MOC Org 2 Summary Sheets
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(2) "Master Organic Chemistry". Introduction to the Diels Alder Reaction. Note - this sheet is not meant to be comprehensive. Your course may provide additional material, or may not cover some of the reactions shown here. Your course instructor is the final authority.. masterorganicchemistry.com. 1. The Basics The Diels-Alder reaction is a concerted reaction between a compound with two adjacent double bonds (a "diene") and an alkene (the "dienophile"), usually attached to an electron withdrawing group. The transition state is "pericyclic", meaning it has cyclic geometry and is concerted The Diels-Alder reaction always forms a six-membered ring with an alkene. A Very Simple Diels Alder. 1. 1 2. 2. 6. 3. 6 5. 3. 5. 4. 4. Form. Break. C1–C6. C1–C2 (π). C2–C3 (π). C3–C4 (π). C4–C5. C5–C6 (π). Rule #3: The two "outside" groups (red)and the two "inside" groups (blue) always end up on the same side of the new cyclohexene. What this means: 1 2. the C2-C3 bond can rotate freely. When the diene is "locked" in an s-trans configuration, no Diels-Alder reaction is possible (the two ends are too far apart). 1 2. 3. 3 4. 4. note how the two alkenes are on the same side of the C2–C3 sigma bond. note how the two alkenes are on opposite sides of the C2–C3 sigma bond. "s-cis". The end carbons (C1 and C4) are too far apart no Diels-Alder reaction possible. 6 5. 3. top view. 3. 7. 2. 6. 7 8. 5. 3. 4. 4. 4. 1. 2. 6. 7. 3. 5. 8. 6 8. 5. side view. 1. 1. top view. 5. side view. Form. Break. C1–C6. C1–C2 (π). C2–C3 (π). C3–C4 (π). C4–C5. C5–C6 (π). note how the pattern of bonds forming and bonds breaking is exactly the same as for the simple case, above.. Rule #2: Stereochemistry in the dienophile is always preserved cis relationship is preserved in product O O. O. A CH3 O. B. C. D. CH3 O. CH3 O. CH3 O. CH3. CH3. + CH3. CH3. + CH3. enantiomers Let's just pick one set of diastereomers. A and C. C A. Exo/endo examples: O. O. O. these are the same molecule (it's meso) trans relationship is preserved in product O O. CH3. CH3. CH3 Endo. H H. CH3 Exo. How to tell if a product is exo or endo One way to do it: if the outside groups (red) end up on the same side of the ring as the electron withdrawing group, the product is endo. If the outside groups end up on the opposite side of the ring as the electron withdrawing group, the product is exo.. O. CH3. O. CH3 O endo. CH3 exo. O. O. CH3. Note how in A, the two methyl groups are on the same side of the ring as the electron withdrawing group (ketone), whereas in C, they are on the opposite side of the ring. Rule #4: Under normal conditions, endo products dominate. O. enantiomers. CH3 O. CH3 O. A is referred to as the endo product. C is referred to as the exo product (note: B is also endo, and D is also exo). or O cis dienophile. H3C H. enantiomers. +. How the stereochemistry of the dienophile works:. O. H3C H. Note how the two "outside" groups (CH3 and H) end up on the same side of the ring, as do the two "inside" groups (CH3 and H). Note how the two "outside" groups (CH3 and CH3) end up on the same side of the ring, as do the two "inside" groups (H and H). 3. Stereochemistry: The Dienophile. Example:. H CH3 and. CH3. H3C H. 6. 4. 4. 4. 2. H3C H. CH3. 1. 2. 7 3. 5. CH3. H CH3 CH3 H. =. Up to 4 products are possible!. 7. 1 2. 7 3. H H. Example:. Diels-Alder of cyclic dienes 6. H. H3C H. What if there's a substituted diene and a substituted dienophile?. These look a little weird, but they're no different than a normal Diels-Alder. 1. H3C H. 5. The Endo Rule. 2. Special Cases Diels-Alder Reactions of Cyclic Dienes:. 2. CH3. these are the same molecule These dienes cannot participate in the Diels-Alder. "s-trans". The end carbons (C1 and C4) are close together. Example 2:. Example 1:. The diene must always be in the "s-cis" conformation. Rule #1. 4. Stereochemistry: The Diene How the stereochemistry of the diene works:. O H 2. 6. 1. 4. H. 2. 1. H. 5. CH2 3. OCH3. 7. 3. 5. 1. 7. 3. CO2Me. 1. 2. 6 4. 5. 4. H exo (top view). EWG. O. endo (side view). OCH3 5. 6 5. OCH3. 6 7. 3. 4. 4. H endo (top view) H O 2. 1. 2. OCH3. 7 3. 7. O 6. exo (side view). EWG. +. Omissions, Mistakes, Suggestions? O trans dienophile. O. these are enantiomers. O. [email protected] This sheet copyright 2015, James A. Ashenhurst masterorganicchemistry.com.
(3) "Master Organic Chemistry". Introduction to Aromaticity 1. An introduction to resonance energy and aromaticity. 3. How to tell if a molecule is aromatic? Rule 4. It must be flat. Hydrogenation of alkenes liberates 119 kJ/mol of energy ΔH = –119 kJ/mol (28.4 kcal/mol). Pd/C H2. Rule 1. It must be a ring. No acyclic molecule is aromatic. Ever. Most molecules that obey the first 3 rules are also flat. One exception is [10]-annulene, which is bent due to repulsion of the hydrogens.. We would expect hydrogenation of benzene to liberate 3 × 119 = 357 kJ/mol. Pd/C H2. ΔH = –207 kJ/mol (49 kcal/mol). 1,3,5 hexatriene not aromatic. benzene aromatic. N H pyrrole aromatic. butadiene not aromatic. H H not aromatic. Instead, 207 kJ/mol is liberated (150 kJ mol less than we expect!) So it is 150 kJ/mol (36 kcal/mol) more stable.. 4. Antiaromaticity Rule 2. The molecule must be conjugated. The extra stability of benzene is called the "resonance energy". Benzene has a particularly large resonance energy, which leads us to classify it as "aromatic". Resonance energy of some compounds:. Meaning: there must be a continuous line of p orbitals around the ring. p orbitals can come from 1) π-bonds 2) lone pairs 3) carbocations. aromatic. H Conjugated. 2. Two major ways in which reactions of aromatic compounds differ from alkenes. H2. easy. H. H. H. Reaction with electrophiles (such as bromine): aromatics give substitution, not addition Br2 Br Addition reaction. Alkene. Br. Br2 AlBr3 benzene. Substitution reaction difficult. easy. not aromatic (antiaromatic). 4. 2. 4. aromatic. O 6 [NOT 8] aromatic. 6. not aromatic (antiaromatic). aromatic. N 6 [NOT 8] aromatic. 6 [NOT 8] aromatic. N H 6 aromatic. H 6 aromatic. 10. H N. 8 not aromatic. N. O. 6 [NOT 8]. 6 [NOT 8]. aromatic. aromatic. 5. Some physical evidence for aromaticity: H. 1. Shows a different reactivity profile than for alkenes (see section on reactivity at left). Rule 3. There must be 4n + 2 π electrons. 6 aromatic. 2 aromatic. All bonds in benzene are the same length (1.4 Angstrom) i.e. 2, 6, 10, 14.... π electrons. π electrons can come from double bonds or lone pairs. Note: A carbocation indicates the absence of π electrons. One tricky part: for a given atom, you can only count electrons from a lone pair if the atom is not part of a π bond. And in that case you can only count a maximum of one lone pair. This is due to the fact that each atom can only share one p orbital with the π system of the molecule. the electrons from the lone pair on N are at 90° to the π system, and do not contribute to aromaticity.. N pyridine 6 π electrons (3 π bonds, 2 electrons per π bond). Similar example: lone pair on this anion does not contribute towards aromaticity.. ignore lone pair for this calculation. furan 6 π electrons (2 π bonds, 2 electrons per π bond) + 2 electrons from lone pair only count one lone pair for this calculation. Compare this to cyclobutadiene, which has short double bonds and long single bonds - like a rectangle. 3. Ring currents in NMR Resonances for aromatic protons in NMR typically show up in the region 6.8–8.0 ppm, whereas those for "normal" alkenes show up in the region from 5.0–6.5 ppm.. 6. "Frost circles" - a trick for obtaining the molecular orbital structures of aromatic rings. General idea: Inscribe a polygon of n sides in a circle. Make sure one of the apices is pointing down. Then, each apex will represent a level in the molecular orbital energy diagram. Frost, J. Chem. Phys. 1953, 21, 572 Examples:. only one of the lone pairs can align itself with the pi system at any given time, so only one lone pair is counted towards aromaticity.. O. aromatic. extremely unstable. 2. All π bonds are of the same length & do not alternate. no reaction without a catalyst such as AlCl3. π electrons - some examples. •cyclic •conjugated •4π electrons. cyclooctatetraene has 8π electrons, but can adopt a "tub" shape, "escaping" antiaromaticity.. H. Not Conjugated. no reaction at normal temperature and pressure. Br. Conjugated. difficult. benzene. Alkene. Conjugated. O. antiaromatic. N. Pd-C H2. H3C CH3. Conjugated H. Hydrogenation: more difficult with aromatic compounds Pd-C. N H. O H Conjugated. H2C CH2. Molecules that obey rules 1,2 and 4 but have (4n) π electrons instead of (4n +2) π electrons have special instabiity. This special instability is called "antiaromaticity".. A good test. Can you push electrons all the way around the ring through resonance? If not, it's not conjugated.. N O N H 121 kJ/mol 67 kJ/mol 92 kJ/mol 12.2 kJ/mol (29 kcal/mol) (16 kcal/mol) (22 kcal/mol) (3 kcal/mol) aromatic aromatic aromatic not aromatic. 150 kJ/mol (36 kcal/mol). Note - this sheet is not meant to be comprehensive. Your course may provide additional material, or may not cover some of the reactions shown here. Your course instructor is the final authority.. masterorganicchemistry.com. Similar examples: only count one lone pair. S. N. For more examples, see section on left. 3. 4. 6. 7. this shows the arrangement of molecular orbitals for benzene. 5. 8. Omissions, Mistakes, Suggestions? [email protected] This sheet copyright 2015, James A. Ashenhurst masterorganicchemistry.com.
(4) "Master Organic Chemistry". Reactions of Aromatic Compounds Six reactions for electrophilic aromatic substitution Cl2. Chlorination. Electrophilic aromatic substitution: Mechanism E. Cl. X. H E. FeCl3. Bromination. Step 1: attack of the double bond at the electrophile (E ). FeBr3 NO2. HNO3. Nitration. SO3H. SO3. R–Cl AlCl3 (or FeCl3) O R C Cl Friedel-Crafts Acylation. X. H. E. X. X. X. E. X. This resonance form is available for the ortho and para adducts, but NOT the meta.. meta. E. E. X. E. H. X. H. X. –NH2 –NHR –NR2 –OR –OH –F –Cl –Br –I. B. X. O. E. Oxidation of side chain. CH3. Halogenation of side chain. –SH –SR. para H. Cl 1,2 (ortho) 1,3 (meta) 1,4 (para) "ortho - meta - para" only applies to di-substituted benzenes. E. H. E. H. E. O. Alkyl groups such as CH3, CH2CH3, etc. are also ortho-para directors. Why? Notice the partial charge:. X. δ The partial negative charge on the carbon H δ− δ+ will stabilize an adjacent positive charge. C H δ+ H. Activating vs. Deactivating : What does it mean? An activating group is a group that causes electrophilic aromatic substitution to be faster, relative to H. conditions Fe / HCl Sn / HCl Zn / HCl. Similarly, if there is a partial positive charge on the atom adjacent to the ring, this will destabilize resonance forms A and B. A deactivating group is a group that causes electrophilic aromatic substitution to be slower, relative to H either of these conditions will work. CH3. Cl. δ+. CO2Me. X. bad!. CH2Br. Benzylic halogenation. light (hν) O C. Reduction of ketone to alkane. relative rate for nitration:. 1. NH2NH2/ KOH (Wolff-Kishner) Zn(Hg) / HCl. O. O. all of these conditions will convert a ketone to an alkane. (Clemmensen). Pd/C / H2 (5 atm) R. m-CPBA. O. KI. strongly activating o/p director. O. Cl Br. CuBr. N N. CuCl. O. Cl CuCN CN. Diazonium salt. NaOH, heat OH. –CH3. –NH2. –NHR. –OH. –OR. –R. H E para. meta. –NR2. NOT OBSERVED Key concept: more activating donor wins. –CN O C H. Not as unstable. –CN. O C OH. O C OR. O C R. O S OH O. O C OR O S OH O. O C H. O C R. –NR3. Deactivating o-p directors –F. –Cl. –Br. –I. O. N H. Moderately deactivating meta directors. Cl. H. O. O. –SH. NO2 Cl. deactivating o/p director. Moderately activating o-p. –NH. NO2. HNO3 H2SO4. Cl. O. –CF3. O C OH. ortho (Minor). –O. I. –NO2. Key concept: para is generally favored due to steric hindrance. Strongly activating o-p. HNO2 acid (e.g. HCl). H3PO2. NO2. NO2 para (Major). Question 2. When two groups "direct" to different carbons What product dominates? H. Xδ. This is why the following groups are meta directors. (Although "ortho-para avoider" is more appropriate). H2SO4. NH2. Formation and reactions of diazonium salts. +. X. Destabilized! adjacent positive charges. O. HNO3. R. Baeyer-Villiger reaction. .004. Cl and CO2Me are deactivating. O Conversion of ketone to ester. .03. Question 1: Ortho or para: what product dominates?. R. O. 24. NBS = N-bromosuccinimide. H C. conditions. δ+. E. ortho. CH3 is activating. conditions H. R. bad!. H E. COOH will convert any carbon with a C–H bond to a carboxylic acid Benzylic oxidation. NBS. O. N H. Cl. NH2. KMnO4. E. This is why the following groups are ortho-para "directors". Pd-C, H2 CH3. H. E H. E. X. H. E. ortho. Transformations of aromatic functional groups NO2 conditions. A. X. H. +. R. AlCl3 (or FeCl3). Reduction of nitro groups. X. H E. Ortho-meta-para : What does it mean? Cl Cl Cl Cl. O C. X. E. Step 2: Removal of a proton from the carbon regenerates the aromatic group. Substituents that stabilize this carbocation (relative to H) are called activating groups.. R. Resonance forms A and B are KEY If X has an electron pair, these resonance forms will be stabilized through formation of a double bond:. The group X on the ring will affect the stability of the carbocation. + H–X. Certain substituents will stabilize this carbocation Stabilize the carbocation, speed up the reaction. H2SO4. Friedel-Crafts Alkylation. E. This forms a carbocation. [Breaks C–C, forms C–E] [Breaks C–H, forms C–C (and X–H)] rate determining step. H2SO4. Sulfonation. What if there's already a group on the ring?. X. Br. Br2. X. Note - this sheet is not meant to be comprehensive. Your course may provide additional material, or may not cover some of the reactions shown here. Your course instructor is the final authority.. masterorganicchemistry.com. –SR. Strongly deactivating meta directors –CF3. –NO2. –NR3. Omissions, Mistakes, Suggestions? [email protected] This sheet copyright 2015 James A. Ashenhurst masterorganicchemistry.com.
(5) "Master Organic Chemistry". Key Reactions of Aldehydes and Ketones A Simple "Formula" for Seven Key Reactions of Aldehydes & Ketones. H. R H Nu. 2. Protonation. Aldehyde ( but also applies to ketones) Reaction. C–Nu O–H. Product OH. Nucleophile R MgX. Grignard Reaction. C–O ( π ). R. H. R. OH. Addition of Organolithiums. R Li. R R. H. OH Reduction by sodium borohydride (NaBH4). Na. R. H–BH3. H. H. OH. Reduction by lithium aluminum hydride (LiAlH4). H–AlH3. Li. Addition of cyanide ion to form cyanohydrins. R H. R H NC OH. R H HO OH. Addition of alkoxide ions to form hemiacetals. OR. R H RO. Each of these reactions follows a "two-step" pattern: 1) addition 2) protonation How to draw the mechanism for this pattern: Step 1 is donation of a lone pair of electrons from the nucleophile to the carbonyl carbon, which bears a partial positive charge [oxygen is more electronegative than carbon]. A bond forms between the nucleophile and carbon, and the carbon-oxygen double bond [π bond] breaks. The oxygen then bears a negative charge. A Step 1: Addition of nucleophile δ– O O δ+ R R H H Nu Nu. Bonds formed. Bonds broken. C–Nu. C–O (π). P Step 2: Protonation of oxygen In the second step of this reaction, acid is added the oxygen is protonated to give a neutral hydroxyl [O-H] group: O. OH. H. R H Nu. R H Nu. Specific example: Grignard addition Step 1: Addition of nucleophile. Step 2: Protonation. MgBr O R. O H BrMg CH3. draw the arrow as coming from the Mg–C bond. 1. Electronic effects In aldehydes and ketones, the C=O bond is polarized; due to the greater electronegativity of oxygen relative to carbon [3.4 vs. 2.5]; the carbon bears a partial positive charge and the oxygen bears a partial negative charge δ– O δ+ R H. R H H3C. H. X. OH R H H3C. MgBrX. Oxymercuration of alkynes. R The oxygen is electron-rich (nucleophilic) The carbon is electron-poor (electrophilic). The more electron-poor the aldehyde or ketone, the more reactive it will be with nucleophiles – – Oδ Oδ δ+ δ+ H H CF3 H3C more electrophilic less electrophilic this aldehyde is more electron-poor than the aldehyde on the right due to the electron-withdrawing fluorines. 1. 2. H. 1) O3. O. 2) Zn. 2. O. O. <. O. < H3C. <. H. H3C. CH3. 3. Ozonolysis cleaves C–C π bonds. If a "reductive workup" is used, C–H bonds attached to the alkene are preserved, leading to aldehydes.. 4. Other Key Reactions of Aldehydes and Ketones Hydration H2O. O R. H. 1. O H. or CH3SCH3 this is "reductive workup". H. The larger the group adjacent to the carbonyl carbon, the more difficult it will be for nucleophiles to attack. This is referred to as steric hindrance. O. R. H2O, H2SO4. 3 4. 2. Steric effects. H. This adds water to the more substituted end of the alkyne, forming an enol, which then tautomerizes to the ketone.. O. Hg(OAc)2. H. Ozonolysis of alkenes. Most of the reactions of aldehydes and ketones involve an electron-rich nucleophile forming a bond with the electron-poor electrophile that is the carbonyl carbon of the aldehyde or ketone.. OH. Addition of hydroxide ion to form hydrates. Synthesis of Aldehydes and Ketones (continued). H. OH. CN. What factors affect the reactivity of aldehydes and ketones?. ↑. R. OH. 1. "Nucleophile". Bonds Broken. ↑. O. Bonds Formed. Note - this sheet is not meant to be comprehensive. Your course may provide additional material, or may not cover some of the reactions shown here. Your course instructor is the final authority.. masterorganicchemistry.com. HO. OH. R. H. Water will add to aldehydes and ketones to give hydrates. Equilibrium favors the starting aldehyde/ketone The reaction is made faster by acid.. Hydrate Hemiacetal formation. H3C. ROH. O. Most reactive Least reactive Aldehydes are more reactive than ketones largely for this reason.. R. H. RO. OH. R. H. Alcohols will add to aldehydes/ketones to give hemiacetals. Equilibrium usually favors the starting aldehyde/ketone, except in cases where a ring is formed.. Hemiacetal Acetal formation. 3. Acid catalysis When acid ("HX" is added to an aldehyde or ketone it can make the carbonyl carbon more electrophilic (and thus more reactive). The reaction is made faster by acid. Electron withdrawing groups on the aldehyde favor hemiacetal formation. O. RO OR Treatment of an aldehyde or ketone R–OH with an alcohol in acid leads to an H R H acetal. The acetal can be removed H X Protonation of oxygen makes by heating with aqueous acid. H H Acetal this resonance form more O O O H–X significant than it normally would be, and therefore there is a Acetals as protecting groups R H R H R H greater positive charge on carbon in the resonance hybrid RMgBr, RLi, RO, OH, RO OR NaBH4, LiAlH4, PCC, etc. no reaction bottom line: carbon is more electrophilic R H Acetals only react with aqueous The only "catch" with using acid to accelerate a reaction is that it can't be used with acid. So forming an acetal is a method strongly basic nucleophiles, because it will protonate them irreversibly. For instance using of "masking" a carbonyl group. strong acid to accelerate a Grignard reaction would not work because Grignard reagents are strong bases; once protonated, they can't be regenerated. Imine formation Acid catalysis works well with neutral nucleophiles like H2O, ROH, and amines, and also R Aldehydes/ketones treated with N O with weakly basic nucleophiles like CN R–NH2 a primary amine will give imines. Mild acid can be used to promote R H R H Synthesis of aldehydes and ketones this reaction + H2O Through oxidation of alcohols Enamine formation OH O Secondary alcohols can also be oxidized Aldehydes/ketones treated with PCC O NR2 R2NH to ketones with oxidizing agents such as H2CrO4 a secondary amine give enamines. Acid catalyzes their formation. and others. R CH3 CH2 PCC = pyridinium chlorochromate H X + H2O Wittig Reaction PCC is a mild oxidant that does not oxidize O PCC R OH the aldehyde further to the carboxylic acid Treatment of an aldehyde/ketone CH2 O R Ph3P=CH2 with a phosphorus ylide leads to H R H R H formation of an alkene. This is the Wittig Reaction. Hydroboration of alkynes + Ph3P=O R. R. H. 1) BH3 2) H2O2. O. R H. This first forms the enol, which then tautomerizes to the aldehyde.. Omissions, Mistakes, Suggestions? [email protected]. This sheet copyright 2015 James A. Ashenhurst masterorganicchemistry.com.
(6) "Master Organic Chemistry". Key Reactions of Carboxylic Acid Derivatives Nucleophilic acyl substitution. Specific example of nucleophilic acyl substitution:. A key pattern for reactions of carboxylic acid derivatives O. O. 1. "Nucleophile". Bonds Formed. Bonds Broken. X ↑ C–Nu leaving group. R X R Nu ↑ Note that the nucleophile nucleophile displaces the leaving group, making this a "substitution" reaction. C–X. Synthesis of carboxylic acids. A Step 1: Addition of nucleophile δ– O O δ+ R R Cl Cl OCH3 OCH3. Bond forming. Base strength:. Special Cases:. O <. weakest. R. O. OR,. <. NR2. OH <. O. <. 2. R. H,. strongest (these groups are never leaving groups) Summary: Reactions of negatively charged nucleophiles with carboxylic acid derivatives (excluding H and R ) O. O. O. O. O. Nucleophile Cl halide. O. O R O carboxylate. R. R R O Anhydride. R OR Ester. NR (no reaction). NR. *. NR. R. R. O. R. R. (or NHR/NH2) amide. R. O. R. O. H. O. R. O. H. R. O NR2. NR. **. O. O NR2. NR. O R. O OH hydroxide. NR. O O. O RO alkoxide. R NR2 Amide. O. H. ***. NR2. R. NR2. Each of these reactions follows a "two-step" pattern: 1) addition 2) elimination A Step 1: Addition of nucleophile δ– O O δ+ R R X X Nu Nu. Cl. Step 2: Elimination of leaving group. C–Nu. Bond forming R X Nu. R. Nu. O R Cl HO. C–O (π). + X. C–O (π). Bonds broken C–X. OH. Deprotonation of carboxylic acids O R. OH. O R. O. H. Treatment of a carboxylic acid with base leads to formation of its conjugate base, called a "carboxylate". O. base R. OH. O. O R. OH. Carboxylic acid. 1) R MgX O R. 2) Acid. HO. R. R. R. O. O. Carboxylate. E. A. P. R. 1) LiAlH4 O R. 2) Acid. HO. H. A. E. A. P. R. H. H O. R. CH3. R. CH3. Tertiary alcohol. OR. Protonation of oxygen makes this resonance form more significant than it normally would be, and therefore there is a greater positive charge on carbon in the resonance hybrid. O. OR. R. H + H2O OR. H2O is a much better leaving group than HO Thus, acid increases the rate of the elimination step. Fischer Esterification: Formation of esters from carboxylic acids. MgBr. CH3. (Acid) Protonation. MgBr O CH3 R. O R. Acid. R. OR. O. H2O OR. Treatment of a carboxylic acid with + H2O an alcohol in the presence of acid leads to formation of an ester. Acid. R. OH. Treatment of an ester with aqueous + ROH acid leads to the formation of a carboxylic acid. Aqueous hydrolysis of amides to carboxylic acids O R. O. H2O NH2. Acid. R. + NH3 OH. Aqueous hydrolysis of nitriles to carboxylic acids. CH3. Alkoxide. O. R–OH OH. Aqueous hydrolysis of esters to carboxylic acids. O R. H3C Mg Br Addition. CH3. H O H. O. Mg Br. HO. R. OR. H. All of these reactions employ acid catalysis:. Example: "Double addition" of Grignard reagent to an ester MgBr Addition Elimination O O O O R R. O. bottom line: carbon is more electrophilic. R. H3C. H. 2) Acid also increases the rate of elimination, because it improves leaving group ability. Primary alcohol. O R. R. OR. R A. O. H–X. R. Tertiary alcohol O. Cl. Acid can't be used as a catalyst with nucleophiles that are strong bases, since it will react irreversibly with them (i.e. protonate them) - Grignard reagents, for example.. Special Cases: 2. Addition of Grignard reagents/ LiAlH4 to esters Esters will undergo "double addition" with Grignard reagents and the strong reducing agent LiAlH4. This is because addition/elimination results in a ketone (or aldehyde, in the case of LiAlH4), which then reacts with another equivalent of nucleophile to give an alkoxide. Addition of acid then give a neutral alcohol. O. R. With poor nucleophiles like H2O and alcohols (ROH) it's possible to use acids to catalyze reactions. Acid serves two purposes: 1) it makes carbonyl carbons more electrophilic (increasing the rate of addition). Acid workup (H +). O. This is how to convert a carboxylic acid into a better + H2O electrophile. O. SOCl2 OH. The role of acid in reactions of carboxylic acid derivatives. Carboxylic acid. R. O R. OH. Bonds broken. E. O. O. O R Cl HO. Also, carboxylic acids will not undergo nucleophilic acyl substitution under basic conditions, since a base will deprotonate them to the carboxylate, and the leaving group for a carboxylate is O2– (a very bad leaving group!). R Bond forming. Ozonolysis followed by H2O2 leads to oxidation of the C–H bond to a C–OH bond (a carboxylic acid) This is called "oxidative workup". R. H. 1. Formation of carboxylic acids. O R. R. *** Conversion of an amide to a carboxylic acid by adding HO(-) is not favorable unless a lot of heat is added.. O. 2) H2O2. Conversion of carboxylic acids to acid chlorides. NR. * If an anhydride is treated with a large excess of a carboxylate nucleophile with a different R group, a new anhydride will be formed. **If an ester is treated with a large excess of an alkoxide nucleophile with a different R group, a new ester will be formed (this is called "transesterification"). OH. Other Important Reactions of Carboxylic Acids (and derivatives). O. R. R. 1) O3 R. C–Cl. When the main product is a carboxylic acid, an "acid workup" step is necessary, since the carboxylic acid will be deprotonated to a carboxylate under the reaction conditions.. Electrophile R Cl Acid chloride. R. Bonds broken. C–O (π). + X OCH3. R. O. or KMnO4. H. O. O. OH. From ozonolysis of alkenes (oxidative workup) Bond forming. R Cl Nu. H2CrO4 R. C–O (π). E. Step 2: Elimination of leaving group If the base strength of the nucleophile is stronger than the leaving group, the reaction proceeds. If the nucleophile is a weaker base than the leaving group, the reaction does not proceed under these conditions.. From oxidation of primary alcohols:. Bonds broken. C–O. The biggest factor in whether this reaction proceeds is base strength.. Cl. Note - this sheet is not meant to be comprehensive. Your course may provide additional material, or may not cover some of the reactions shown here. Your course instructor is the final authority.. masterorganicchemistry.com. R. C. N. O. H2O Acid. R. Omissions, Mistakes, Suggestions? [email protected]. + NH3 OH This sheet copyright 2015 James A. Ashenhurst masterorganicchemistry.com.
(7) "Master Organic Chemistry". The Oxidation Ladder. Note - this sheet is not meant to be comprehensive. Your course may provide additional material, or may not cover some of the reactions shown here. Your course instructor is the final authority.. http://masterorganicchemistry.com 2015 Version. Oxidation state of carbon • To keep things relatively simple, several common functional groups (amines, epoxides, ethers, and many more) have been omitted.. CO2. Indicates oxidations Indicates reductions Functional group transformations. Carbon dioxide. • All alkyl halides are drawn as chlorides ("Cl"). For Br and I, the corresponding reagent containing those atoms should be employed.. (from combustion!). • Oxidation here is defined as: loss of a C–H bond or gain of a C–O bond (or equivalent) Reduction here is defined as: gain of a C–H bond or loss of a C–O bond (or equivalent). H2O, acid ROH, acid O LiAlH4. R. HO. Carboxylic acid. O. SOCl2 H2O or NaOH. R. Cl. NH3 or other amine. Acid halide. O. P2O5 R. H2N. N. H2O, acid. Amide. O C. R. RO Ester. Nitrile. R. H2O, acid. R E D U C T I O N. O X I D A T I O N. amine, DCC. NH3 or other amine m-CPBA. O3, H2O H2CrO4 or H2O2. H2CrO4 or KMnO4. H2O, H2SO4 or HgSO4, H2O, H2SO4. BH3, H2O2 O. NaNH2. Cl. R. H Aldehyde. NaBH4 or PCC LiAlH4. NaNH2. R. R Cl Dihalide (Vicinal) Cl2. R Ketone. Dihalide (Geminal). H2, Lindlar's catalyst. O3, Zn (or DMS) H2SO4, heat. NaOH (SN2). Alcohol (Primary). Cl PCl3 or SOCl2. R. NaBH4 or LiAlH4. PCC or H2CrO4. H2O, H2SO4 or Hg(OAc)2, H2O, then NaBH4. BH3, H2O2. R. RMgCl or RLi. O. R. HCl. Alkyne. O3, Zn (or DMS). Cl Cl. H2SO4, heat. HO. RMgCl or RLi. DIBAL. R base (e.g. NaOEt). Alkene. Alkyl halide (Primary). Pd/C H2. Mg, then acid. NaOH (SN2). Cl. HCl. base (e.g. NaOEt). R Alkyl halide (Secondary). HCl. OH R Alcohol (Secondary). OH R Alcohol (Tertiary). Mg, then acid. Cl2, light. Cl2, light R. R. Alkanes Omissions, Mistakes, Suggestions? [email protected] This sheet copyright 2015, James A. Ashenhurst masterorganicchemistry.com.
(8) Enols and Enolates Structural Features of the Carbonyl Group: Name. Structure. pKA* of H. Example. O. O. 17. aldehyde R. H O. ketone. R. R'. R. (. OR. H3C. O. H2C. OMe O. H O. (. )n. H3C. nitrile. R. OH O. * H3C. Cl O O. R–CN. Note 2. Cl O. * R H3C. H. O O. Me-CN. Note 2 Me. H. For acetone (R=CH3) the keto:enol ratio is ~6600:1 at 23 °C. Main reason is the difference in bond strengths between the two species.. OMe O H CH3. O. M. M. Enolate (Carbanion resonance form). Note 1: The carboxylic acid is deprotonated at oxygen first. Subsequent deprotonation of the α-carbon would form a dianion, which has a high activation barrier due to charge repulsion. It can be done, but requires a very strong base.. H. Note 2: It is difficult to measure the pKa of these species due to their reactivity. *source: P.Y. Bruice, "Organic Chemistry" Note that some of these values differ slightly from textbook to textbook and instructor to instructor. However, there is universal agreement that for a given structure, pKas increase in the order: aldehyde < ketone < ester < amide. 1) evans.harvard.edu/pdf/evans_pka_table.pdf 2) www.chem.wisc.edu/areas/reich/pkatable/. Me. Me 24 : 76 (at 23 °C). pKa = 9. O. O. O. OMe MeO. pKa = 11. O t-Bu. O. H X. t-Bu. O NEt2. OMe. O NR2 >. forms readily!. O OR >. O CH3>. O CF3. >. RO. O OR. increasing reactivity toward nucleophilic attack increasing stability of enolate This means we can predict the course of the reaction by pKa!. Key Reaction: Enolate Formation Enolate = deprotonated enol i-Pr. O H3C. OEt. i-Pr N Li (LDA). O Li. O Li H. (or other strong base) Carbonyl compound. OEt. H ester enolate O-bound form. H. OEt H. C-bound form. Important: the Enolate is a NUCLEOPHILE Amphiphilic =nucleophilic at both O and C; note: though an ester enolate here we focus on the reactions at C. is shown here, the reaction of any enolate with an aldehyde is generally called an "Aldol". Two key examples: O. O M. pKa = 13. OEt. The rate of keto/enol interconversion isgreatly enhanced by acid: Acid makes carbonyl more electrophilic, increasing acidity of αprotons, facilitating formation of enol: this increases K1. 4. Conjugation is stabilizing.. H. O OH. Me. O. O. NEt2. Enolate (oxy-anion resonance form). Me Me. does not form. R. OH H. O. R. OEt. Aldol reaction. Me. 3. Strongly hydrogen bonding solvents can disrupt this, however. The above equilibrium is 81:19 using water as solvent.. O. O. CH3 NEt2. H. 2. O. > OH > OR, NHAc > CH3, R > Cl, Br, F, I > C(O)OR CF3, etc.. O. t-Bu LiNEt. H. least acidic. Me. X. NEt2. The reactivity of the alkene toward nucleophilic attack is directly related to the stability of the enolate that forms -. The aromatic electrophilic substitution chart is a good proxy for the ability of a functional group to donate to a carbonyl:. Exclusive. H. CH2. enolate: stabilized!. OMe CH3. most acidic. NR2 , O. M. LiNEt2. Li O. Answer: The more electron-poor the carbonyl, the greater will be its ability to stabilize negative charge. Conversely, the greater the donating ability of a substitutent on the carbonyl, the less it will be able to stabilize negative charge.. 2. Hydrogen bonding stabilizes the enol form. H-bond H O O O O Me. H. Question: How do you explain the relative acidity of the following series? O O O O > > > NR2 H3C H3C CF3 H3C CH3 H3C OR. Five factors that influence the relative proportion of keto/enol: 1. Aromaticity O OH H H Not observed. H. H. Substitution of the α-carbon by a second carbonyl derivative makes the α-proton even more acidic:. 25. H. highly unstable. Why the huge difference in acidity? The lone pair is stabilized by donation into the carbonyl π system.. enol form. H. O. CH3. M Conjugate base (enolate) ~1025 more acidic just by replacing H with a carbonyl!. R H. Acetone in D2O will slowly incorporate deuterium at the α− Note 1 carbon. The enol form is responsible for this behavior. The rate of keto/enol tautomerism is greatly increased by acid (see below right). O. O anhydride. N Me. NH(R) H C 2. OH. R. R. C H2. H2C CH3. OMe O. CH3. H Methyl propionate pKa = ~25. The enol tautomer is most significant for ketones and aldehydes. (You may also encounter it with acid chlorides in the mechanism of the Hell-Vollhard-Zolinsky reaction). Esters and amides are less acidic and exist almost exclusively as the keto form (e.g. >106 : 1 keto: enol for ethyl acetate). O. O acid chloride. 30. NMe2. H2C. O carboxylic R acid. Conjugate base. Tautomerism: a form of isomerism where a keto converts to an enol through the movement of a proton and shifting of bonding electrons. O NR2. M. Ethane pKa = ~50. H. OH. keto form. NH2 = 1° amide NHR = 2 ° amide NR1R2 = 3 ° amide O lactam (cyclic amide). O. )n. R. H3C CH3. OMe. Key Concept: Tautomerism. 25. Effect on reactivity of alkenes: Likewise, the presence of a carbonyl group activates alkenes toward nucleophilic attack:. The carbonyl is an electron withdrawing π system with low-lying π* orbitals. It stabilizes adjacent negative charge.. O. O. O amide. 20. Me. H3C. O lactone (cyclic ester). δ+. O. O ester. Oδ –. H. H3C. Effects on acidity of alkyl groups. •Carbon, oxygen: sp2 hybridized •O–C–C bond angle ~120 ° •C=O bond strongly polarized toward oxygen. •Carbonyl carbon is partially positive therefore electrophilic! •Lone pairs render oxygen weakly nucleophilic (will react with strong acid). Me Preferred enol form. 5. As with alkenes, increasing substitution increases thermodynamic stability (assuming equal steric factors). R. R. H X R. H H Keto. O. K1 R. H H. K2. H O R. R. H X. H Enol. X:. Enol is nucleophilic at α-carbon, acid is excellent electrophile: this increases K2. Net result: Addition of acid speeds proton exchange between the keto and enol forms.. O. O M OEt. R. OH OR. R. O. Claisen Condensation OEt. 2015 Version copyright James Ashenhurst, 2015 suggestions/questions/comments? [email protected].
(9) 1. 2. Copyright 2014 James Ashenhurst masterorganicchemistry.com R–MgX [email protected]. O. A. OH. R. H. R. OH. R. 2° alcohol. Aldehyde. OH. Aldol Reaction. OH. NR2. R. O. OH. R. R. Cl. Acyl chloride. O. C. R. R'. O. R'. Ketone. R. R'. NR2. O. O R. R. O. R. O. O. R. OR. OH. R. R. 3° alcohol. O. NR2. O R. OH R. OR. R'. Aldol Reaction. R. R. OH. O R. R. R'. R. R. O. O. NR2. R. R. Aldol Reaction. N R. R. O R α, β unsaturated ketone (enone). F. Varies with conditions: 1,2 adduct is kinetic pdt.. Ester. O OR. Michael Reaction. OH OR. O. O. R. NR2. O R. R. R. O. R. R. R. 3° alcohol. O. O OR. β−keto ester: Claisen Condensation. R. Deprotonation. Deprotonation. Acid nitrile. NH2. Deprotonation. 1° and 2° amides: deprotonation 3°amides: NR. Acetal. R. CN. Ester. Acid nitrile. R. Ester. Borderline. R. OR. HO. OH. R'. R. R. R'. Acetal Requires acid catalysis. 1,3 diketone: Claisen Condensation. Deprotonation. NR. Deprotonation. R. 1° and 2° amides: deprotonation 3°amides: NR. R. R. O R. X. Mix of addition /deprotonation. R. R. R. R. R. O. H H 1° alcohol. R. H H. OH R'. H. 2° alcohol. OH R. R'. H. 2° alcohol. Varies with conditions: 1,2 adduct is kinetic product, 1,4 adduct is thermodynamic.. O OR'. R. OH OH. NR. OR'. Borderline reaction: requires strong acid, alcohol as solvent, heat. OH. O R. H H 1° alcohol R. H OH. H H. 1° alcohol. NR. –––. R. NR. R. H NH2. Amine. O R. RO. OH R. 1° alcohol. Amide Hydrolysis Requires strong conc. acid, heat. NR2. O OR. Borderline. Fischer esterification (requires acid, heat). NR. 1° alcohol. Note: Easily reversible. NR. NHR. H. RO. Amide. I. H 1° alcohol. Transesterification Saponification Can be done under basic (basic conditions) or acidic conditions. Can also hydrolyze with aqueous acid O. NR. NR. NR. R. O. Amide. H. R. H. R. O R. RO. NR. 1° alcohol. R. Hydrate see above: even less favored than with aldehydes due to sterics. O R. NHR. H. Carboxylic Acid. Note: in both cases, very prone to the reverse reaction (elimination). Borderline. OH. H. OH OH. R. O R. OH. O R. RO. NC. LiAlH4 Lithium aluminum hydride. OH OH. Carboxylic acid. OR. O. NaBH4. O R. OR. 11. Sodium borohydride. R. Hydrate (usu. thermodynaically disfavored, except for electron poor aldehydes) If aldehyde is enolizable, hydroxide can form enolate.. O. R. Usually requires dehydration agent (e.g. DCC). O R. H. OH. RHN. Carboxylic acid. H. CN. O OH. OH. R. R CN R' Cyanohydrin. R. O. G. HO. H. O. R. R. O. R. OR. R. Requires acid catalysis to form. O. R. Michael Reaction. O. R. OH. RO. O. O R. O R. RO. R. Imine (ketimine). Note: best when ketones are identical or when only one can enolize (to avoid scrambling). E. Cyanohydrin. 10. H2O/ M–OH water/ hydroxide. O NHR. Amide. OR. CN. H. O R. O. RO. 9. R–OH/ R–OM alcohol/ alkoxide. O NHR. Amide (Schotten-Bauman reaction). R. O. R. R. R. RO. H. OH R. O. R O. 8. Cyanide. R. Imine (aldimine). OH. RO. O. OH. R. O. R. R R R 3° alcohol. O. D. O R. OR. M–CN. N R. Knoevenagel Condensation. β−keto ester. OH. Anhydride. O. R. R 3° alcohol. O O. O. R. R–NH2 amine (primary amine). R. Aldol Reaction. 7. O. RO. heating under basic conditions will lead to elimination of OH - Aldol condensation also note that reaction can be reversible under basic conditions : Retro-aldol reaction. B. R. O. R. 6 M. β−keto ester enolate. Enamine. R. O. RO. R. O. R. OR. 5 O. NR2. R Ketone enolate. O. R. M. O. OR Ester enolate. Grignard. 4. 3 M. O. R. NHR. R. CN. R. OR. R. OH. NR. R. H. R Alkyl halide. Enolate Alkylation. Enolate Alkylation. Amine. Stork enamine reaction note: capable of alkylating a second time. caution! product is a good nucleophile; multiple alkylations usually result. Williamson Ether Synthesis requires basic conditions. requires basic conditions. Alkane.
(10) from "Master Organic Chemistry" masterorganicchemistry.com 2015 Version, Copyright 2015 James A. Ashenhurst [email protected]. Identifying the Patterns in Carbonyl Reaction Mechanisms. O Grignard Reaction. R–MgX. Cyanohydrin formation. NaCN. R. R O. R. NaBH4 or LiAlH4. R. O CH2R H. R. R. HO. CN. R. R. HO. H. R. R. R. O. Base-catalyzed aldol reaction. R. R O. Ketone or aldehyde reduction. R. HO. O. base R. A. P. A. P. Reactions of anionic nucleophiles with alkyl halides. R HO. RO. NR2 R. X. R. X. R. X. O R. R. OR. OH. R. CN. SN2. O. base R. D. R. SN2. R O. R. D. R. R. CH2R. OH. R. SN2. R. CN. Enolate alkylation (ketones or esters). P. A. NR2. Reactions of neutral nucleophiles with alkyl halides. D. A. P. Reduction of esters. LiAlH4. A. E. D. Grignard Reaction + acid chloride, ester, or anhydride. RMgX. E. Imine formation. RNH2. *note 1. Fischer esterification. ROH. Amide hydrolysis. H2O. R. HO. H. R. H. HO. R. R. R. OR. A. E. A. P. A. E. A. P. P. A. PT. E. D. P. A. PT. E. D. P. A. PT. E. D. P. A. PT. E. A. D. P. E. A. PT. E. D. P. T. A. PT. T. 14E. R Addition of neutral nucleophiles to acid halides or anhydrides (e.g.amines, alcohols, water). O. HO. R. Cl. O Claisen condensation. R. Cl. O. Addition of anionic nucleophiles to acid halides or anhydrides (e.g.RO , H2N , HO ). CH2R R. NHR. O. RO. O R. O. R. OH. O. base OR. O. R. H2N. O. R. O. RNH2. R. R. OR. O A. NH2. R. A. 14A. P. E. N. R. O D. R. R. acid. R. O. R. Cl. R O. acid. R. R. OH. OR. R O 1,4 addition of Gilman reagent. O. O. R2CuLi R. R. O. acid. R. NR2. R. OH. RO. OR. R. R. R O Michael reaction. O. R. O. base R. CH2R. O. O. R. D. R. P. 14A. Formation of acetals. ROH. Hydrolysis of acetals. H2O. R. acid R. R O RNH2. 1,4 addition of neutral nucleophiles. O R. 14A. R. PT. RHN. RO. OR. R. R. O Acid catalyzed aldol. R. R. O CH2R. H. O. acid. R O. acid R. R. R. D. R *note 1 - There is actually a fourth step; base removes a proton from the acidic alpha-carbon, rendering the reaction irreversible. Acidic workup gives the final product.. A Cα. X. O. Nu. R. X. E. O. Nu. R. X. SN2 R. Nu. O R. Nu. OH R. Nu. 14E. R X β. Deprotonation O. O. O. R H X. R. R. R. H. [1,4] elimination. O. Nu. O. Nu. [1,4] addition 14A. SN2. Elimination [1,2-elimination]. Addition to carbonyl [1,2-addition] O. The Nine Mechanistic Components (with examples). D. O. O. T R. H3C. H2C. R. OH R. H. R H. P. H2C. O. acid R. Intramolecular acid-base reaction example:. R. Protonation O. PT. H HO OR. Removal of a proton from substrate. Keto-Enol Tautomerization H. base R. H3C. Proton Transfer O. H3C. Addition of a proton to substrate. R. R. H2O OR R. R. This can either be drawn as an intramolecular reaction (one step) or as a deprotonation (D)followed by a protonation (P).
(11) from "Master Organic Chemistry" masterorganicchemistry.wordpress.com 2015 Version copyright 2015 James A. Ashenhurst [email protected]. Nine Key Mechanisms In Carbonyl Chemistry Description. Mechanism Addition [sometimes "[1,2] addition"] O Cα. Nu. O X. Attack of a nucleophile at the carbonyl carbon, breaking the C–O π bond.. Cα. Nu. X. Elimination Lone pair on carbonyl oxygen comes down to carbonyl carbon, forming new π-bond and displacing leaving group X.. [sometimes "[1,2] elimination"] O. Nu. O Cα. X. Cα. Nu. Promoted by. Hindered by. Anything that makes the carbonyl carbon a better electrophile (more electron-poor). Examples. 1) Anything that makes the carbonyl carbon a poorer electrophile (more electron-rich) 2) Sterically bulky substituents next to the carbonyl X-groups that are strong π-donors (e.g. amino, hydroxy, alkoxy). Electron withdrawing groups on α carbon Electron-withdrawing X groups that are poor π-donors (e.g. Cl, Br, I, etc.) Addition of acid (protonates carbonyl oxygen, making carbonyl carbon more electrophilic. Note: acid must be compatible with nucleophile;alcohols are OK, strongly basic nucleophiles (e.g. Grignards) are not.. Grignard reaction Imine formation Fischer esterification Aldol reaction Acetal formation Claisen condensation. Sterics: X=H (fastest) > 1° alkyl > 2° alkyl > 3° alkyl (most hindered, slowest) X=Cl (poorest π-donor, fastest addition) > OAc > OR > NH2/NHR/NR2 (best π donor, slowest rate). The better the leaving group X, the faster the reaction will be. The rate follows pKa very well. Acid can turn poor leaving groups (NR2, OH) into good leaving groups (HNR2, H2O). Fischer esterification Formation of amides by treatment of acid halides with amines. Claisen condensation. X groups that are strong bases are poor leaving groups. Alkyl groups and hydrogens never leave. Amines and hydroxy are poor leaving groups under basic conditions, but are much better leaving groups under acidic conditions.. I > Br > Cl > H2O > OAc > SR > OR >> NR2, O2– H alkyl >40 –8 –7 –2 4 12 17 35. –9 Nucleophile attacks alkene polarized by electron withdrawing group, leading to formation of enolate.. [1,4] addition O. O R. Nu. R. [1,4] elimination OH. O. R. Lone pair on oxygen comes down to form carbonyl, enol double bond displaces leaving group on the β-carbon. H R. X β SN2 R H. Backside attack of nucleophile onto electrophile (alkyl halide or equivalent). O. O. R. R. R. H. Keto-Enol Tautomerization O H3C. MIchael reaction Addition of Gilman reagents (organocuprates). [1,2]-addition can compete in the example of Grignard reagents. The more electron rich the carbonyl, the slower will be the rate of reaction (less able to stabilize negative charge). So addition to α,β-ketones > α,β−esters > α,β-amides.. Nu. Nu. X. So-called "soft" nucleophiles such as Gilman reagents (organocuprates) will add [1,4], as will amines, enolates etc. The more stable the conjugate base (enolate) of the carbonyl, the faster the reaction. Extra electron withdrawing groups on the α-carbon will promote the reaction.. OH R. H. Internal oxygen ↔ proton transfer with change in hybridization of oxygen and carbon.. Facilitated if X is a good leaving group (just like [1,2]-elimination) In the aldol condensation, addition of acid helps OH group leave as H2O.. Aldol condensation Knovenagel condensation. As with [1,2]elimination, X groups that are strong bases are poor leaving groups. Addition of acid will promote elimination of groups such as NR2 and OH/OR.. Note that in the Aldol reaction run under basic conditions, the enolate is a stronger base than OH(–), so in the base-promoted Aldol reaction, the [1,4]-elimination is favorable.. Facilitated by good leaving group on electrophile (alkyl halide or tosylate). Polar aprotic solvent is ideal. Enolate α-carbon is excellent nucleophile for SN2 The higher the pKa of the carbonyl compound, the more reactive the conjugate base will be in the SN2.. Enolate alkylation Carboxylate alkylation. Rate of reaction will go primary alkyl halide > secondary alkyl halide Tertiary alkyl halides unreactive in SN2.. Facilitated by acid The enol form is stabilized by internal hydrogen bonding if there is a carbonyl present at the β position.. Tautomerism under acidic conditions only significant for ketones, aldehydes, and acid halides (the latter under the conditions of the Hell-Vollhard-Zolinski reaction).. Acid-catalyzed aldol Acid-catalyzed bromination of ketones. R H. Deprotonation. Acid Base Reactions. Protonation. Proton Transfer. The conjugate base is always a better nucleophile than the conjugate acid. Deprotonation increases nucleophilicity. E.g. enolate > enol, alkoxide > alcohol, NH2(–) > NH3 Conjugate base can perform reactions the conjugate acid cannot. Deprotonation is also the last step in acid-catalyzed reactions, in order to generate the final (neutral) product. 1) catalyzes [1,2] addition to carbonyls 2) promotes [1,2] elimination 3) to promote tautomerization. 4) quench (e.g. enolate from 1,4.. An internal acid-base reaction. Not mechanistically distinct from the above, but often drawn as one step. Can proceed either intramolecularly or intermolecularly (both pathways operate) hence distinct arrow pushing steps often not drawn, and we just say "proton transfer". R. OH. Base R. H RO. O. O R. H. faster [1,2] addition. H R. R. R. OH2. R. R. deprotonation at end of acidcatalyzed acetal formation provides neutral product. OH. H. O. H. H2O OR R. R. R. OH. H. R. H faster enolization. R. OR. R. CH3. H HO OR. O OH. OH2. faster [1,2] elimination. O. RO. –[H]. R. O. HO X. H. OR. R. forms alkoxide (more nucleophilic). R. reaction quench. R. R.
(12) "Master Organic Chemistry". Introduction to Carbohydrates. Carbohydrates have the molecular formula Cn(H2O)n. What's a Carbohydrate? For example:. Glucose C6H12O6. = C6(H2O)6. a hexose. Fructose C6H12O6. = C6(H2O)6. a hexose. Sucrose C12H24O12. = C12(H2O)12. a disaccharide. = C3(H2O)3. a triose. Glyceraldehyde C3H6O3. The Fischer Projection O H. O. H. H. OH CH2OH. H OH. What's D and L?. H. H CH2OH L-glyceraldehyde. OH CH2OH D-glyceraldehyde. HO. Examples H. O. O. H. H H H. OH OH OH CH2OH. D-Ribose. HO HO HO. H H H CH2OH. L-Ribose. H HO H H. In the Fischer projection, assign D and L by placing the most oxidized carbon of the sugar (i.e. the aldehyde) at the top, and then if the stereocenter furthest from it is on the right, it's D. If it's on the left, it's L.. CHO OH H OH OH CH2OH. D-Glucose. HO H H HO. CHO H OH OH H CH2OH. CHO OH H OH OH CH2OH CH2OH D-glyceraldehyde D-erythrose a tetrose a triose H H. O. 3. H OH. H H H. OH OH OH CH2OH. D-ribose a pentose. O. H. HO HO. H H. OH H. OH. D-Glucose. CHO OH H H OH CH2OH. HO. HO. HO HO. H. OH OH. H. β−D-Glucose. 6. 4. HO HO. 5. 1. OH. H2 OH H H β−anomer C-1 OH is up Mnemonic: "β" stands for bird, which flies up in the sky 3. H. H. OH OH OH. HOH. H. OH. OH H. H H. α−D-Fructose. OH. 2. 1. OH. 2. 3. Step 4 OH. O H H. HO H. O H. H. HOH. O H H OH. OH H Maltose. OH. O. H. Ag, NH3. OH CH2OH. H2O. H. OH OH CH2OH. Aldonic Acid synthesis: Br2, H2O; oxidizes aldehyde to carboxylic acid O H. O. H. Br2. OH CH2OH. H. H2O. OH OH CH2OH. Aldaric acid synthesis: HNO3, H2O; oxidizes both ends to acids O. O. H. HNO3 H2O. OH CH2OH. OH. H. OH. O. OH. Ruff degradation: Br2, H2O, then FeCl3, H2O2; shortens sugar by one carbon O H 1 O 1) Br2 H2O 2 + CO2 H 2 OH H 1 2) H2O CH2OH CH2OH 3. CH2OH. HO. H HO. 4. Tollens Test: Ag+, NH3, H2O : oxidizes aldehyde to carboxylic acid. CH2OH. O. α−D-Ribose. CH2OH O H HO. CH2OH O OH. 5 1. Step 3 OH. 3. D-galactose a hexose. Aldoses contain an aldehyde; ketoses contain a ketone CH2OH H OH O HO CH2OH O HO H HO H HO HO OH HO H OH H H OH OH H H H OH OH H It's trickier to see this in CH2OH Ring closed form the ring-closed form. D-Fructose (a ketose) D-glucose (an aldose). 4. 1. Step 2. H. CH2OH. HO OH. HO. 6. Reactions (not a complete list). HO. H OH. OH. β−D-Galactose. CH2OH H O O H H H HO HOH H O CH2OH HO H HO OH H Sucrose not a reducing sugar - no hemiacetal!. Kiliani-Fischer Synthesis: Convert aldehyde to cyanohydrin, then reduce and hydrolyze. Extends sugar chain by one carbon. O H O H 1) HCN H HO 2) H2, Pd H OH H OH then H O 3 CH2OH CH2OH Glycosides: Acetal formation. Aldoses and Ketoses O C H H OH H HO H OH H OH CH2OH. 1. Step 1. H OH. OH H OH O H CH2OH. O H H H. 6. CH2OH O OH. 5. H. Examples of reducing sugars (the hemiacetal is highlighted in red) H OH. CH2OH O. 5. OH 3. A cyclic sugar with a hemiacetal is in equilibrium with the open chain form. And since the open chain form can be reduced to an alcohol with NaBH4, it is termed a "reducing sugar".. HO. H. H HO HO H. 4. "Reducing Sugars". L-Galactose. H. H HO H H. HO 1. Triose, Tetrose, Pentose, Hexose. H. 3. Mnemonic: "α" looks like a fish, Open chain form which swims down in the sea The two anomers (α and β) are in equilibrium with each other. A pure sample of either α-D-glucose (optical rotation +112°) or β-D-glucose (optical rotation +19°) will change over time to +52.7° which is an equilibrium mixture of 64% alpha and 36% beta. This change in optical rotation is known as mutarotation.. Each of these terms simply denotes the number of carbons in the sugar O. 5. H 2 OH H OH α−anomer C-1 OH is down. He guessed right!. H. 6. 4. HO HO. D and L are arbitrary terms assigned by Emil Fischer in 1891 to denote the enantiomers of glucose. The absolute configuration wasn't determined until 1951. O. OH H OH 5 O H 6 CH2OH. Note that a stereocenter is formed on C1 ! This leads to two isomers of the cyclic sugar, called "anomers" (designated alpha and beta) O. H. A sugar with a five-membered ring is called a furanose. 1. A bond is forming between the oxygen on C-5 and C-1 . So draw a six membered ring with oxygen at the top right. 2. Since the sugar is D, on C-5, place the CH2OH pointing "up" on the ring (if it was L, CH2OH would point "down") 3. For C-2, C-3, and C-4, every group on the right of the Fischer will be down on the ring, and every group on the left of the Fischer will be up on the ring. 4. The configuration of the anomeric carbon (C-1) will be a mixture of alpha (α) and beta (β). H. 2. The alcohol on C5 attacks the aldehyde on C1, forming a cyclic hemiacetal (after proton transfer). Fischer projection. O. H HO H H. A sugar with a six-membered ring is called a pyranose. OH H OH O CH2OH. 1. Ring form. Open chain form. Mnemonic: "the arms come out to hug you" (or strangle if you prefer). OH CH2OH. H H HO H H. OH H OH O H CH2OH. O. new stereocenter. OH. H. O. A 3-D molecule is "projected" as a flat molecule. H. Converting a Fischer to a Ring Form. Chain and Ring Forms of Sugars Sugars can exist as mixtures of their open chain and ring forms.. H HO H H. Note - this sheet is not meant to be comprehensive. Your course may provide additional material, or may not cover some of the reactions shown here. Your course instructor is the final authority.. masterorganicchemistry.com. H OH. Haworth Projections 6. CH2OH O H H OH. 5. H 4. OH. 3. H. 2. OH. α−D-Glucose (Haworth). H OH H 1. OH. The Haworth projection makes it more clear which groups are "up" and "down" in a cyclic sugar. The ring isn't "actually" flat; it's really in a chair conformation.. 4. HO HO. 6. 5. HO 2. 3. H. H OH. 1. H H. OH OH. H. ROH, H. HO. HO HO. H H. OR OH. H. H. OH. α−D-Glucose (Chair). H OH HO. HO HO. Omissions, Mistakes, Suggestions? [email protected] This sheet copyright 2015, James A. Ashenhurst masterorganicchemistry.com.
(13) "Master Organic Chemistry". Introduction to Amines Important nitrogen-containing functional groups. Basicity of amines (cont'd). Primary amine. N H. N. Secondary amine. Tertiary Amine. (1° amine). (2° amine). R. O NH2. N. N H A secondary amide. sp hybridized least basic. R. R. Acidity of amine derivatives (ammonium salts) The weaker the base, the stronger the conjugate acid. NH3. N. O. N H2 less acidic. The nitrogen of amides is considerably less basic than that of amines due to the contribution of the right-hand resonance form. R. NH2. less acidic. more acidic. N H more acidic. R. R. N. H. R. imine "Aldimine". NR2. N. R. OH. R. imine "Ketimine". enamine. N. R. R. oxime. R. hydrazone. "exotic" variations of imines, less frequently seen. 1. Resonance NH2. NH2. CH3–I. resonance stabilization less basic. N. NH2. N. more basic. NH2. key resonance form. N. N. less basic. more basic. N. NO2 less basic. N. An azide "R–N3 ". R. H. Note: under acidic conditions, the conjugate acid of the imine is formed ("the iminium ion") and this is what is actually reduced here. R. H. R'. N R. R'. O + H2O. H. R. Imine. H2N R. R'. N R. H. Ketone. N H H. N. R. + H2O. Imine. Enamines are good nucleophiles, due to the importance of this resonance form: N. O. R'. + H2O. N. R. R. R enamine. This carbon is nucleophilic, and will react with electrophiles such as alkyl halides, etc.. N. NH2NH2. NH2. The Hoffmann elimination of ammonium salts. (hydrazine). Ag2O. N. The less substituted alkene is formed here.. heat. Non-Zaitsev product The Hofmann rearrangement:. NH2. Pd/C H2. Nitro groups can be reduced to amines with Pd-C/H2, or Zn/HCl, or Sn/HCl. O R. NaOH Br2. NH2. R. NH2. + CO2 These reactions both proceed through an isocyanate intermediate. The Curtius Rearrangement Nitriles can also be reduced NH2 with Pd-C or Pt-C and H2. LiAlH4. Both nitriles and azides can be prepared through SN2 reactions with alkyl halides. O. O R. heat N3. R. R–OH. N H. R O. R + N2. NH2. can also use LiAlH4. C. O. isocyanate. Formation of diazonium salts. N Pd-C H2. N. NH2. NaNO2 H. N. N. For reactions of diazonium salts, see the summary sheet on aromatic chemistry. diazonium salt. Reduction of amides. Electron withdrawing groups will make the nitrogen less electron-rich, and therefore more stable (less basic). >. N. R'. O. (phthalimide). Reduction of azides. Other examples of electron donors - OH, OR, CH3, NR2. N. H. Reduction of nitriles N. H. H. HN. NaCNBH3 R. primary amine O Alkylation of phthalimide with alkyl halides stops after one alkylation. The phthalimide is then removed with hydrazine (NH2NH2) to give the free amine.. C. >. H2N. R. O. 2. Electron donating and withdrawing groups Electron donating groups will make the nitrogen more electron rich, and therefore more unstable (more basic). N. NaCNBH3 is sodium cyanoborohydride, a reducing agent. NaBH(OAc)3 is also sometimes used. R'. Formation of enamines When ketones (or aldehydes) are treated with a secondary amine and acid, an enamine is formed. This is also a condensation reaction.. N. O. NO2. R. Imine. Aldehyde. Gabriel synthesis - a way of making primary amines. NH2. no resonance stabilization more basic. R. doesn't stop after just one reaction. Goes on to form ammonium salt.. Br. H. R. H. Reduction of nitro groups. O NH2. resonance stabilization less basic. R'. R'. HN. NaCNBH3. Formation of imines. Alkylation of amines with alkyl halides is not a good way of making amines; it will lead to ammonium salts. Basicity of amines. no resonance stabilization more basic. R. O. N. Factors that affect the basicity of amines The more stable the lone pair, the less basic it will be. Examples of factors that stabilize the lone pair are 1) resonance 2) electron donating/withdrawing groups, and 3) orbitals. NH2. R. R'. When ketones or aldehydes are treated with a primary amine, imines are formed. Mild acid can catalyze this reaction. The byproduct is one equivalent of water, so this is a condensation reaction. Imines can be hydrolyzed back to the aldehyde/ketone by adding water.. Synthesis of amines. NR2. N. Imine. Ketone. Imines are the nitrogen-containing analogues of ketones and aldehydes. Enamines are the nitrogen-containing analogues of enols R. R'. H. H2N. R. Imines and Enamines. N. H. O. NH3. A tertiary amide. O NH2. H2N. Aldehyde. Important to note: Amides have a significant resonance form. R. O. sp2 hybridized less basic. O. R. A primary amide. A very versatile method for amine synthesis involves making the imine, and then reducing it to the amine. Primary or secondary amines can be used; often, imine formation and reduction is done under slightly acidic conditions.. HC N N H sp3 hybridized more basic. Quaternary ammonium technically not an amine not a base (no lone pair). Amides An amide has a carbonyl group adjacent to an amine nitrogen O. Reductive amination. The more s-character the orbital, the more stable the nitrogen lone pair will be (and therefore less basic) N. (3° amine). Synthesis of amines (cont'd). 3. Orbitals. An amine is classifed as primary, secondary, or tertiary depending on how many carbons the nitrogen is attached to NH2. Note - this sheet is not meant to be comprehensive. Your course may provide additional material, or may not cover some of the reactions shown here. Your course instructor is the final authority.. ←. Amines. masterorganicchemistry.com 2015 Version. O N O. O. LiAlH4 NH2. NH2. Depending on the type of amide (primary, secondary, tertiary) the corresponding amine will be formed. Omissions, Mistakes, Suggestions? [email protected] This sheet copyright 2015, James A. Ashenhurst masterorganicchemistry.com.
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