mol of halide ions (gas phase). Energy differences are larger for carbocations, while t-butyl carbocation is 276-301 kJ/mol more stable than carbocation, while t-butyl free radical is only 50 kJ/mol more stable than methyl free radical. Steric effects are responsible for small reactant potential energies differences.

Nucleophile Strength

Factors that influence _____________ _____________: -Lewis basicity- stronger= more this -Effective size- Smaller = more this - Polarizability- more polarizable (softer) = more this -Solvation- Less solvated = smaller effective size and more this

Alkene

For alkyl halides with nonequivalent Beta-hydrogen atoms, ___________ mixtures form.

Halogen Carbanion Formation

For irreversible carbanion formation test: -A ______________ ____________ ___________ would be difficult to measure since the mass difference between 35C and 37C (or other halogen isotopes) is only a few percent. No rate difference would be observable anyway if the C-X bond breaks in a fast step 2. -Reaction rates should be the same for R-F, R-Cl, R-BR, and R-I if the C-X bond breaks in a fast step 2. - Experimental R-X elimination activity: R-I >R-Br > R-Cl > R-F -Rate difference are similar to those of SN2 and SN1, where the C-X bond breaks in the rate determining step - R-I reacts 25,000 times faster than R-F. These large differences are called the "element" effect. -A large element effect is consistent only with E2 and not E1cB

Rearrangement

G. Olah has measured some __________________ rates spectroscopically in super acid solutions. Usually they are much faster than SN1 step 2.

Leaving Group

Group departing from carbon with an electron pair. -Must have an electronegative atom bonded to C, so that C has a dipole positive charge and is electrophilic (susceptible to nucleophilic attack). Electronegative atom stabilizes- charge in transition state - commonly X, O, N, S, and P.

Nucleophicity

In the gas phase, ____________________ parallels Lewis basicity. For the halide exchange reaction : stronger F-> Cl->Br->I- weaker. In methanol or water (polar protic solvents) this is reversed. F- is the hardest ion, and the most strongly solvated (stabilized) by H-bonding. This in polar protic solvents is similar to the gas phase due to weak solvation.

Primary Isotope Effect

Largest isotope effect type - if a bond to an atom is broken in the rate determining step, the overall reaction will be slower with a heavier atomic isotope.

CH2Cl2

Less toxic than CHCl3- suspect carcinogen - used in degreasers, paint removers, and as coffee decaffeinator (now replaced by safer liquid CO2). Can be converted by O2 into deadly phosgene.

Base Strength

Measures equilibrium position as a base reacts with H+ ion (or another Lewis Acid).

Nucleophilicity

Measures how fast a nucleophile reacts with a positive dipole moment C.

SN1

Methyl, primary, secondary, and tertiary alkyl halides all react at least partly via _________ in nonnucleophilic solvent CF3COOH. Rate differences are larger for SN1 than for SN2.

SN2

Methyl, primary, secondary, tertiary alkyl bromides all halogen exchange mainly via __________ in dimethylformamide solvent.

SN1

Most carbocations are stabilized by delocalization (polar effects) and are soft ions ( not as strongly solvated as the anion X-). Better solvated X- -> great solubilty, lower activation energy, and faster step 1. This is usually faster in protic solvents, where X- is strongly solvated (esp. by hydrogen bonds)

Polarizable

Nucleophile electron orbital cloud derformability (attacking the dipole positive C atom). Higher shell and pi orbitals are more this than second shell orbitals.

Alkyl Halide Heterolytic Reactions

Nucleophilic alphatic substitution - Example: bromomethane +sodium hydroxide an SN2 mechanism. Nucleophile and lewis base HO- forms a coordinate covalent bond to C. Simultaneously, Br takes both bonding electrons as C-Br bond heterolyzes.

Reactants

Once formed, alkene products do not normally revert back to ________________ under the reaction conditions. Bet-2-ene predominates over but-1-ene because it formers (irreversibly) faster. Often (but not always) a more stable product will form faster.

SN1 Stereochemical Evidence

Optically active n-holooctane yields partially racemized products. A nucleophile can attack either carbocation face (backside preferred, but not exclusive). (R)-product has retained configuration, while (S)-product has inverted configuration.

Protic

Proton donating solvent, forms hydrogen bonds, contains at least one -OH or -NHR group (R 2X bond H or alkyl)

Nucleophile

R-X is weakly solvated by strongly ionizing (polar) solvents since it is relatively nonpolar. A _______________ (such as OH-) with a full (hard) - charge on oxygen forms ion-dipole bonds with strongly ionizing solvents, which dramatically stabilizes (and weakens) this. (SN2 in gas phase)

Substrate

Reactant (R-X) attacked by a reagant (a nucleophile in this case).

SN1

Reactant R-X is only weakly solvated by a polar solvent. Stabilization is small compared to a nonpolar solvent.

Alkene

Rearranged (via 1,2 shifts) ______________ products are consistent with carbocation intermediates.

Stereospecificity

Rotation about a C-C bond can occur before step 2- leads to _____________________ loss.

Stereospecific

SN2 is ___________________ - starting with one of the two possible reactant configurations, only one of the two possible product configurations is obtained.

Rate Law

Shows how a reaction rate depends on reactant concentrations (at a given temperature). The general rate expression collision frequency term includes concentrations.

Walden Inversion

Stereochemical evidence supports _____________ ________________ in SN2; product configuration inverts from R to S like an umbrella turning inside out. Inversion cannot be proven for optically inactive substrates.

Molecular Dipole Moments

Structural geometry determines ____________ __________ ____________ - individual bond dipole moment vector sum.

Solvation

Surrounded by solvent molecules. Stripping off solvent molecules is endothermic.

Alkene Character

The E2 transition state structure has "_____________ _________________". The same factor that stabilizes product alkenes (R-group number bonded to sp2 C atoms) also stabilizes the transition state structure. If a transition state is more stable (more substituted) activation energy will be lower and E2 will be faster.

Transition State

The three fully bonded hydrogen or methyl groups on pentavalent C cannot stabilize the ___________________ ____________ through electrical charge delocalization since the central C has little or no charge. The three substituent group polar effects are small and do not affect reaction rate much.

SN1

The transition state C-X partial bond is assumed to be strongly poalrized since C and X are on their way to becoming ions. Transition states is highly stabilized in polar vs. nonpolar solvents (in gas phase). Activation energy is much lower and step 1 is much faster in polar solvents.

Heterolyses

These are usually done in liquid (solution) phase; + and - ions are involved.

Alkyl Halide

These can be made by free radical alkane halogenation which is commonly named from an alkyl group and halogen as if ionic. Example: methyl chloride. These are often synthetic reactants which are converted to other functional groups. A C-X bond is polar and weak- heterolyzes easily. Often have higher boiling points and densities than alkanes.

Freons

These were developed to replace (toxic) ammonia. Leaking refrigerators once killed people. Properties: compressible, inert, nontoxic.

Transition State Structure SN1

This structure is near the carbocation on the reaction curve, since step 1 is very endothermic. If a carbocation is more stable, the nearby this structure will also be more stable. The activation energy for step 1 will also be lower and reaction will be faster.

Alkyl Halide

Uses: Useful solvents chloromethane, dichloromethane, trichloromethane, and tetrachloromethane are separated by fractional distillation. Polychlorinated solvents are toxic (liver damage, dermatitis) and carcinogenic.

CHCl3

Was used as a general anesthetic - also good degreaser and paint remover. Halothane, F3CCHClBr is a safer general anesthetic. Chloroethane is a topical anesthetic- numbs partly by freezing (bp 12 degrees C)

CCl4

Was used in dry cleaning and fire extinguishers. Ozone layer depleter. Now replaced by Cl3CCH3 and other solvents.

Biomolecule, Polymer

Weak secondary attractive forces between molecules determine _________________ and _______________ shapes. -An individual ion-dipole bond is fairly weak, but many such bonds working together can be stronger than a full ionic or covalent bond.

Zaitsev's Rule Exceptions

When -X is fluoride or a quaternary ammonium salt, factors besides hyperconjugation (in the alkene-like transition state) come into play.

Threo

When like groups are on the opposite sides in Fischer projection drawings.

Erythro

When like groups are on the same side of the Fischer projection drawing.

Molecular Orbital Theory

Z- electron density flows into the backside of the p3-C-X anti bonding sigma orbital (since sigma bonding orbital is full already) as Z- approaches R-X. The added electron density helps puch out X-.

Two Isotopic Reaction Rates

________ ________________ ______________ ________ can be measured separately, or from competition experiments using a limited Z- reagent amount with a hydrogen relative H-Z vs. D-Z yields. The higher yield product is assumed to form faster.

Gas

________ phase SN2 reactions, where nucleophiles are not solvated at all, can be up to 10^20 times faster than in solution.

C-H, C-Hbeta

_________ bond breaking in the second (fast) step is consistent with no deuterium isotope effect. The __________ sigma orbital must be coplanar with the adjacent 2pz-orbital.

SN1

_________ is very slow in the gas phase. Heterolytic bind breaking is very endothermic.

Elimination

___________ competes with SN2 because strong nucleophiles are also strong bases. E2 predominates and SN2 is very slow for tertiary alkyl halides.

Alkane, Alkyl Halide

_____________ (nonpolar) and ____________ ____________ (weakly polar) molcules are attracted to each other only by weak London and dipole-dipole attractions. They have weaker attractions for water molecules than water molecules have themselves (due to H-bonding). These are practically insoluble in water - hydrophobic or lipophilic.

Good Yields

_____________ __________ are obtained when all H atoms are equivalent, or when one hydrogen class is much more reactive than another (bromination).

Solvent

_____________ can exert an even larger rate effect than polar and steric factors in heterolytic chemistry. It is not really an inert medium. Solute-these interactions and entropy must be larger than solute-solute + this-this attractions and entropy for dissolution to occur. Reactant and transition state energies are related to their structures which include solvation molecules.

Hydrogen Isotopes

______________ ____________ have the greatest proportional mass differences of any isotopes. These rate differences are the largest observed.

Incomplete Racemization

______________ ________________ (excess inversion) is due partly to ion pair formation after R-X bond cleavage, and partly to leaving group steric hindrance.

Anions

_______________ are strongly solvated (stabilized) by polar protic solvents, lowering their nucleophilicity. Small "hard" (nonpolarizable) ions, like F-, are more strongly solvated than larger (polarizable) ions, like I- or C double bond N-. -Protic solvent this stabilization. Some - charge is delocalized onto H2O molcules. Hard these are only weakly solvated (naked ions) in polar aprotic solvents, and are up to a million times more nucleophilic.

Nucleophiles, Alkyl Halides

________________ (often polar or ionic) and _______________ ____________ (nonpolar or covalent) molecules must collide with each other in a medium that dissolved both substrates in order for SN2 to occur. Only proptic solvents (such as alcohol/water mixtures) were practical until the advent of polar aprotic solvents.

Irreversible Carbanion Formation

________________ _________________ ________________ cannot be ruled out by the 2-phenyl-1-bromoethane experiment, K2 could be much larger than K1 and forward step 1 could be rate limiting. If step 2 were rate limiting, deuterium exchange should be observed. If step 1 is rate limiting, overall reaction rate would be independent of the C-X bond breaking rate, since this occurs in the second (fast) step.

Carbocation Rearrangements

________________ ____________________ are involved in natural product biosynthesis, such as menthol, camphor, and alpha-pinene (common names).

Carbocations

______________________ can: 1. Combine with a nucleophile (SN1) 2. Rearrange to a more stable carbocation throug a 1.2-alkyl or 1,2-hydride shift 3. Eliminate a proton to form an alkene (E1) i.e they are bronsted-lowry acids. SN1 and E1 are not usually synthetic reactions because product mixtures are often obtained. They are used in these studies.

Pentavalent

________________________ C has little electrical charge (because bond breaking and bond formation are nearly equal) in all four transition states. Reactants and products are far from it. The more crowded the groups about the central C atom -> higher activation energy and slower reaction.

Syn-eliminations

___________________________ can occur in cyclic compounds where an anti configuration is not possible.