Biomass Fundamentals Modules 3-5: Fundamental Concepts of Organic Chemistry A capstone course for BioSUCCEED: Bioproducts Sustainability: a University Cooperative Center of Excellence in EDucation The USDA Higher Education Challenge Grants program gratefully acknowledged for support

This course would not be possible without support from: USDA Higher Education Challenge (HEC) Grants Program www.csrees.usda.gov/funding/rfas/hep_challenge.html

Atomic view of matter Quiz M3/5.1 Democritus (ca. 460 BC – ca. 370 BC) was an ancient Greek materialist philosopher who indicated that: All matter was composed of discrete smaller particles called “atoms” that retained the fundamental identity of that matter. The “atomic” viewpoint he espoused was very clever: e.g., oily substances were made of atoms that slid past each other Quiz M3/5.1 What is a element: (a) a compound; (b) a molecule; (c) smallest identifiable part of anything; (d) earth, wind, water, and fire 2. How do atoms form compounds: (a) ionic coupling; (b) covalent coupling; (c) coordination; (d) none of the above 3. What is the smallest element on record: (a) iron; (b) aluminum; (c) hydrogen; (d) beryllium Compounds are groups of two or more elements that are bonded. There are two main types of bonds that hold those atoms together, covalent and ionic bonds. Covalent compounds occurwhen the atoms share the electrons, and ionic compounds occurwhen electrons are donated. Coordination compounds happen when ligands or similar material engages in a quasi-ionic bond with a metal. An examples is shown below – t-dichlorotetrammine cobalt (III). The blue/white balls = amines (NH3)4 , the green balls = chlorides, and the light blue atom = cobalt; note that complexing amines are written “ammine”

Atom and molecules What are they? HIGHLIGHT: Carbon Atoms as described previously are the building blocks of matter Made up of three primary subatomic particles: the neutrons and protons (nucleus, positively charged) comprise the atomic weight, whereas the protons are the atomic number (identity); the last subatomic particle, the electrons, balance the charge (they are negative) and engage in chemical reactions (bonding, oxidation, reduction, polymerization, etc.) The protons CANNOT be divided without losing the identity of the material they represent; e.g., a carbon atom has 6 protons, 6 neutrons, and 6 electrons – if you change the number of neutrons you get an ISOTOPE of the element, if you change the number of electrons, you get an ION (CATION or ANION), but if you change the protons, you GET A DIFFERENT ATOM!!! Molecules are combinations of atoms This is a natural and stable isotope of carbon 1.1% of all natural carbon is in this form It is also resonance frequency active meaning that it is amenable to imaging by NMR spectrometers, hence providing a structural profile of a substance Carbon dating is done using the 14C12 isotope which can date up to 60K years An NMR magnet is a nuclear magnetic resonance device that depends on the fundamental magnetic properties of several nuclei. All nuclei that contain an odd numbers of protons or neutrons have an intrinsic magnetic moment and angular momentum. The most commonly measured nuclei are hydrogen (the most receptive isotope at natural abundance) and carbon-13, although nuclei from isotopes of many other elements (e.g.113Cd, 15N, 14N 19F, 31P, 17O, 29Si, 10B, 11B, 23Na, 35Cl, 195Pt) can also be observed. NMR resonant frequencies for a particular substance are directly proportional to the strength of the applied magnetic field. Carbon-14 has a half-life (time to lose HALF of the identity of the isotope) of 5730 years and would have long ago vanished from Earth were it not for the cosmic rays on nitrogen in the upper atmosphere. The neutronsresulting from the cosmic ray interactions with nitrogen participate in the following reaction on the atoms of nitrogen (N2) in the atmospheric air:

Bohr’s concept of an atom Quiz M3/5.2 1. Where do the electrons in an atom reside: (a) inside nucleus; (b) in orbits; (c) paired; (d) both b & c 2. What forms of energy are released by electronic transitions: (a) heat; (b) light; (c) vibrational; (d) all of the above 3. Is all matter “quantized:” (a) yes; (b) no The Bohr model was proposed in 1915 by Niels Bohr who suggested that the electrons (recall) orbit the nucleus of the atom [see model at right ] He indicated that each electron had its own position (or orbit), but jumping/falling was allowed whose energy consequences resulted in radiative emission This lead to the concept of quantization of energy, or the idea that discrete (separate) energy levels in matter were allowed, viz., energy paths are NOT a continuum, but broken into LEVELS or orbits An excellent review of the topics discussed on this slide can be found at the following URL: http://csep10.phys.utk.edu/astr162/lect/light/bohr.html If you are an instructor and interested in selecting good textbooks to discuss the mathematics, physics, and framework around Bohr’s model and the ensuing evolution of quantum mechanics, a revolution in the world of physics, please see the following article in the Journal of Research in Science Teaching; http://www3.interscience.wiley.com/cgi-bin/fulltext/45494/PDFSTART If you have trouble accessing it due to user restrictions, please paste the contents of the second paragraph with the link to: biosucceed@ncsu.edu and we will be happy to forward it to you as a .pdf Quantization has been applied to all forms of matter principally through the de Broglie equation: lambda = h/mv; used to describe the wave properties of matter, specifically, the wave nature of the electron, where lambda is wavelength, h is Planck's constant, m is the mass of a particle, moving at a velocity v. de Broglie suggested that particles can exhibit properties of waves For information on electronic transitions, see a Jablonski diagram: (http://micro.magnet.fsu.edu/primer/java/jablonski/lightandcolor/index.html)

Overview of periodic table All the elements are described!!! Many contributors to this: The “periodic” table is so named because the properties of all of the elements are periodic functions of their atomic number Although Mendeleev is credited for the Table, many others had enormous contributions to its development It is now a wonderful teaching tool to describe the properties (physical and chemical) of all the elements in the UNIVERSE The groups (columns) are numbered 1-18. Some groups have non-systematic names as well. They include Group 1 (alkali metals), Group 2 (alkaline earth metals), Group 15 (pnictogens, or pnicogens), Group 16 (chalcogens), Group 17 (halogens) and Group 18 (noble gases). While not groups in the periodic table, some other groupings of elements are often named as well. These include the lanthanoids (less preferably lanthanides) and actinoids (less preferably actinides). While the name Dmitri Mendeleev is usually credited with the with the form of periodic table as we know it today, many other excellent researchers made profound contributions to its development, including Antoine Lavoisier, Jöns Jakob Berzelius, Johann Döbereiner, John Newlands, Alexandre-Émile Béguyer de Chancourtois, Lothar Meyer, and others. If you wish to see the original Table of Mendeleev, please go to: http://www.google.com/imgres?imgurl=http://61.19.145.8/student/m5year2006-2/502/group11/periodic_table.gif&imgrefurl=http://61.19.145.8/student/m5year2006-2/502/group11/index.html&h=480&w=580&sz=18&tbnid=G4wY8RtD2Q0J::&tbnh=111&tbnw=134&prev=/images%3Fq%3Dperiodic%2Btable&hl=en&sa=X&oi=image_result&resnum=1&ct=image&cd=1

Molecular bonding I Quiz M3/5.3 Petro-economy vs. bio-economy During the 18th century, Antoine Lavoisier began the science of elemental analysis (chemical analysis) by measuring the amount of carbon dioxide and water when a substance was completely combusted. For example, organic substance + 2O2  ____CO2 + ____H2O We learned from a great British experimentalist, Sir Davy, that chemical bonds can be broken by electrolysis: A-----B  A+ + B- (electrically charged) If we determine that 36g of water are collected and 88 g of carbon dioxide are collected, while 2 moles or 64 g of oxygen are consumed by the organic substance, then what is the organic substance? An “organic substance” will be comprised of the atoms that BALANCE the equation, i.e., whatever is on the right side of the equation (Cn Hm Oo where n, m, & o are subscripts that describe the relative mole value of the atoms in a stoichiometric economy of the reaction (FIRST LAW OF THERMODYNAMICS: matter (elements) can neither be created nor destroyed) In order to calculate the molar values, note that the atomic mass of any atom or compound = the number of grams of one mole of that substance, e.g., C = 12.000g/mole and 1 mole = one subscript unit in a molecular formula such as C6 H12O6 or sugar (in this case it is 6 moles of C per 12 moles of H per 6 moles of O) Example When 10.0 g pure calcium carbonate (CaCO3) is heated and converted to solid calcium oxide (CaO), how much calcium oxide should be obtained? If only 5.0 grams CaO is obtained, what is the actual yield? Hint: Under ideal condition, amounts of substance in the reaction equation is as indicated below: CaCO3  CaO + CO2 100.0 . . . . . 56 . . . 44 g/mol (formula weights) 10 .0 g CaCO3 x 1 mol CaCO3 /100 g CaCO3 x 1 mol CaO/1 mol CaCO3 x 56 g CaO/1 mol CaO = 5.6 g CaO Discussion An inefficient conversion is given here, but the method shows the details of consideration. If the amount of CaO obtained is not 5.6 g, one can conclude that the sample may not be pure.

Molecular bonding II ESSAY Ionic bonding Charged, but charges must cancel according to the conservation of charge. Salts are classic examples. Please list several here (see periodic table): In 1916, Kossel (Germany) introduced concept of stable ion formation to approach “Noble Gas” configurations. Li+ Be+2 B+3 C+4 N-3 O-2 F-1 Ne0 Ionization is the tendency to lose an electron. The ionization energy decreases, becomes more negative as one goes to the lower left of the periodic table. Electron Affinity is the attraction an atom has for an electron. The more negative this value is, the higher the affinity - it increases as one goes to the upper right of the periodic table. The affinity can be described by classical coulombic laws of physics: E = q1q2/r2, where q are the charge on the particles, r is the distance between them, and epsilon () is the shielding factor between them (as this increases, the attraction is minimized). ESSAY At this point, describe in a page or less, why the properties of ionic substances are so important to life. Think about electrolytes and find out how they influence the overall metabolic activity of living organisms To make a salt, one must have a cation (metal without an electron(s)) and an anion (non-metal with an excess of electron(s)). If you go back to the “Overview of the periodic table” slide, you can see the metals and non-metals by their different coloring. For example, it is possible to make a salt of sodium (alkali metal) and chloride (halogen) that looks like this NaCl, where sodium is a MONOVALENT (one charge) cation (POSITIVE) and chloride is a MONOVALENT (one charge) anion. The law of combining salts in chemistry is by switching their VALENCIES (SODIUM = GROUP I, hence monovalent, CHLORIDE = GROUP 7 (needs to get one electron to be electronically stable, hence monovalent); typically, non-transition metals are positively charged to +4 (GROUP IV), whereas non-metals are negatively charged to -3 (GROUP V). The periodic table below provides the necessary information:

Molecular bonding III Covalent bonding This is the most important bond that we will be dealing with in our studies - Do you think that a covalent compound would conduct electricity? In 1916 (same year as Kossel’s work on ionic bonds), G.N. Lewis proposed the concept of a chemical bond in which electrons are equally shared between atomic partners and introduced the concept of the “Lewis Dot Structure:” H3C-CH3 H2C=CH2 HC:::CH Shown above are representative Lewis dot structures for different bond orders (levels of bonding) between C atoms. In the top one, we have a single bond consisting of 2 electrons represented by a dash (ethane); in the second one, we have the same basic unit, except that it is 2 dashes, each of which = 2 electrons for a total of 4 (ethene or ethylene); finally, we have the last one (ethyne or acetylene) which has 3 pairs of electrons (6) shown by the dots. Lewis dot structures can use dashes (typical to illustrate covalency) or dots. A good site to visit to learn more about the value and power of Lewis dot structures for electronic properties, bonding paradigms, and valency can be found at: http://www.ausetute.com.au/lewisstr.html A classic representation of the concept of covalent bonding between C and H atoms; shown above is methane, the simplest hydrocarbon in the universe

Molecular bonding IV Quiz M3/5.4 Bond order & Formal charge The concept of BOND ORDER involves the number of bonds between atoms, considering that two electrons make up one stable bond. In the previous slide (see notes section), we have three forms of C2 in which each one represents a different bond order C-C bonds have bond order of 1 (2 electrons) C=C bonds (double bonds or “unsaturated” bonds) have a bond order of 2 The higher the bond order, the tighter the bond, the more energy it contains, and hence, more difficult to break Formal charge is the charge assigned to an atom in a compound that mathematically allows to obtain the overall charge of the molecule (Following always holds  O = -2; H = +1) 1. Acetylene has a bond order of: (a) 1; (2) 2; (3) 3; (4) 4 2. True or false: the higher the bond order, the stronger the bond 3. What is the formal charge of N in [NO3]-1 ? Formal charge is a partial charge on an atom in a molecule assigned by assuming that electrons in a bond are shared equally between atoms, regardless of relative electronegativity. The formal charge can be calculated by the following equation: Formal charge = number of valence electrons (see Group number) of the atom minus the number of lone pairs of electrons on this atom minus half the total number of electrons participating in covalent bonds with this atom. For example: carbon in CH4 (methane): FC = 4 - 0 - 8/2 = 0 Nitrogen in the Nitro group NO2-: FC = 5 - 2 - 6/2 = 0 double bonded oxygen in NO2-: FC = 6 - 4 - 4/2 = 0 single bonded oxygen in NO2- FC = 6 - 6 - 2/2 = -1

Molecular structural paradigms I Lewis Acids & Bases A Lewis acid is an electron acceptor A Lewis base is an electron donor A lot of chemical reactivity can be explained using these two concepts Shown above is an example of a classic Lewis acid and Lewis base reaction: ammonia (NH3), the Lewis base, directing its lone pair of electrons by virtue of electrostatic forces to the empty p orbital of boron trifluoride (BF3 ) forming a coordination complex/adduct. The Arrhenius Theory of acids and bases: Acids are substances which produce hydrogen ions in solution. Bases are substances which produce hydroxide ions in solution. Neutralisation happens because hydrogen ions and hydroxide ions react to produce water. The Bronsted-Lowry Theory of acids and bases An acid is a proton (hydrogen ion) donor. A base is a proton (hydrogen ion) acceptor. Please see the following for an excellent description of the theory of Lewis acid-base interactions: http://chemistry.umeche.maine.edu/CHY251/Lewis.html An article with good information for the technically minded: Lewis acid - base behavior in aqueous solution: some implications for metal ions in biology. Hancock, Robert D.; Martell, Arthur E. Advances in Inorganic Chemistry (1995), 42 89-146. Again, we would be happy to deliver this article to you by .pdf if you cannot retrieve it: biosucceed@NCSU.edu Other concepts in this area of relevance: Hard/Soft interactions (see Pearson 's hard - soft acid-base principle as a means of interpreting the reactivity of carbon materials. Wisniewski, M.; Gauden, P. A. Adsorption Science & Technology (2006), 24(5), 389-402.

ALKANES Hydrocarbons can be saturated or unsaturated Alkane (CH4), alkene (CH2CH2), alkyne (CH1CH1) Benzene (“tri-alkene” with RESONANCE) see 2.2d computer animation

Polar Covalent Bonds Dipolar bonding (force of dipole = charge x distance) Polar (CHCl3) and non-polar (CCl4) How about water and ammonia?

Functional Groups

Alkyl Halides, Alcohols, and Organic Chemistry’s Most Wanted Primary, secondary, and tertiary designate degree of carbon substitution on carbon bearing halide (-Cl, -Br, -I) or alcohol (-OH) Ethers: CH3OCH3 (dimethyl ether) or R-O-R Amines: NH3 (ammonia), NHR, NR2, NR4 where N formal charge = +1 Aldehydes, Ketones: RR’C=O, R=H (Aldehyde)

Alkyl Halides, Alcohols, and Organic Chemistry’s Most Wanted Carboxylic acids: RCOOH Amides: RCONH2 Esters: RCOOR (similar to carboxylic acids)

Intermolecular Forces Forces such as ion-ion between atoms or molecules that affects melting/boiling points dipole-dipole forces are very important hydrogen bonding van der Waals forces (see 2.15 computer animation

Structure and Preparation of Alkenes: Elimination Reactions

Common Alkenyl Groups Vinyl (CH2=CH-) Allyl (CH2=CHCH2-) Isopropenyl(CH2=CH(CH3)-) Exo vs. Endo Alkene Structures

p orbitals are indeed “perpendicular” They are perpendicular to molecular axis The molecule is planar Substituents are “fixed” Isomerism leads to cis and trans forms EZ Notation (relates to atomic number of substitutents)

Stabilities CnH2n + aO2  bCO2 + cH2O Isomers of highest energy have the highest heat of combustion and are the least stable (i.e., more stable forms release less energy, reflective of generation) Degree of substitution affects the stability status of alkenes (mono, di, tri, tetra alkyl groups stabilize sp2 orbitals) Steric strain among substituents affects stability – less strain, lower heat of combustion

ELIMINATION REACTIONS X-CH2-CH2-Y  CH2=CH2 + X-Y (what general reaction concept is this an example of?) Dehydration of alcohols H-CH2CH2OH + ?  CH2=CH2 + H2O (need to make OH good leaving group – how?) Identify the alkene obtained by he dehydration of the following: 1.) 3-ethyl-3-propanol 2.) 1- propanol 3.) 2-butanol

ZAITSEF RULE Look at 2-butanol dehydration products. Which is preferred? Regioselectivity is rule “du jour” – elimination reactions of alcohols yield the most highly substituted alkene as the major product What is the mechanism of reaction? (think of carbocation formation) – use smartboard page

Rearrangements (RAR) – bizarre!!! (CH3)3CCH(OH)CH3 + H+  (CH3)2C=C(CH3)2 (64%) + CH2=C(CH3)2 (33%) Sigmatropic RAR of methyl groups (move like a proton does or a doublebond) Hydride shifts like methyl shifts also occur (see 1-butanol)

Dehydrohalogenation Same as dehydration, except leaving group is a halide Instead of acid catalysis, requires a strong base (alkoxide – which are best?) 1-chlorocyclohexane + Sodium ethoxide/ethanol, 55C  ? Mechanism? It is second order!! The best substrates (R-X) have the heaviest halides

Conformations Need model kit! Shapes of alkane are very much zig-zag because of tetrahedral nature of sp3 hybridized orbitals (build propane, butane, pentane, isobutane, isopentane, neopentane) Isomer numbers grow exponentially as number of carbons increase

Nomenclature and Boiling Point Branched: “alkyl” Alkene: Propane becomes propene Alkyne: Propene becomes propyne Note that branching causes lower bp since less surface area (van der Waals) for attraction

Sigma Bonds and Rotation C-C bonds can rotate and give rise to temporary “conformations;” Newman projection formulae are great ways of visualizing these rotations Sawhorse is a simpler method for visualization Ethane: a torsional barrier exists (see p. 88) staggered and eclipsed conformations

Conformational Analysis Anti, eclipsed, and gauche conformations Draw potential energy diagram (PE vs. torsion angle - see p. 91) Ring strain is fairly significant, in cyclopropane causing bonds to deviate from ideality by almost 50 degrees

Cyclohexane Conformations See 4.12 computer animation Boat, half-boat, and chair More than 99% of cyclohexane is in the chair (p. 159 Solomon for diagram) Axial and equatorial hydrogen atoms or other substituents

Cis-Trans Isomerism Distinguish between cis and trans-1,2-dimethylcyclopentane How about trans-1,6-dimethylcyclohexane What happens to the axial nature of these methyls in going from one chair to the other?

Cyclic Alkanes Cyclopropane - see p. 103 Cyclopentane - see p. 105 What is positional preference (axial or equatorial) of a large, bulky group (like t- butyl) on the 1 position of a cyclohexane? Heterocyclics: epoxides, tetrahydrofuran, piperidine

Enantiomers Mirror images (assemble CHClBrI) are not superimposable if they are dysymmetric (chiral) – hand Asymmetric (w/o symmetry) geometry defines a tetrahedral system Stereoisomers have the same exact atoms in the same pattern (connection), but differ in spatial arrangements of these atoms – ENANTIOMERS!!! Stereogenic centers are chiral centers

How to define achiral centers Plane of symmetry or center of symmetry must be present for an achiral center Achiral molecules do not possess optical activity: rotate the plane of plane-polarized light (light that has been polarized – one direction of propagation for the electric field) Enantiomeric excess must be present for net rotation of plane-polarized light

Configuration Stereogenic centers have absolute configurations designated as either (+) or (-) for the two enantiomers: sign for rotation of light The same relative configurations of different compounds may not have same rotation (+ or - )

Cahn-Ingold-Prelog R-S System Like E/Z, cis/trans for alkenes, this system ranks absolute configurations at a stereogenic center Rank substituents according to decreasing AW Orient molecule with the lowest ranked substituent at back Look at direction of decreasing ranking (clockwise or counterclockwise?) If clockwise (R, rectus, right; S, sinister, left)

Fisher Projection Formulae CH3+OH represents a tetrahedral carbon CH2CH3 The horizontal bar substituents point toward you, whereas the vertical substituents point away Enantiomers differ in ability to interact with receptors

Elimination Bimolecular Must be bimolecular since fastest reactions occur with weakest R-X bonds Regioselectivity is also a factor in deciding where elimination occurs Must be periplanar transition state (look at cis vs trans 4-t-butylcyclohexylbromide – use model kits)

Reactions that Generate Stereogenic Centers Epoxidation (propene) Hydrobromination (2-butene) Chiral molecules with 2 stereogenic centers possess diastereomeric properties (R,R  S,S; R,S S,R, but R,R is not an enantiomer of R,S and these two are diastereomers  stereoisomers R,R and S,S have rotations equal in magnitude but different in sign, likewise R,S and S,R have rotations equal to each other, but opposite in sign Erythro: like substituents on same side of Fisher projection form, threo is opposite

Reactions that Generate Stereogenic Centers Epoxidation (propene) Hydrobromination (2-butene) Chiral molecules with 2 stereogenic centers possess diastereomeric properties (R,R  S,S; R,S S,R, but R,R is not an enantiomer of R,S and these two are diastereomers  stereoisomers R,R and S,S have rotations equal in magnitude but different in sign, likewise R,S and S,R have rotations equal to each other, but opposite in sign Erythro: like substituents on same side of Fisher projection form, threo is opposite

E1: Elimination Unimolecular Rate = k[alkyl halide] Mechanism involved formation of carbocation

Alcohols and Alkyl Halides C-X bond is polarized; dipole moment is strong! Classes of alcohols: primary, sec, tert Bonding is polar covalent Polarizability (induced dipole-dipole interactions)

Acid/Base Theory B: + H-A  B+-H + :A- What is base, acid, conjugates? HA + H2O H3O+ + A- Ka = ? pKa = -logKa Acid dissociation constants (as you go from lower to higher pKas, acidity decreases) – why?

Acid/Base Reactions: Mechanism HBr + H2O  Show reaction mechanism and TS diagram Alkoxide ions (anions) – which are more stable (primary, sec, tert?)

Alkyl Halides Preparation Alcohols + alkyl halides Mechanism (animation 6.11) Bonding and stability Carbon’s inductive effect*

SN1 Mechanism Unimolecular in nature, kinetics Nucleophile (“Lover of Nucleus”) attack is non-directional RDS Eact lower for higher C sub centers

Free Radicals Consider them “electrophilic” – they have an unfilled 2p orbital Stability like carbocations Homolytic cleavage is how they are generated

Enantiomers Mirror images (assemble CHClBrI) are not superimposable if they are dysymmetric (chiral) – hand Asymmetric (w/o symmetry) geometry defines a tetrahedral system Stereoisomers have the same exact atoms in the same pattern (connection), but differ in spatial arrangements of these atoms – ENANTIOMERS!!! Stereogenic centers are chiral centers

How to define achiral centers Plane of symmetry or center of symmetry must be present for an achiral center Achiral molecules do not possess optical activity: rotate the plane of plane-polarized light (light that has been polarized – one direction of propagation for the electric field) Enantiomeric excess must be present for net rotation of plane-polarized light

Configuration Stereogenic centers have absolute configurations designated as either (+) or (-) for the two enantiomers: sign for rotation of light The same relative configurations of different compounds may not have same rotation (+ or - )

Cahn-Ingold-Prelog R-S System Like E/Z, cis/trans for alkenes, this system ranks absolute configurations at a stereogenic center Rank substituents according to decreasing AW Orient molecule with the lowest ranked substituent at back Look at direction of decreasing ranking (clockwise or counterclockwise?) If clockwise (R, rectus, right; S, sinister, left)

Fisher Projection Formulae CH3+OH represents a tetrahedral carbon CH2CH3 The horizontal bar substituents point toward you, whereas the vertical substituents point away Enantiomers differ in ability to interact with receptors

Reactions that Generate Stereogenic Centers Epoxidation (propene) Hydrobromination (2-butene) Chiral molecules with 2 stereogenic centers possess diastereomeric properties (R,R  S,S; R,S S,R, but R,R is not an enantiomer of R,S and these two are diastereomers  stereoisomers R,R and S,S have rotations equal in magnitude but different in sign, likewise R,S and S,R have rotations equal to each other, but opposite in sign Erythro: like substituents on same side of Fisher projection form, threo is opposite

Reactions that Generate Stereogenic Centers Epoxidation (propene) Hydrobromination (2-butene) Chiral molecules with 2 stereogenic centers possess diastereomeric properties (R,R  S,S; R,S S,R, but R,R is not an enantiomer of R,S and these two are diastereomers  stereoisomers R,R and S,S have rotations equal in magnitude but different in sign, likewise R,S and S,R have rotations equal to each other, but opposite in sign Erythro: like substituents on same side of Fisher projection form, threo is opposite

Achiral molecules with 2 stereogenic centers Meso forms are R,S/S,R forms that are superimposable on each other (achiral, and thus optically inactive) – 2,3-butanediol (2S, 3R form) Reactions that produce diastereomers: bromination – 2-butene yields the meso forms (homework)

“Nucleophilic” “Seeking the nucleus” R-X + Y:-  RY + X- C-X bond is polarized toward the halogen Common nucleophiles include alkoxide, sulfide, cyanide, and azide Substrate is sp3 hybidized

Halogen Substitution Reactions Halide-halide exchange: Nucleophilic component must be soluble in medium and salt product should fall out! RCH2CH2Br + NaI/acetone  RCH2CH2I + NaBr (solid) Halide leaving group is based on relative acidity (RF<<RCl<RBr<RI, where I is the best leaving group)

SN2 Reaction CH3Br + -OH  CH3OH + Br- Rate = k? Hughes and Ingold defined a concerted bimolecular process Simple primary and secondary carbon substrates are typical electrophiles Retention of configuration vs. Inversion of configuration are two pathways (RR’R’’-C-X + N:- ?)

Principles of SN2 Reactions Pentacoordinate TS, lower E product and halide LG Solvents influence the generation of the TS and the solvation of the final products/leaving group

Steric Effects in SN2 (Reactivity) Alkyl Bromide Structure Class Relative Rate Methyl bromide CH3Br Unsub. 221,000 Ethyl bromide CH3CH2Br Primary 1,350 Isopropyl bromide (CH2)2CHBr Secondary 1 t-butyl bromide (CH3)3C-Br Tertiary <<1

Substitution with LiI/Acetone Alkyl Bromide Structure Rel. Rate Ethyl bromide CH3CH2Br 1.0 Propyl bromide CH3CH2CH2Br 0.8 i-butyl bromide (CH3)2CHCH2Br 0.036 Neopentyl bromide (CH3)3CCH2Br 0.00002

Nucleophilicity Reactivity Nucleophile Rel. Reactivity Very good I-, HS-, RS- 105 Good Br-, HO-, RO-, CN-, N3- 104 Fair NH3, Cl-, F-, RCO2- 103 Weak H2O, ROH 1 Poor RCO2H 10-2

SN1 Mechanism STERIC HINDRANCE defines the operability of this mechanism! Unimolecular (single order) (CH3)3C-Br + H2O  Reactivity for SN1 is reversed compared to SN2: (methyl<primary<sec<tert) Stereochemistry is “racemic” RAR can occur because of incipient carbocation

Relative Rate of SN1 Solvolysis of t-butyl chloride Solvent Dielectric constant Rel. Rate Acetic acid 6 1 Methanol 33 4 Formic acid 58 5,000 Water 78 150,000

Notable Carbocations The allylic group is very prominent [CH2=CHCH2+  +CH2CH=CH2] and serves to highlight resonance well Hand-in Exercise (HIE): Draw the allylic cation in a cyclopentene system with the two resonant structures 3-chloro-3-methyl-1-butene undergoes bond homolysis at the chloro position to give an allylic carbocation [(CH3)2CH+CH=CH2] which can make an alcohol upon reaction with water – it can form 2 isomeric forms, name them (HIE)!

Dienes 1,4-pentadiene is a classic diene (CH2=CHCH2CH=CH2) – (HIE) are they conjugated? Isolated double bonds are separated by at least on sp3 carbon 1,3-butadiene has all sp2 carbons (C1H2=C2HC3H=C4H2) Allenes are cumulated dienes, i.e., have a central sp hybridized carbon (CH2=C=CH2)

Aromaticity Special property associated with benzene Reactivity is attenuated relative to analogous triene (the imaginary cyclohexatriene) Bonds in benzene are all the same Exhibits “resonance,” a special property related to the conjugation of the six  electrons

Chemical Characteristics of Benzene Planar molecule with all carbons in sp2 hybridization 3 bonding orbitals filled and 3 empty anti-bonding orbitals Benzene can be substituted, but requires catalysts or strong conditions Typical substituted benzenes include: styrene (vinyl sub.), acetophenone (acetyl sub.), phenol (hydroxy sub.), anisole (methoxy sub.), and aniline (amine sub.)