Organic Reactions Winter 2013

Home , Allylic strain, Cope rearrangement, Julia olefination, Molecular orbital theory

O’Neil Organic Reactions Winter 2013

Chemistry 425b: Organic Reactions Dr. Gregory O’Neil Department of Chemistry Western Washington University

O’Neil Organic Reactions Winter 2013

Preface - Meyers, A. “Chemistry 215 Handouts,” available at: http://www.chem.harvard.edu/groups/myers/page8/pag This text/workbook was designed to accompany a one- e8.html quarter advanced undergraduate chemistry elective. Presentations of topics are by no means a complete treatise on Gregory O’Neil, November 29,2012. the subject. Rather, these provide an entry point to core principles governing organic reactions. Selected examples are given to highlight these reactions in the context of complex molecule synthesis. An effort has been made to provide students Table of Contents with references that encourage further reading on a given topic. The text is divided roughly into two halves (see Table of Chapter Page Contents), beginning with a more detailed analysis of reactions that should be familiar to students that have completed 1. Principles of Organic Reactions 3 sophomore organic chemistry. Topics discussed include FMO- and conformational analysis. This then is followed by more synthesis- 2. Conformational Analysis 18 oriented subjects including fundamental reactions like oxidations and reductions plus more specialized topics like selectivity 3. Kinetics and Thermodynamics 24 models for carbonyl additions and methods for alkene synthesis. It is the intention of the author to supplement this text with information on special topics that include protecting groups and 4. Pericyclic Reactions 31 palladium-catalyzed cross-coupling reactions. 5. Oxidation Reactions 46 Significant inspiration was gained from the following sources: 6. Reactions at the Carbonyl 56 - Boger, D. “Modern Organic Synthesis, Lecture Notes,” TSRI Press, La Jolla, CA. 7. Alkene Synthesis 71 - Evans, D. “Chemistry 206: Advanced Organic Chemistry,” available at: 8. Alkene Metathesis 77 http://isites.harvard.edu/icb/icb.do?keyword=k7863 - Phillips, A. “Chem 5311, Advanced Synthetic Organic Chemistry I”, Univ. Colorado, Boulder, 2006.

O’Neil Organic Reactions Winter 2013

Ch. 1 What do we need to know to understand, Classes of Mechanisms predict, and design organic reactions? Three general types:

Methodology: An organic chemist’s toolkit. a) Polar Retrosynthesis: A strategy for analyzing complex problems. Movement of PAIRED electrons

Mechanism: A framework for predicting and understanding the products and stereochemistry of a reaction

Mechanism Basics

Notation:

b) Free radical Movement of UNPAIRED electrons

O’Neil Organic Reactions Winter 2013

c) Pericyclic Universal Effects Governing Chemical Reactions: Movement of electrons within a closed ring (there are no intermediates, ions or radical species)  Steric Effects – Nonbonding interactions (Van Der Waals repulsion) between substituents within a molecule or Pericyclic reactions can be subdivided into 4 categories: between reacting molecules.

i. Cycloadditions

 Electronic Effects (Inductive Effects) – The effect of bond and through-space polarization by heteroatom

substituents on reaction rates and selectivities. ii. Electrocyclic Reactions

Rate decreases as R becomes more electronegative

iii. Sigmatropic rearrangements  Stereoelectronic Effects – Geometrical constraints placed upon ground and transition states by orbital overlap considerations.

iv. Group Transfer reactions

O’Neil Organic Reactions Winter 2013

Steric vs. Electronic Effects: Case studies when steric and MO Theory: The H2 Molecule (revisited) electronic effects lead to differing stereochemical outcomes: Let’s combine two hydrogen atoms to form H2. Woerpel et al., J. Am. Chem. Soc. 1999, 121, 12208 . Rule 1: A linear combination of n atomic orbitals (AOs) will create n Molecular Orbitals (MOs).

O EtO2C (Bu)2CuLi O What happens when you add two electrons to the MO diagram EtO C Bu 2 OR above? How about four electrons?

O EtO C OR Bu Al 2 3 . Rule 2: Each MO is constructed by taking a linear Bu O combination of the individual atomic orbitals: EtO C OR 2 Bonding MO σ = C1ψ1 + C2 ψ2

Antibonding MO σ* = (C1*)ψ1 + (C2*) ψ2

Bu OR Al The coefficients C1 and C2 represent the contribution of Bu Bu each AO.

Yakura et al., Tetrahedron 2000, 56, 7715 The squares of the C-values are a measure of the electron density on the atoms in question.

O’Neil Organic Reactions Winter 2013

 Rule 3: Both wave functions must contribute one net Chemical Bonding orbital.  Bond strengths (Bond Dissociation Energies) are composed

of a covalent (δ Ecov) and ionic contribution ((δ Ecov).

Consider the C-O pi-bond of acetone.  As two molecules collide: a) The occupied orbitals of one molecule repel the occupied orbitals of the other. b) Any positive charge on one attracts negative charge on the other. c) The occupied orbitals of each interact with the unoccupied orbitals of the other.

Overlap between orbitals is most effective for orbitals of similar size and energy (Frontier Molecular Orbital Theory).

In the ground state, pi C-O is polarized toward oxygen.

Note that the antibonding orbital is polarized in the opposite direction (Rule 3)

What does this mean in terms of reactivity?

O’Neil Organic Reactions Winter 2013

. Consider Group IV elements Carbon and Silicon: Case 1: Anti nonbonding electron pair and C-X bond.

Compare anti (favored) vs. syn (disfavored) E2 eliminations.

Case 2: Two anti sigma bonds.

Weak bonds have corresponding low-lying antibonding orbitals.

. Orbital orientation greatly affects the strength of the interaction.

O’Neil Organic Reactions Winter 2013

Donor Acceptor Properties . The interaction of a vicinal bonding orbital with a p- orbital is referred to as hyperconjugation. Consider the energy levels for both bonding and antibonding orbitals:

Stereoelectronic requirement: Syn-planar orientation between interacting orbitals.

MO Description:  C-R

H H

The greater electronegativity of oxygen lowers both the bonding and antibonding C-O states. Hence:  C-R

σ C-C is a better donor orbital that σ C-O σ* C-O is a better acceptor orbital than σ* C-C The new occupied orbital is lower in energy. When you stabilize . Hierarchy of Donor Acceptors: the electrons in a system, you stabilize the system as a whole.

O’Neil Organic Reactions Winter 2013

 Consider the following X-ray structures of adamantine. . Delocalization of nonbonding electrons into vicinal antibonding orbitals is also possible. Bonds participating in hyperconjugation (e.g C-R) will be lengthened while the C(+)-C bond will be shortened.

M.O Description

As the antibonding C-Y orbital energy decreases, the magnitude of this interaction will increase. T. Laube, Angew. Chem. I. E. 1986, 25, 349. Note that σ C-Y is slightly destabilized.

O’Neil Organic Reactions Winter 2013

. Since nonbonding electrons prefer hybrid orbitals, this Example: N2F2 orbital can adopt either a syn or anti to the vicinal C-Y bond. This molecule can exist as either cis or trans. Which is preferred?

Syn Orientation

Orbital Interactions:

M.O Description

Anti Orientation

Electrostatic Interactions (Dipole)?

Overlap is better in the anti orientation.

O’Neil Organic Reactions Winter 2013

Anomeric Effect . Other electronegative atoms such as Cl, SR, etc. also participate in anomeric stabilization. A methoxy substituent on a cyclohexane ring prefers to adopt the equatorial conformation.

Why is the axial C-Cl bond longer? Whereas the closely related 2-methoxytetrahydropyran prefers the axial conformation. . There is also a rotational bias on the exocyclic C-OR bond.

The effect that provides the stabilization which overrides the inherent steric bias is referred to as the anomeric effect.

Principle HOMO-LUMO interaction:

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. Spectroscopic Evidence Rationalize why B is more stable than A.

Can you explain the following IR trends?

Katritsky, J. Chem. Soc. B 1970, 135.

Compare the C-H stretching frequency for an aldehyde and related alkene. Carboxylic Acids and Esters . Conformations: There are two planar conformations.

Specific Case: Methyl Formate.

The N-H stretching frequency of cis-methyl diazene is 200 cm-1 lower than the trans isomer.

Me H Me The (E) conformation of both acids and esters is less stable by 3- NN NN 5 kcal/mol. Sterics would predict that the (E) conformer of methyl formate would be preferred (H smaller than O). Since -1 H  N-H = 2188 cm this is not the case, electronics must be considered.  N-H = 2317 cm-1

N.C Craig & coworkers J. Am. Chem. Soc. 1979, 101, 2480.

O’Neil Organic Reactions Winter 2013

. Conjugation and Hybridization Esters vs. Lactones

Note that the alkyl oxygen is sp2 hybridized in order to allow for Esters prefer to adopt the (Z) conformation while small ring conjugation (resonance). lactones are constrained in the (E) conformation. Explain the following:

1. Lactone 2 is significantly more susceptible to nucleophilic

attack at the carbonyl carbon than 1. 2. The pKa of 2 is 25 while ester 1 is 30.

Reactions . Peracid epoxidation of alkenes.

. Hyperconjugation

(Z) Conformer:

Identify the important orbital interactions.

(E) Conformer:

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. Baeyer-Villiger reaction. How important is the trajectory of approach for reacting molecules?

3 Can you rationalize the rate date below? (Hint: Why is that the . sp hybridized: SN2 displacement. preferred intermediate?)

k O R RkR /kMe R C O Me CH CH 72 O 3 2 C +CF3CO3H R Me (CH3)2CH 150 O (CH ) C 830 kMe C Me 3 3 R O

via RS OH where R = large substituent O CF3 L R O L RS = small substituent O

. Tether Nu and X

Eschenmoser Helv. Chim. Acta 1970, 53, 2059.

O’Neil Organic Reactions Winter 2013

O O 2 O O . sp Hybridized: C=O and C=C. S CH3 O S O Some history: Nu: CH3 Nu OMe OMe O O OMe OMe O O S MeI, MeOH O intramolecular not possible X H C H N sealed tube, 48 h N I not 180° O O Nu H har sh O O

OMe . Endocyclic Restriction Test - NH2-OH OMe SO3CH3 + SO3 HO (CH3)2N (CH3)3N N X exclusively N O intramolecular O Perkin J. Chem. Soc. 1916, 109, 815. O Me N H S X Me O CO 1. Led to the idea of a partial through-space bond between H H Nitrogen and the carbonyl. King et al. Tet. Lett. 1982, 23, 4465. 2. Later, Brent proposed that X-ray structures of donor- acceptor systems might represent the early stages of chemical reactions. (Chem. Rev. 1968, 68, 587)

N O

Beak Acc. Chem. Res. 1992, 25, 215. Burgi J. Am. Chem. Soc. 1973, 9515 5065.

O’Neil Organic Reactions Winter 2013

Required Trajectories: Summary B. Endo-cyclization – The bond that is breaking is endocyclic to the forming ring.

C. Ring Closures are classified according to hybridization of the electrophilic component and size of the ring formed.

Baldwin J. Chem. Soc., Chem. Commun. 1976, 734. Examples:

Baldwin’s Rules: Stereoelectronic Considerations for Ring-Closure.

Baldwin’s Rules provide a qualitative set of generalizations on the probability of a given ring-closure.

They do not apply to non-first-row elements or electrocyclic processes.

. Nomenclature: A. Exo-cyclization – The bond that is breaking is exocyclic to the forming ring.

O’Neil Organic Reactions Winter 2013

Most exo cyclizations are allowed. Case 2:

Example: Formation of 3-membered rings:

Some endo cyclizations are disallowed.

Case 1:

Case 3:

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Conclusions The eclipsed conformer may be broken down into its individual destabilizing interactions. EXO ENDO Tet Trig Dig Tet Trig Dig Structure Eclipsed Atoms ΔE (kcal mol-1) 3   X X  4   X X  Ethane H H 1.0 5 X X     Propane H H 1.0 6    X   H CH3 1.4 7    X  

Further reading: FMO Analysis: Johnson, C. D. Acc. Chem. Res. 1993, 26, 476.

Ch. 2 Conformational Analysis

Reviews: Hoffmann, R. W. Angew. Chem. I. E. 2000, 39, 2054 Hoffmann, R. W. Chem. Rev. 1989, 89, 1841

Ethane and Propane

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Butane Pentane Me Me H H H H H H H Me H Me staggered eclipsed

E=?

Torsional Energy Diagram

Heirarchy of Me – Me Interactions

H3C CH3 CH3 CH3 CH3 CH3 CH3 CH3

ca 3.1 3.7 3.9

Can you calculate the magnitude of the Me – Me interaction? ~7.6 19

O’Neil Organic Reactions Winter 2013

Consider the conformation of zincophorin: Propylene (Propene) Torsional Strain:

Can you identify the lowest/highest energy conformations?

Allylic Strain: Propane vs. Propene 3-methyl-1-butene

2-Z-butene

Hybridization changes the C-C-C bond angle.

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Can the following selectivity: Amides

J. Am. Chem. Soc. 1979, 101, 259.

This has important consequences for the enolate chemistry of Allylic Strain: Definition amides:

Ketones and Aldehydes

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Can you predict the stereochemical outcome of this reaction? Cyclohexane

A chair ring-flip interconverts axial and equatorial substituents:

Cyclic Systems

Strain Energy and Ring Size 10 Substituted Cyclohexanes:

8 Methylcyclohexane 6

4 kcal/mol 2

0 345678 Ring Size 22

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Typical A Values (kcal/mol): Stereoselective Reductions:

FG A Value FG A Value

F 0.25 OEt 0.9

Cl 0.6 CO2Et 1.15

Br 0.5 NH2 1.4

I 0.5 CH3 1.8

OH (in C6H6) 0.7 CH2CH3 1.9

OH (in i-PrOH) 0.9 CH(CH3)2 2.1

OCH3 0.75 C(CH3)3 4.9

Note the difference between iPr and tBu A Values.

Six-Membered Rings with Heteroatoms

Consider the following A-Values:

Consider 3-methylcyclohexanone:

O’Neil Organic Reactions Winter 2013

Note on axial vs. equatorial interconversion: To achieve a high ratio of products in a thermodynamically controlled reaction, you need the following ΔG’s (kcal/mol):

K (25 °C) ΔG K (0 °C) ΔG K (-78 °C) ΔG

2 (67:33) 0.41 2.1 (68:32) 0.41 2.9 (75:25) 0.41

5 (83:17) 0.95 5.7 (85:15) 0.95 11.6 (92:8) 0.95

 A values are additive 9 (90:10) 1.30 10.9 (92:18) 1.30 28.5 (97:3) 1.30

20 (95:5) 1.74 27.5 (96:4) 1.80 103.3 (99:1) 1.80

Consider the following hydrogenation reaction:

 Even though Cl has a very small A value, the energy of

activation (Ea) is high (it must go through a half-chair conformation).

Ch. 3 Kinetics and Thermodynamics of Organic Reactions

Overall this reaction is exothermic (ΔG = -17 kcal/mol), so the reaction is favorable or spontaneous.

 But experimentally this reaction is very slow, it takes An equilibrium can be described by: about 2 x 104 years to hydrogenate one mole of ethylene (without a catalyst).

O’Neil Organic Reactions Winter 2013

Kinetic vs. Thermodynamic Control

A transition state (TS) possesses a defined geometry and charge delocalization but has no finite existence. If this is an irreversible reaction, the major product will be B. If the reaction is reversible, C will be major (more stable product).

Intra- versus Intermolecular Reactions Hammond Postulate

The transition state most closely resembles the side (i.e reactant or product) to which it is closer in energy. CH3 Consider the solvolysis of tert-butyl chloride: MeOH H3C Cl  Step 1: CH3

Intramolecular reactions have a far more favorable entropy of Step 2: activation.

O’Neil Organic Reactions Winter 2013

The transition states will resemble the geometry of the carbocation intermediate and not the reactant or product.

Conformational Effects on Reactivity

 Ester Hydrolysis  Oxidation

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 Substitution Reactions  Elimination Reactions

Which of the following SN2 reactions is faster? Can you explain the following ratio of elimination products?

Consider the E2 Elimination of:

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 Epoxide Opening

Under kinetically controlled conditions (irreversible), product ratios are dependent on Ea (ΔΔG‡).

Consider the following:

path (a) path (b) CH SPh CH3 CH3 3 (b)

O O H O- H H twist boat conformation (a) 1,3-diaxial exclusive product SPh CH3 SPh CH3 H CH3 H HO H PhS  Epoxide Opening OH H O- H H H less stable product chair conformation more stable product

Atom under attack moves toward the nucleophile.

Reactions that proceed via a ground state conformation are typically faster. 28

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 Rearrangements

From the previous example, how does the rate of conformer intercoversion effect the product distribution?

There are two limiting cases to consider:

a) The rate of reaction is much faster than interconversion i.e k ,k >> k ,k 3 4 1 2 b) The rate of reaction is much slower than interconversion i.e k3,k4 << k1,k2

Case A: The two conformers cannot equilibrate during the reaction. The product ratio thus depends solely on the initial ratios of the two conformers (aka “Kinetic Quench”).

Case B: The two conformers can equilibrate during the reaction. The product ratio depends on the difference in activation energies (Ea) leading to the respective products (“Curtin- Hammett conditions”).

O’Neil Organic Reactions Winter 2013

Ch. 4 Pericyclic Reactions Some things to consider:

 A pericyclic reaction is characterized as a change in a. The number of electrons involved is important. bonding relationships that takes place as a continuous, concerted reorganization of electrons.

 The term "concerted" specifies that there is one single transition state and therefore no intermediates are

involved in the process. To maintain continuous electron flow, pericyclic reactions occur through cyclic transition states.

 More precisely: The cyclic transition state must

correspond to an arrangement of the participating orbitals which has to maintain a bonding interaction b. Pericyclic reactions are stereospecific between the reaction components throughout the course of the reaction.

Is it possible to predict the stereochemical outcome of this reaction?

c. Reactions behave differently under different conditions (i.e thermo- vs. photochemical)

Huisgen Tet. Lett. 1964, 3381.

O’Neil Organic Reactions Winter 2013

We can explain and predict the outcome of pericyclic reactions Disrotatory Closure: using Frontier Molecular Orbital (FMO) theory (HOMO and LUMO interactions) and orbital symmetry.

For further reading see:

Woodward, Hoffmann, The Conservation of Orbital Symmetry, Academic: New York, 1970. Some Observations Fleming, Frontier Orbitals and Organic Chemical Reactions,  butadienes undergo conrotatory closure under thermal John-Wiley and Sons, New York, 1976. conditions Fukui, Acc. Chem. Res. 1971, 4, 57.; Angew. Chem. I. E. 1982, 21, 801.

Some Classes of Pericyclic Reactions

1. Electrocyclic Ring Closure/Opening

Ring closure (and hence opening) can occur in two distinct ways:

Conrotatory Closure:

 hexatrienes undergo disrotatory closure under thermal conditions.

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 Under photochemical conditions 4 electron systems FMO Analysis undergo disrotatory motion Butadiene π Molecular Orbital Diagram:

 while 6 electron systems undergo conrotatory motion.

conrotation  4 π electron thermal reaction h Me Me Me Me

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 6 π electron thermal reaction  4 π electron photochemical reaction

Overall: No. π electrons Thermal hν 4n (n = 0,1…) conrotatory disrotatory 4n + 2 disrotatory conrotatory

Photochemical Activation:

When light is used to initiate an electrocyclic rxn, an electron is excited from Ψ2 to Ψ3. Treating Ψ3 as the HOMO now shows 2. [1,3]-Sigmatropic Rearrangements that disrotatory closure is allowed and conrotatory closure is forbidden. Consider the following H-Migration:

‡ H ion X Y

H H

X Y X Y ‡ H radical X Y

O’Neil Organic Reactions Winter 2013

The hydrogen can move across the pi system in one of two ways. The bridging distance is too great for the antarafacial migration. If hydrogen migrates on the same side of the system, it is said to Hence, [1,3] hydrogen migrations are not observed under migrate suprafacially with respect to that system. If hydrogen thermal conditions. Under photochemical conditions, the [1,3] migrates from one side of the pi system to the other, it is said to rearrangement is allowed suprafacially. migrate antarafacially. How would you predict this using FMO?

What about a [1,5] Hydrogen Shift? FMO Analysis of Hydrogen Migration:

O’Neil Organic Reactions Winter 2013

3. [3,3]-Sigmatropic Rearrangements The Cope rearrangement proceeds in a concerted manner via a chair transition state and requires no acid or base catalysis.

Consider the following:

Me Me Z Me Me E 99.7% Me

The reaction can proceed via a chair or boat transition state Me E Me Me Me Me E 0.3%

Can you explain the following product distribution?

Some examples of [3,3]-Sigmatropic Rearrangements:

a) Cope Rearrangement

Doering Tetrahedron 1962, 18, 67. 35

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 Applications Mechanism:

Oxy-Cope  Applications Evans and Golob showed that the oxy-Cope rearrangement could be greatly accelerated by deprotonation of the alcohol.

J. Am. Chem. Soc. 1975, 97, 4765.

Review: Paquette Tetrahedron 1997, 53, 13971.

O’Neil Organic Reactions Winter 2013

b) Claisen Rearrangement A general mechanism:

Review: Wipf Comprehensive Organic Synthesis 1991 Vol. 5 pp 821-871.

There are a number of important variants of this important reaction:

Applications

Aromatic Claisen:

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Johnson Claisen: Ireland deprotonation model:

Ireland Claisen:

The stereochemical outcome can be controlled by careful control of the enolization conditions. Compare the following to the previous related Johnson Claisen.

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The chair TS may not always be accessible:

Some common cycloaddition reactions include:

4. Cycloaddition Reactions

A cycloaddition reaction is the union of two smaller, How do we explain the following observations? independent pi systems. Sigma bonds are created at the expense of pi bonds.

Cycloaddition reactions are referred to as [m + n] additions when a system of m conjugated atoms combines with a system of n conjugated atoms.

In a cycloaddition, a pi system may be attacked in one of two distinct ways. If the pi system is attacked from the same face, then the reaction is suprafacial on that component. If the system is attacked from opposite faces, then the reaction is antarafacial on that component.

O’Neil Organic Reactions Winter 2013

Role of FMO’s: Can you design suitable substrates for an inverse electron demand Diels-Alder reaction?

[2+2]-Cycloaddition

Two geometries of approach can be envisioned. Consider thermal activation:

 HOMO-LUMO gap controls the rate of reaction. Smaller gap = faster reaction.  Electron-withdrawing groups lower the energy of the HOMO and LUMO.  Electron-donating groups raise the energy of the HOMO and LUMO

Reactions between electron-rich dienes and electron-poor dienophiles are referred to as normal electron demand Diels- Alder reactions. The most significant orbital overlap is between the HOMOdiene and LUMOdienophile.

For a normal electron demand process the most valuable feature The simplest approach (Supra/Supra) is forbidden under thermal of a good dienophile is a low-energy LUMO, usually achieved by activation. The less obvious approach (Antara/Supra) is allowed conjugation to an electron withdrawing group. thermally but geometrically rather congested.

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Photolytic [2+2]-cycloadditions are quite common. a) Stereochemistry

The Diels-Alder reaction is stereospecific (i.e the relative stereochemistry in the diene and dienophile are preserved in the product).

Compare:

[4+2]-Cycloaddition

Normal Diels-Alder reaction under thermal activation:

 Suprafactial with respect to both reaction components.  Reaction proceeds through a boat transition state.

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Endo products are typically favored even though exo products Because of the well-defined stereochemical and regiochemical are often more stable. behavior, the Diels-Alder reaction has been used extensively in complex molecule synthesis.

Required Reading: Nicolau, Angew. Chem. I. E. 2002, 41, 1668.

see also: Tadano et al. Chem. Rev., 2005, 105, 4779.

Some examples:

b) Regiochemistry

Regiochemistry can often be predicted by considering polarity of the reacting substrates.

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Enantioselective Diels-Alder Reactions. Chiral Lewis Acid Catalyst:

One system of broad utility employs an oxaolidinone as a chiral auxiliary.

Role of Lewis Acid:

Organocatalyst

O 10 mol% cat. CHO Me H 90% ee H2O, 0 °C Me 90% endo cat O N O

Ph N H Macmillan JACS 2002, 122,2458 43

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Ch. 5 Oxidation Reactions. Organic Syntheses, Coll. Vol. 10, p.696 (2004); Vol. 77, p.141 (2000). Alcohol Oxidations.  Good for small scale reactions.  Tolerant of a wide range of functionality.

 Can buffer with pyridine or NaHCO3(s).

Some examples: General mechanism:

O O There are a number of reagents for this purpose, this is a survey OTMS OTMS of some of the most common reagents used in synthesis. O O H Dess-Martin, H 1. Dess-Martin Periodinane OTMS OTMS O NaHCO3,CH2Cl2 O Dess, Martin, J. Org. Chem. 1983, 48, 4155. O O Dess, Martin, J. Am. Chem. Soc. 1991, 113, 7277 HO H H O Preparation:

Synlett, (4), 313-14; 1992 44

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2. Swern  Tolerant of a large range of functionality.  Basic conditions can cause electrophilic additions α to the carbonyl or β-eliminations:

Swern, J. Org. Chem. 1978, 43, 2480.

Mechanism:

Some Examples:

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3. Tetrapropylammonium Perruthenate (TPAP) 4. TEMPO

Review: de Nooy et. al Synthesis 1996, 1153.

 Essentially neutral conditions.  Good selectivity for 1° vs. 2° alcohols.  Ruthenium is expensive, used catalytically with NMO as  Cheap, stoichiometric oxidant is bleach. the stoichiometric oxidant. Mechanism (See Tetrahedron 1998, 54, 667.):  Molecular sieves are used to prevent overoxidation of aldehydes to carboxylic acids.

Selected Examples:

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Examples:

b) PCC (Tet. Lett. 1975, 2647) O Cr N O Cl - Only slightly acidic. H O Workup and removal of chromium - "PCC" salts can be laborious.

Still widely used:

5. Chromium-Based Oxidations

a) Jones Reagent (J. Chem. Soc. 1953, 2548.) - Simple Prep: 67 g. of chromium trioxide in 125 ml. of distilled water. To this solution is added 58 ml. of concentrated sulfuric acid and the salts which precipitate are dissolved by addition of a minimum quantity of distilled water; the total volume of the solution usually does not exceed 225 ml. - Very acidic, good for the oxidation of simple primary alcohols to carboxylic acids or secondary alcohols to ketones.

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6. Oxidation of primary alcohols to carboxylic acids. c) Two Step:

a) TEMPO plus NaClO2 (J. Org. Chem. 1999, 64, 2564.) - Two step cycle consisting of TEMPO oxidation to the

aldehyde followed by NaClO2 oxidation to the carboxylic acid. - There are many choices for step 1.

- Step 2 can be achieved using NaClO2 in the presence of a phosphate buffer and 2-methyl-2-butene as an acid scavenger.

b) RuCl3-NaIO4 (J. Org. Chem. 1981, 46, 3936). - Will also oxidize alkenes.

O 2.2 % RuCl3,NaIO4 Ph OH Ph OH O 1h, rt. 75% O

cat. Ru, NaIO CO2Me 4 CO2Me Ph rt. Ph CO2H Ph JACS 1996, 118, 6897.

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Oxidation of Carbon-Carbon Double Bonds  Stereochemistry

1. Epoxidation Reactions. Consider the following:

 Peroxyacids:

Mechanism:

Rickborn, J. Org. Chem. 1965, 30, 2212.

Singleton and Houk, J. Am. Chem. Soc. 1997, 119, 3385.

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Three of the following reactions are diastereoselective the fourth is not. Explain.

There is a small difference in the energies of the products, but a larger difference for reagent approach in the transition states.

 Allylic Alcohols

Henbest, J. Chem. Soc. 1957, 1958.

Original proposal for selectivity:

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 Enantioselective Epoxidation: Sharpless Asymmetric The enantiofacial selectivity is determined by the choice of Epoxidation ligand. As drawn, (-)-DET would result in epoxidation from the top face while (+)-DET would give the epoxide on the bottom Sharpless, Katsuki, J. Am. Chem. Soc. 1980, 102, 5974. Review: face. Pfenniger, Synthesis 1986, 89. Sharpless Tetrahedron 1994, 50, 4253.

The original paper described the first truly general and useful asymmetric reaction.

1 2 3 R R R yield ee(%) 3 Å or 4 Å molecular sieves are required to ensure both high conversion and ee. A typical reaction is run with 5 mol% Ti(i- H H Me 15 73 PrO) , and 6 mol% (+) or (-) tartrate ester. H Pr H 80 89 4 H n-decyl H 82 90 Some recent examples: Ph H H 87 95 n-decyl H Ph 79 95

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Some useful patterns of reactivity for 2,3-epoxy alcohols: observation and chiral cinchona alkaloids ligands as the source of asymmetry.

Pthalazine (PHAL) and diphenylpyrimidine (PYR) derivatives of DHQ/DHQD give generally higher ee and allow for the formulation of AD-mix-α (contains (DHQ)2PHAL) and AD-mix-β (contains (DHQD)2PHAL). These commercially available systems contain: Asymmetric Dihdroxylation: Sharpless (DHQ)2PHAL or (DHQD)2PHAL 0.0016 mole Potassium carbonate, 0.4988 mole Hentges, Sharpless J. Am. Chem. Soc. 1980, 102, 4263. Potassium ferricyanide 0.4988 mole (reoxidant) Review: Chem. Rev. 1994, 94, 2483. Potassium osmate dihydrate 0.0007 mole (non-volatile Os(VIII))

The catalytic variant of an old and powerful reaction:

Criegee noted that dihydroxylation could be accelerated in pyridine. Sharpless’ asymmetric variant builds upon this 52

O’Neil Organic Reactions Winter 2013

The facial selectivity can be predicted by: Ch. 6 Reactions at the Carbonyl: Formation of C-H and C-C Bonds.

For mono-substituted alkenes, locate RL, then orient as shown.

Some examples:

Reduction with Hydride Reagents

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 Nucleophilic Hydride Reagents NaBH4 LiBH4 LiAlH4 BH3 DIBAL-H

a) Sodium Borohydride, NaBH : Most commonly used in 4 RCHO      MeOH to reduce ketones and aldehydes.

b) Lithium Borohydride, LiBH4: In THF or Et2O the increased R2CO     

Lewis acidity of Li+ vs. Na+ makes this a more powerful RCO2R   

reductant that NaBH4. Can reduce some esters and RCO2H   lactones, commonly used to cleave oxazolidinone auxiliaries. RCONR’2 

c) Lithium Aluminum Hydride, LiAlH4: Powerful hydride RCN  reagent that reduces essentially all carbonyl groups as alkene well as other functional groups.  Some Examples: d) Lithium tri(sec-butyl)borohydride, Li(s-Bu)3BH: Bulky hydride that is valued for increased stereoselectivity. e) Sodium Cyanoborohydride, NaCNBH3: Stable in acid (pH=3), primarily used to reduce imines (as part of the reductive amination process).

 Electrophilic Hydride Reagents

a) Borane, BH3: Most commonly as the THF- or Me2S- complex. Used to reduce amides and acids, but will also react with olefins and several other functional groups. b) Diisobutylaluminum Hydride, DIBAL-H): The reagent of choice for the reduction of nitriles to aldehyde (via the imine), lactones to lactols, some esters to aldehydes, and α,β-unsaturated esters to allylic alcohols.

O’Neil Organic Reactions Winter 2013

Cyclic Ketones Enantioselective Ketone Reductions Review: Itsuno, S. Org. React. 1998, 52, 395.

 Chlorodiisopinocampheylborane, (−)-Ipc2BCl, DIP-Cl

reagent axial equitorial Probably the most widely used of the many reagents for this NaBH4 14 86 purpose. Particularly useful for aryl/methyl ketones. LiAlH4 10 90 L-Selectride 96.5 3.5 Mechanism:

SMALL reagents prefer axial attack while LARGE reagents prefer equatorial attack.

These reactions are under kinetic control:

Example:

Org. Process Res. Dev., 2010, 14, 193–198.

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Oxazaborolidines: Itsuno-Corey System (“CBS” Reduction) Organolithium, Grignard, and Organocopper Reagents: Hard vs. Soft Nucleophiles Corey, E. J. Angew. Chem. I. E. 1998, 37, 1986. We saw previously that according to Frontier Molecular Orbital A broadly useful catalytic enantioselective reducing system. Theory, the most important interactions are between the HOMO of a numcleophile and the LUMO of an electrophile.

- Hard nucleophiles are characterized by a relatively low- energy HOMO. These react fastest with hard electrophiles which have high-energy LUMO’S. The large separation between the HOMO and LUMO makes these interactions more coulombic in nature and therefore typically involve charged species. - Soft nucleophiles in contrast have a relatively high- energy HOMO. These react with soft electrophiles that have low-energy LUMO’s. Reactions of this type are therefore governed primarily by orbital overlap Corey, E. J. et al. J. Am. Chem. Soc. 1969, 91, 5675. considerations.

Example: Catalytic Cycle: The hydroxide ion is a hard nucleophile, because it has a charge, H Ph H Ph and because oxygen is a small, electronegative element. Ph Ph BH3-THF Accordingly, it reacts faster with a hard electrophile like a N O N O B B proton than with a soft electrophile like bromine. However, an H3B Me Me alkene is a soft nucleophile, because it is uncharged and has a high-energy HOMO. Thus it reacts faster with a soft electrohile OBH O H 2 like bromine which has a low-energy LUMO. RL RS RL RS

H Ph HO- +H+ is faster than HO- + Br Br Ph H Ph Ph N O B N O H2B B H B + O 2 H2C=CH2 +H is slower than H2C=CH2 + Br Br H H O RL RS 56 RL RS

O’Neil Organic Reactions Winter 2013

Hard vs. Soft (contd.) Example:

1,4-Addition Mechanism:

2. Organocopper Reagents - Organolithium + Copper(I) salt:

Reagent Synthesis If “R” is precious (note that only one R group gets transferred to 1. Organolithium and Grignard Reagents the substrate) one can prepare “mixed” higher-order cuprates - Halide + Metal0 (most common): that utilize a non-transferable or “dummy” ligand (e.g CN or 2- thiophenyl):

- Metal-Halogen Exchange:

O’Neil Organic Reactions Winter 2013

Example: Review: Knochel, Chem. Rev. 1993, 93, 2117.

Enantioselective Organozinc Additions:

Review: Pu. L.; Yu, H.-B. Chem. Rev. 2001, 101, 757

Initial Report:

Some other organometallics to consider:

 Organochromium Reagents

Review: Fürstner, Chem. Rev. 1999, 99, 991.

More recently:

Many examples in complex molecule synthesis:

See also Halichondrin: J. Am. Chem. Soc. 1992, 114, 3162.

 Organozinc Reagents 58

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Alkyne Additions: Diastereoselective Additions at CO.

 Cram proposed the earliest model to account for the diastereoselectivity obtained upon addition to a carbonyl group that contains a stereocente at the α-carbon.

• 90° approach of Nucleophile

• activated carbonyl is the

largest group

• doesn’t consider torsional

interactions between R and RL

Cram, D. J.; Elhafez, F. A. A. J. Am. Chem. Soc. 1952, 74, 5828.

 Cornforth introduced a model to account for the stereochemistry observed with α-chloroketones. Recently supported both experimentally and theoretically for additions of enolboranes to α-alkoxy-aldehydes. Note: Carreira system reported to give no product. • 90° approach of Nucleophile

How can you explain the result with no chiral ligand? And that • activated carbonyl is the the stereoselection is opposite for the following: largest group

O OBn • net dipole is minimized Et2Zn, Ti(i-PrO)4 OH OBn OH OBn + TMS Cornforth, J.W.; Cornforth, R. H.; Mathew, K. K.; J. Chem. Soc. TMS TMS 1959, 112; MAJOR Evans, D. A.; Siska, S. J.; Cee, V. J. Angew. Chem. I. E. 2003, 42, 1761 59

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Karabatsos introduced an alternative predictive model where the  Felkin-Ahn Model:

CO group eclipses either the C-RL bond or the C-RM bond

O • 90° approach of Nucleophile RM R Nu L • first model to consider R S R torsional effects

Anh and Eisenstein computationally studied various conformation • 90° approach of Nucleophile preferences and added:

• activated carbonyl is the largest group • Burgi-Dunitz trajectory of • product ratio is determined by theinteraction of R and O O M RM attack vs R and O Felkin-Anh L RL Model Nu R • places the best acceptor σ* S R Karabatsos, G. J. J. Am. Chem. Soc. 1967, 89, 1367 (usually the large group) perpendicular to attack

 Felkin Noted that these models do not explain the effect Anh, N.T.; Eisenstein, O. Tetrahedron Lett. 1976, 26, 155 of the R-group on selectivity The Felkin-Anh Model does not accurately explain:

Chérest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968, 18, 2199.

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In 1959, Cram proposed a model to account for the addition of Allyl Organometallic Additions nucleophiles to α-hydroxy and α-amino compounds. Allyl organometallic reagents can react in one of two ways. Consider the following:

• Chelation of the metal favors attack from one face of the

carbonyl

• Chelation control can be

extended to Most reagents give predominantly the γ-addition product via two different mechanisms:

Cram, D. J.; Kopecky, K. R. J. Am. Chem. Soc. 1959 81, 2748 a) For M = B, Ti, or Cr; The reaction proceeds via a “closed transition state”:

O’Neil Organic Reactions Winter 2013

b) For M = Si or Sn, the reaction proceeds via an “open E-Crotylborane reagents give anti-products via a closed T.S: transition state” under Lewis acid (LA) catalysis:

Z-Crotylborane reagents give syn-products via a closed T.S: Reactions that proceed via a closed transition state are stereospecific, meaning that E-crotylation reagents give anti products while Z-crotylation products give syn.

O’Neil Organic Reactions Winter 2013

Reactions that proceed via an open transition state give Chiral Reagents: Brown Allylation and Crotylation predominantly syn products for both E and Z crotylation reagents. Brown, J. Am. Chem. Soc. 1990, 112, 2389. Allylborane:

E- and Z-crotylborane:

O’Neil Organic Reactions Winter 2013

Some recent examples:

Although the stereochemical outcome of the allylboration of aldehydes using B-allyldiisopinocampheylborane is typically reagent controlled, this selectivity may be challenged with certain substrates:

How can you explain the different ratios above?

Note: Removal of the campheol byproduct can be problematic.

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The Aldol Reaction: An Alternative to Crotylation for Consider the following aldol reaction: Propionate Synthesis.

How many possible stereoisomers can be formed? What needs to be controlled in order to select for a single stereoiosomer?

1. Enolate Geometry:

Nature’s Method:

2. Enolate Facial Selectivity:

O’Neil Organic Reactions Winter 2013

3. Aldehyde Facial Selectivity How do we control enolate geometry?

Consider a Z-enolate reacting via a closed transition state: Recall the Ireland deprotonation model:

In general, Z-enolates give syn-propionate products while E- enolates give anti products.

- Z-enolates:

Depending on the nature of R, one can select for E or Z using LDA, although in practice a mixture is generally observed.

Example:

- E-enolates:

O’Neil Organic Reactions Winter 2013

Boron Enolates Case Study: Enantioselective Aldol Reactions using chiral oxazolidinone auxiliaries: Formation of a boron enolate occurs in two steps, activation of the carbonyl followed by deprotonation with base:

What are the important orbital interactions during the activation step?

What is the purpose of the activation step? Evans, D. A. J. Am. Chem. Soc. 1981, 103, 2876 and 3099.

Exclusive Z-enolate formation:

Depending on the nature of the borane (BR X) and Base one can 2 select for either the E or Z enolate:

 Facial Selectivity:

R Cy2BCl, Et3N 9-BBNOTf, i-Pr2EtN

Et 79 : 21 3 : 97

i-Pr 97 : 3 12 : 88

t-Bu 97 : 3 90 : 10

O’Neil Organic Reactions Winter 2013

Example: Ch. 7 Alkene Synthesis.

1. Phosphorous-Based Methods

a) G. Wittig received the 1979 Nobel Prize in Chemistry for “many significant contributions to Organic Chemistry.” The Wittig reaction is arguably the most widely used alkene synthesis protocol, due in part to its predictable selectivity:

First report: Wittig and Geissler, Liebigs Ann. 1953, 580, 44

Some Examples:

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The reaction involves addition of a phosphorous ylide to an The Wittig reaction is thought to proceed via a “puckered” aldehyde or ketone to generate a betaine intermediate that is in transition state. equilibrium with the corresponding oxaphosphetane:

The reaction of non-stabilized ylids to give cis-alkene products is under kinetic control while the reaction of stabilized ylids is under thermodynamic control.

O’Neil Organic Reactions Winter 2013

b) Horner-Wadsworth-Emmons Reaction. The electron withdrawing effects are presumed to decrease oxephosphetane lifetime and prevent equilibration. Similar to the Wittig reaction, the HWE reaction involves phosphonate stabilized carbanions. The carbanion stabilizing group (W) is necessary for elimination to occur. Non-stabilized phosphonates give stable beta-hydroxyphosphonates. The HWE reaction is particularly useful for macrocyclizations:

Horner, L.; Hoffmann, H. M. R.; Wippel, H. G. Chem. Ber. 1958, 91, 61- 63. Horner, L.; Hoffmann, H. M. R.; Wippel, H. G.; Klahre, G. Chem. Ber. 1959, 92, 2499-2505. Wadsworth, W. S.; Emmons, W. D. J. Org. Chem. 1961, 83, 1733-1738.

Z-alkenes from the HWE: Stille-Gennari Modification 2. Sulfur-Based Methods: The Julia Olefination Still, Gennari, Tet. Lett. 1983, 24, 4405. Classically the reaction is carried out in two steps:

Base R trans:cis

t-BuOK Me 5 : 2 KHMDS, 18-C-6 Me 8 : 1 K2CO3, 18-C-6 CH2CF3 1 : 6 KHMDS, 18-C-6 CH2CF3 1 : 12

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The mechanism for elimination is thought to proceed by first E2 Consider the following chemoselective elimination: elimination of the acyl group followed by single electron reduction of a vinyl sulfone:

Manipulations at sulfur has led to the development of a one-step Samarium diiodide (SmI2) can be used for the elimination of “modified Julia” reaction. These typically involve benzoyloxysulfones. This reaction involves first single-electron- phenyltetrazole (PT) or benzothiazole (BT) sulfones. transfer (SET) to the benzoyl group followed by elimination of the sulfone:

Blakemore J. Chem. Soc., Perkin Trans. 1, 2002, 2563-2585. 71

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Installation is typically via Mitsunobu displacement of the While understanding and predicting the stereoselectivity of a corresponding alcohol followed by oxidation: modified Julia reaction can be challenging (see Blakemore ref. above), some generalizations can be made:

 PT-sulfones tend to be more stereoselective than BT.

 BT-sulfones work best with α,β-unsaturated aldehydes. Mechanism:

 Pyridine sulfones give predominantly the cis-alkene.

This is presumably the result of reversible carbonyl addition and Stereochemistry is determined upon sulfone addition to the an inability of the anti hydroxysulfone intermediate to undergo carbonyl. the Smiles rearrangement.

O’Neil Organic Reactions Winter 2013

Ch. 8 Alkene Metathesis. Ruthenium catalysts: most widely used metathesis catalysts because of their relative air/moisture stability (can be handled without special precautions) and excellent functional group Olefin metathesis is one specific type of metathesis reaction: tolerance. L  Sigma bond metathesis Ph Ph Cl Ru Ph X RuCl2(PPh3)3 + R X + Y R R1 Cl 1 R + -PPh3 L Y Ph  Alkyne Metathesis L = PPh R + R R R + 3 1 1 = P(i-Pr) 3 =PCy3  Enyne Metathesis N2 1. PCy3 Ph Grubbs' 1st RuCl (PPh ) Cl R R 2 3 3 Ru Generation Catalyst 1 + R2 Cl R R2 PCy Ph 2. 3 PCy3  R1 Alkene Metathesis Grubbs et al. J. Am. Chem. Soc. 1992, 114, 3974.

CH R1 2 R + R1 R + CH2 Catalyst Initiation:

Historically, olefin metathesis was used in polymer chemistry Ti, W, Mo, and Ru catalysts with poor functional group tolerance. F C 3 Ph F3C O Mo O CHCMe3 O W N • Electron-donating phoshines with large cone-angles Ph ArO OEt F3C 2 F C Cl 3 increase catalyst activity [PCy3 > P(i-Pr)3 > PPh3].

• Initiation is faster if R1 = Ar compared to CH=CPh2. Schrock catalyst • If R1 = electron-withdrawing (-COOR) or electron-

donating (-OR, -SR, -NR ), initiation is much slower. Schrock J. Am. Chem. Soc. 1988, 110, 1423 2 73

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Types of Alkene Metathesis: Note that each step in a metathesis reaction is reversible.

Olefin cross-metathesis Recent investigations suggest that a pathway involving dissociation of one of the phosphine ligands is dominant: catalyst H C R' R' H CCH R CH2 + 2 R + 2 2

Ring-closing metathesis

catalyst + H2CCH2 n n

Ring-opening metathesis polymerization

catalyst Grubbs J. Am. Chem. Soc. 1997, 119, 3887

n 1. Ring-Closing Metathesis (RCM)

“Caught in the act”: RCM PCy Pr Cl 3 H2C CH2 Pr Ru Grubbs' 1 Cl H [M] CH2 H Me Ph Me Snapper, M.L. J. Am. Chem. Soc. 1997 119, 7157.

H2C [M] [M]

CH2 CH2 H2C [M] 74

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 Effect of Alkene Substitution: Tetrasubstituted alkenes:

 Effect of Ring Size: 5- ,6-, and 7-membered ring formations are generally straightforward, however larger rings can be challenging.

Grubbs, R. H. J. Org. Chem. 1997, 62, 7310 There is an entropic driving force for RCM with the generation of Reactions above performed using Grubbs’ second generation ethylene: catalyst:

Recently there have been reports of performing metathesis reactions under slight vacuum to remove gaseous products.

See: J. Am. Chem. Soc. 2000, 122, 58-71.

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 Conformational Requirements: It is important however that this interaction not be too strong/stable:

Grubbs' I Ru () Ru O n oligomers O high dilution R R

diminished activity

O O O O Despite the challenges, there are many complex examples of Grubbs' I large ring formation by ring-closing metathesis. Note the dense high dilution functionality in the following examples: 79%

Furstner, A.; Langemann, K. J. Org. Chem. 1996, 61, 3942.

Polar functional groups are thought to provide an internal conformational bias for cyclization.

Ru L L

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2. Cross-Metathesis. Challenging due to the mixture of Through the accumulation of data, alkenes can now be products that are possible: characterized in terms of their reactivity toward cross- metathesis:

Type I terminal alkenes, allyl alcohols, styrenes, allyl-silanes, allyl-sulfides, (fast homodimerization) protected allyl-amines

Type II Acrylates, vinyl ketones, acrolein, 3°/2° allylic-alcohols, vinyl epoxides (slow homodimerization)

Type III 1,1-disubstituted alkenes, phenyl vinyl- sulfone, 4° allylic carbons, protected (no homodimerization) 3° allylic-acohols Statistically:

Type IV vinyl nitro-olefins, trisubstituted allylic alcohols (spectator to CM)

J. Am. Chem. Soc., 2003, 125, 11360.

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This then allows for the design and execution of selective cross- More recently, Z-selective cross-metathesis catalysts have been metathesis reactions: developed:

Hoveyda et al. Nature 2011, 471, 461

Putting it all together: