Download Chemistry 730 - OSU Chemistry

Chemistry 730
Autumn 2006
Lecture 1
• Distribute handouts
1. Syllabus and Course Outline
2. Model Homework
3. “Molecules in the News”
4. Stereochemistry: Glossary and Primer
5. Nomenclature of Chirality and Prochirality
6. Appendix: Prochirality
7. Glossary of stereochemical terms (Eliel p. 1191-1210)
8. Glossary of problematic terms in organic stereochemistry
9. Chirality in molecules devoid of chiral centers
10. Model Midquarter Examination 1
• Explain syllabus course expectations (use overheads of #1 and 2)
• Why learn organic chemistry?
Compounds of interest (handout # 3 “Molecules in the News”), learn the mechanisms of processes,
make functional materials
• Challenges in organic chemistry
(a) New transformations (amination or hydration of alkenes, C-H activation)
(b) Atom economy (example of Wittig reaction)
(c) Selectivity- Key factor in utility of compounds, environmental factors –more selective more green
the chemistry
• Efficiency and selectivity (chemo-, regio-, and stereo-) in organic synthesis
1. Chemoselectivity
2. Regioselectivity
3. Stereoselectivity (diastereoselectivity/enantioselectivity)
Structural differences at different levels
• Constitution
Molecular connectivity is different (isomeric)
All are C3H6O
Properties different
• Configuration
Same constitution yet different spatial arrangement of atoms (Stereoisomerism).
To clarify distinction between stereoisomers - configuration must be specified.
Stereoisomers: enantiomers and diastereomers
- enantiomers- Stereoisomers that are related by a mirror-image relation (related by having nonsuperimposable mirror images) homochirally related when the enantiomers are similar); when they
are mirror images they are said to be heterochirally related- DO NOT CONFUSE HOMOCHIRAL
WITH ENANTIOMERICALLY PURE- see definitions in handout, especially # 8
-Stereoisomers that are not enantiomers are diastereomers.
e.g., E and Z olefins, cis-trans isomers of disubstituted cyclohexanes, molecules that have more than
one chiral center or other elements of chirality (see later) with one of these elements being the same in
both molecules. (Provide two examples?)
Conformation
Discrete molecular arrangements with energy minima arising from facile rotations about bonds (most
commonly single bond).
Well-known examples are the chair-boat conformations of cyclohexanes. More later.
A special case - Atropisomerism: When bond rotation is restricted, one can isolate different conformers
(conformational isomerism or atropisomerism).
e. g., 1,1-Binaphthalene derivatives.
• Enantiomeric Relationships
 Confusion between chirality and optical activity
 Chirality is a property of molecular assembly (or for that matter, assembly of any objects) that can have
non-superimposable mirror images.
 Optical activity is one of the properties of a chiral molecule, when it is non-racemic
 Racemic  equal mixtures of both enantiomers
 Compounds in single enantiomeric form are called homochiral (see handout for proper definitions of
homochiral and heterochiral relations)
• Optical Activity
- measured as  = rotation of plane of polarization - related to enantiomeric excess (ee)
- ee (enantiomeric excess) = (% of major isomer - % minor isomer) or enantiomeric ratio er
-For example 70% ee (S)  85%S and 15% R. The corresponding er will be 85:15
- Determination of optical purity done by ()D- measure rotation at 589 nm (sodium-D line) - []D Optical
purity = []Dt, mix X 100 //[]D, pure
- Optical Rotatory Dispersion (ORD) - optical rotation vs. - can be used to relate configurations of like
molecules
circular dichroism - extinction coefficient for right and left circularly polarized light are different
• Modern methods to determine enantiomeric excess- Chiral HPLC, GC and NMR techniques (more
later under consequences of diastereoisomerism)
SOURCES OF CHIRALITY
1. Asymmetric (or better stereogenic) carbon atom
2. Asymmetric Heteroatom (Scheme 2.1, p. 80)
Overhead of Scheme 2.1 p. 80
• Sulfoxide, barrier to inversion
• Amines- Barrier to inversion low. Cannot exist as chiral molecules, unless inversion is prevented by
structure e.g. Troger’s base
• Chiral Phosphines - higher activation barrier (>30 kcal/mole)- important - in the synthesis of chiral
metal complexes which catalyze enantioselective reactions (more later)
 SPECIFYING stereogenic centers [Review basic organic. Text, also handout #5]
• Cahn-Ingold-Prelog (CIP) convention (R, S -notation) –priority rules (handout # 5)
Examples:
• Fischer convention - KEY: D-glyceraldehyde: sugars and amino acids
Should know how to go from Fischer formula to conformational diagram in sugars
3. Atropisomerism
Chirality is defined by the molecular topology - Property of not being superimposable on one’s mirror
image. That does not have to depend on the presence of stereogenic atom.
Consider: e.g. mirror images of butane gauche conformations - G# = 3.6 kcal/mol
Freely rotating - easily interconverts –NOT possible to isolate as individual enantiomers
But, consider axial chirality (atropisomerism) in biphenyls
SPECIFYING ATROPISOMERISM -axially chiral molecules (CSA Scheme 2.2, p. 83 also Handout # 9)
Overhead of CSA Scheme 2.2 Axially Chiral Molecules
- Identify the relevant axis of chirality: In this case it is the line connecting the phenyl groups
- View from top (or bottom) along this axis.
- Assign priority rules - in CIP system except the front groups get higher priority before the ones in the
rear. i.e. nearest groups precede those on the far side.
Diastereomeric Relationships
Stereoisomers that are not related as object and its mirror image.
e.g., ephedrine:
Properties of enantiomers vs diastereomers:
Enantiomers
• same mp, bp, physical characteristics, chemical properties except when reacting with another
asymmetric molecule or asymmetric environment - e.g. another asymmetric molecule, plane polarized
light, chiral elements on a surface or an enzyme. ‘hand-in-glove analogy’
Diastereomers differ in chemical and physical properties.
 different mp’s, boiling points, spectral characteristics, solubility, []D
 Reactivity could be drastically different -
 Spectral properties could be different
IMPORTANT - Diastereomeric relationships could be in ground state or in transition states leading to
reactions
These have important consequences - later...
Specifying Diastereomeric relationships
Olefins: (Z/E nomenclature) - special cases E/Z enolates, Oximes etc. • Geometric isomers based on
Double bond geometry (CSA Scheme 2.8, p. 96)
For others:
 Best: CIP rules as indicated in the case of ephedrine [or in your text : 2,3,4-trihydroxybutanal]
 Also original sugar related convention for two adjacent chiral centers: threo/erythro nomenclature
D/L erythrose and threose
Looking for like/unlike groups is often confusing.
Alternate syn/anti relationship: e.g. Aldol reaction
Maximum number of stereoisomers - 2n where n is the number of independent asymmetric centers. In
cyclic systems less
Chirality is a property of a whole molecule - juxtaposition of 2 or more asymmetric chiral centers can
produce a chiral object or an achiral object, e.g., tartaric acid.
Read: Discussion dimethyl alkanes (P. 87 C&S A)
Bottom-line:
presence of a plane  achiral molecule
-not often recognized: presence of a center of symmetry (i) or an improper axis of symmetry (Sn = Cn
followed by ) renders the molecule achiral
e. g. trans 1,3-dibromo-trans-2,4methylcyclobutane and the ammonium salt shown below.
Consequences of Diastereoisomerism
• Diastereomeric Ground state, intermediate or transition states are different in chemical and
physical characteristics – This has very important consequences for synthesis, separation and analysis of
optically active compounds
1.
2.
3.
4.
5.
6.
Resolution of enantiomers
Resolution via chromatography
Identification of absolute stereochemistry (example; dithiadecalin)
Determination of enantiomeric ratio (er) or enantiomeric excess (ee)
Diastereoselective synthesis
Kinetic resolution
7. Enantioselective synthesis and asymmetric catalysis
1. Resolution of enantiomers (see Scheme 2.4, P. 88, see also handout # 12) via-diastereomeric salts
(Overhead Scheme 2.4, P. 88)
e.g. 2-phenyl-3-methylbutanoic acid
Limitations: Multistep, time-consuming, maximum yield only 50 % unless the undesired
compound is recycled, resolving agent should be recovered, disposal of solvents undesired isomer.
Preparative (difficult, yet feasible, especially with large preparative columns)
e.g. Separation of amino acid methyl esters:
Mainly used as an analytical technique
(Overhead Fig 2.4 and Scheme 2.5)
2. Chromatography of diastereomers (when enantiomer separation is difficult)
e.g. Ibuprofen (-)-menthyl esters
3. Identification of absolute stereochemistry (example; dithiadecalin)
4. Determination of ee
Important: analytical (e.g. ibuprofen + (-)-menthol) - chromatography or by NMR
• Mosher acid chloride
• Chiral shift reagents (see example p. 95, C&S A, J. Am. Chem. Soc. 1974, 96, 1038.)
5. Diastereoselective synthesis
(e.g. alkylation of N-acyloxazolidinone; Evans, J. Am. Chem. Soc. 1982, 104, 1737.)
6. Kinetic resolution
• Principles – Fig. 2.5, 2.6 pp. CSA 91
(overheads Fig 2.5 and 2.6)
• Examples - Schemes 2.6 and 2.7, pp. 93, 94
(i) Stoichiometric use of reagents (Handout # 12A:Ibuprofen resolution J. Am. Chem. Soc. 1989, 111,
7650. Handout #13: Binaphthol resolution: Tetrahedron Lett. 1995, 36, 7991.)
(overheads Scheme 2.6: Examples of kinetic resolution Handout # 12 A: Ibuprofen)
(ii) Catalytic reactions
(i) Organometallic methods for kinetic resolution (Scheme 2.6)
• Hydrogenation of allyl alcohols Handout # 12 B(J. Org. Chem. 1988, 53, 708.)
(Overhead 12B: Hydrogenation of allyl alcohols)
• Sharpless epoxidation with kinetic resolution (J. Am. Chem. Soc. 1981, 103, 6237.)
• Kinetic resolution of secondary alcohols by acylation Handout # 12C (J. Am. Chem. Soc.1997, 119,
1492)
(ii) Enzymatic kinetic resolutions (Scheme 2.7, CSA p. 94)
(overhead Scheme 2.7: Enzymatic kinetic resolutions)
7. Asymmetric catalysis (Organometallic catalysts (e. g. p.108 - 110, C&S A, and Handout # 14:
Noyori, “Asymmetric catalysis by chiral metal complexes”, Chemtech 1992, 360.)
• Will discuss this in greater detail later
Example: Rh catalyzed hydrogenation of acetamidocinnamic acid derivatives:
(Overhead Schemes 2.12 and 2.13, and Overheads 15 and 16: Catalytic Hydrogenations)
STEREOCHEMISTRY OF DYNAMIC PROCESSES
So far - discussions on stereochemistry of molecules as static objects
To understand chemical reactions, stereochemical relationships between reactants in the course of a
reaction should be understood - establish the relationship between the stereochemistry of the starting
material and that of the product. (Dynamic stereochemistry)
-That means understand the stereochemistry of the proposed intermediates and transition states
consistent with experimental observations. (Mostly MODELS - nonetheless of very high predictive value)
• When a new stereogenic (chiral) center or a double bond is formed, both forms may result to varying
degrees. It is useful to distinguish between two kinds of processes under these conditions - (confusing
usage very common here, pay special attention).
(See also Warren’s text for an excellent discussion on the topic. See index at the end of the book)
(i) Stereospecific processes and (ii) stereoselective processes
A stereospecific reaction: Stereoisomeric starting materials give stereoisomerically different products.
Stereospecificity is a consequence of the reaction mechanism.
(Or, in a more general definition, a reaction is stereospecific if two stereoisomerically different starting
materials give product(s) at different rates, See later).
Examples: CSA Scheme 2.9: Sterospecific Reactions
(Overhead CSA Scheme 2.9: Sterospecific Reactions)
A stereoselective reaction: A single reactant can give one or more stereoisomeric products, but one is
formed preferentially. Thus a stereospecific reaction is a special case of a stereoselective reaction. All
stereospecific reactions are stereoselective, but the reverse is not true. Reactions may proceed with 100
% stereoselectivity. That does not qualify it to be stereospecific. This is one of the most common
misconceptions.
Specifying stereochemistry of reactions
Addition/elimination - could be syn or anti
Substitution - could be with retention, inversion or racemization (Epimerization is a special case of
racemization of a single center in a diastereomer).
You should be familiar with definitions of all there terms.
Examples of stereospecific reactions (Scheme 2.9 C&S A, p. 98)
Overhead: Examples of stereospecific reactions (Overhead 11K: Scheme 2.9 C&S A, p. 98)
Examples of stereoselective reactions (Overhead iiL: Scheme 2.10 C&S A, p. 101)
Completely selective and partially selective reactions
Origin of stereoselectivity - three examples
(i) HI elimination from 2-iodobutane / KOBut
(ii) Diastereoselectivity in addition of hydride to cyclohexanones (reagent control?)
(iii) Diastereoselectivity in addition of Grignard reagents to 2-phenylpropanal
Stereoselective formation of a particular configuration at a new stereogenic center is called
asymmetric induction- Prediction of these and developments of new reagents that can effect
these transformations are at the heart of organic synthesis
(e. g., Crams rule and models of transition states - more later)
A broader definition of STEREOSPECIFICITY is sometimes useful:
A stereospecific reaction is a reaction in which stereochemically different molecules react differently (to
give stereochemically different products) or react at different rates.
Examples:
(Overhead 11M. Scheme 2.11 Enzymatic reactions of enantiotopic substituents)
Kinetic resolution is a special case of stereospecificity- how?
Racemization processes - 3 mechanisms (I) planar intermediates (ii) inversion such as in N-inversion in
chiral tertiary amines (iii) bond rotation (in atropisomers also see gauche conformers of butane).
Prochiral Relationships
• Handout Prochirality
Same atoms connected to a given carbon can be topologically non-equivalent.
Consider 1,3-propanediol
C2-hydrogens are homotopic- i.e., replacement of either with another atom gives the same molecule
If a chiral molecule is produced when a ligand (group or atom) is replaced with a new ligand the original
assembly is prochiral. C1 and C3 of 1,3-propane diol are prochiral centers.
Specifying prochiral centers:
Applying sequence rules to heterotopic ligands pro-R and pro-S : The assignment is done by selecting
one of the heterotopic ligands at the prochiral center and arbitrarily assigning it a higher priority than the
other (for example replace it with a heavier isotope) without disturbing priorities of the remaining ligands.
Now application of the CIP rule results in assignment of R (written in italics) as the configuration of the
prochiral center, then the selected ligand is pro-R. If the prochiral center is S, then the selected ligand is
pro-S. For propane diol the atom specifications are:
Enantiotopic atoms (or groups) are identical in all chemical and physical properties except
towards a chiral reagent (including an enzyme). For example the oxidizing enzyme, liver alcohol
dehydrogenase, can distinguish between the enantiotopic hydrogens of ethanol, which is a prochiral
molecule. The pro-R hydrogen is lost in the reaction. NAD+ acts as the H– acceptor.
A Chemical example: enantioselective deprotonation by a chiral base.
Defining prochiral faces: So far we defined prochiral atoms. What about prochiral faces?
Consider the carbonyl carbon of acetaldehyde. Addition of a 4th ligand produces a chiral molecule-
This can be added to either the top or the bottom face of the planar molecule- each resulting in
enantiomers. The molecule presents two enantiotopic faces to an approaching reagent.
re or si is defined by looking at the atom and assigning priorities to groups connected to it- In this case:
Enantioselective synthesis
Chiral reagents can react with prochiral centers or prochiral faces to give partially or completely
enantiomerically pure products
An example from enzymatic reactions: Hydration of fumaric acid to get L-malic acid - addition of water
catalyzed by fumarase proceeds on the si- face of one of the carbons.
Enzymes exhibit high degree of selectivity towards reactions of enantiotopic functional groups.
Hydrolysis of enantiotopic esters (Scheme 2.11: Enantioselective enzyme catalyzed hydrolysis, p. 107)
(Overhead: #11 M Scheme 2.11: Enantioselective enzyme catalyzed hydrolysis, p. 107)
Other Examples:
(a) achiral unsymmetrical sulfides to sulfoxides via chiral oxidizing agents
(b) Rh-catalyzed hydrogenation of acetamidocinnamic acid derivatives (See handouts # 14, 15, 16 and
CSA Table 2.12, p. 109, CSA)
See also: “Noyori’ review on asymmetric catalysis (Handout # 14)
(c) Ru-catalyzed hydrogenation of acrylates (Noyori, J. Org. Chem. 1987, 52, 3174.)
(d) Enantioselective reduction of ketones (CSA Table 2.12)
(Overhead Handout # 11I: CSA Scheme 2.13)
-Unsymmetrical ketones possess prochiral faces and a chiral reluctant can lead to enantioselectivity
(Itsuno-Corey reduction) J. Org. Chem. 1993, 58, 799.; Tetrahedron Lett. 1992, 33, 7107.; J. Org. Chem.
1991, 56, 763.
Midland reduction (Alpine-borane): J. Org. Chem. 1982, 47, 2495.
Ru-catalyzed reduction of ketones: J. Am. Chem. Soc. 1995, 117, 2675.
(e) Sharpless epoxidation of allylic alcohols (J. Am. Chem. Soc. 1987, 109, 5765.)
Diastereotopic Groups
The concept of heterotopic groups can be extended from enantiotopic to diastereotopic groups
and faces.
If replacement of each of the two nominally equivalent ligands by a test group, results in
diastereomers, then the ligands are diastereotopic. The pro-R/pro-S nomenclature is also valid here.
Example:
• L-phenylalanine (structure and reactions with phenylalanine ammonia lyase)
• Environment of diastereotopic groups are different, and therefor they will be chemically nonequivalent towards both chiral and achiral reagents.
• NMR characteristics will be different also. The groups will have different shielding and hence can have
different chemical shifts (NOTE: enantiotopic groups will not have different chemical shifts since they are
identical.)
Study the example in the text of the benzyl methylene protons of cis- and trans- 1-benzyl-2,6dimethylpiperidine.
In general CH2-groups in a chiral molecule are topologically different, and hence are diastereotopic.
Example: 2-bromomethy-1,1’-binaphthyl. The methylene protons diastereotopic or enantiotopic?
Diastereotopic faces- Two faces of a trigonal carbon (carbonyls or olefins with two different groups
attached to the same carbon) are diastereotopic as long as there is another chiral element is present in
the molecule. Both chiral and achiral reagents will be able to distinguish the two faces.
e.g. Diastereoseelctive carbonyl additions. (p. 113) and Cram’s rule (more later)