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Organic Chem II final Exam Review

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by: MelLem

Organic Chem II final Exam Review CHEM 225

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Cumulative to Orgo I. 2 semesters worth. 200 reactions, memorize forwards and back. ACS examination from American Chemistry Society.
Organic chemistry 2
Professor gurney
Study Guide
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Samuel Croteau

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This 52 page Study Guide was uploaded by MelLem on Sunday May 8, 2016. The Study Guide belongs to CHEM 225 at Simmons College taught by Professor gurney in Spring 2016. Since its upload, it has received 34 views. For similar materials see Organic chemistry 2 in Chemistry at Simmons College.

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Date Created: 05/08/16
Unit  1  Carbonyl  Chemistry     Lecture  2  -­‐  Acetal  Mechanism  and  Hydrolysis       20.5  Oxygen  Nucleophiles   Hydrate  Formation:   • When  an  aldehyde  or  ketone  is  treated  with  water,  the  carbonyl  can  be  converted  into  a   hydrate.         • Equilibrium  will  generally  favor  the  carbonyl  group,  unless  it  is  the  case  of  a  simple  aldehyde,  in   that  case  the  hydrate  is  favored.   • A  simple  aldehyde  my  be  Formaldehyde     • The  rate  of  reaction  is  relatively  slow  under  neutral  conditions.   • When  under  acidic  a  and  basic  conditions,  the  rate  of  the  reaction  is  increased.   • Basic  Condition  Steps:   o 1  step,  a  hydroxide  ion  rather  than  water  acts  as  the  nucleophile   o in  the  second  step,  the  tetrahedral  intermediate  is  protonated  with  water  which   regenerates  a  hydroxide  ion.   • Acidic  Condition  Steps:   o The  carbonyl  group  is  first  protonated,  this  generates  a  positively  charged  intermediate   that  is  extremely  electrophilic.   o This  intermediate  is  then  attacked  by  water    to  form  a  tetrahedral  intermediate  which  is   deprotonated  to  give  the  product.     Acetal  formation   • When  an  alcohol  attacks  an  aldehyde  or  ketone       (The  hemiacetal  is  the  intermediate,  the  hemiacetal  is  not  as  stable  as  the  acetal)   • In  acidic  conditions,  an  aldehyde  or  ketone  will  react  with  two  molecules  of  alcohol  to  form  the   acetal.   • The  [H+]  shows  that  the  acid  is  a  catalyst  (  [H3O+]  can  be  used  as  well  when  a  proton  source  is   present  to  keep  the  a  constant  across  all  boards).     Common  Acids  used  include   p-­‐toluenesulfonic  Acid       Sulfuric  Acid         • In  the  presence  of  an  acid,  the  carbonyl  is  protonated,  this  makes  the  carbon  atom  even  more   electrophilic.                   Acetal  Formation  -­‐  Mechanism  Analysis:   1. The  carbonyl  is  protonated  in  the  presence  of  an  acid   2. The  protonated  carbonyl  is  a  very  powerful  electrophile  and  is  attacked  by  a  molecule  of   alcohol  (ROH)  to  form  a  tetrahedral  intermediate  that  has  a  positive  charge.   3. The  tetrahedral  intermediate  is  deprotonated  by  a  weak  base,  which  is  likely  to  be  a  molecule  of   alcohol  present  in  solution     1. Proton  Transfer   2. Nucleophilic  Attack   3. Proton  Transfer     • Form  many  simple  aldehydes,  the  equilibrium  favors  the  formation  of  the  acetal.   • However  –  for  ketones,  the  equilibrium  favors  reactants  rather  than  products.     Acetals  as  Protecting  Groups     • Acetal  formation  is  a  reversible  process  that  cen  be  controlled  by  carefully  choosing  reagents   and  conditions   • Acetal  formation  is  favored  by  the  removal    or  water.               Stable  Hemiacetals   • In  most  cases,  it  is  very  difficult  to  isolate  the  intermediate  hemiacetal         (Favored  when  water  is  removed)   • The  hemiacetal  is  not  favored  whether  or  not  the  water  is  removed     Hydrolysis  Of  Acetals   • Acetals,  imines  and  enamines  can  be  converted  back  to  ketones  by  treatments  with  excess   water  under  acid  catalyzed  conditions.   • All  of  the  below  reactions  are  called  Hydrolysis    reactions,  this  is  because  in  each  case  bonds   are  cleaved  by  treatement  with  water.   • The  reactions  are  essentially  the  reverse  reaction  of  how  to  form  acetals.     Steps:   • Begin  by  drawing  al  of  the  intermediates  without  any  curved  arrows   • After  drawing  the  intermediates  by  working  backwards,  work  forwards  and  add  any  curved   arrows.   Unit 1 – Carbonyl Chemistry Sugars – Carbohydrates 24.1 Introduction to Carbohydrates  Carbohydrates are commonly referred to as sugars and are abundant in nature.  Carbohydrates are now understood to be poly-hydroxy aldehydes or ketones. (Multiple –OH groups w/ ketones and aldehydes)  Monosaccharides – Simple sugars –ex. glucose, fructose  Disaccharides – 2 Units of monosaccharides that are chemically linked together –ex. sucrose.  Oligosaccharides – in between mono- and di- 3-8 units of monosaccharides.  Polysaccharides – greater than 8 monosaccharides units – ex. Starch, glycogen, and cellulose.  Monosaccharides are further divided into different divisions o Aldoses – contains aldehydes (Aldehydes are only at the top of the molecule due to the H-C=O bond. o Ketoses – contains ketones (center of molecule, can be constitutional isomers)  Based on the number of carbons in monosaccharides o 3 – triose o 4 – tetrose o 5 – pentose o 6 – hexose o 7 – heptose (Aldo sugar – pent-ose) Hydroxy groups go to the left and the right If the ANOMERIC carbon, the last carbon in the projection that is NOT the CH2OH, it determines whether or not it is a D or L sugar.  Hydroxyl group on left = L sugar  Hydroxyl group on Right = D sugar  D sugars are the only sugars that occur naturally in the environement 24.2 Classification of Monosaccharides Aldoses Vs. Ketoses  Simple sugars are called monosaccharides  Complex sugars such as disaccharides and polysaccharides are formed by joining monosaccharides together through chemical linkages  Monosaccharides generally contain multiple chirality centers, Fischer projections are used to indicate the configuration.  Glucose and fructose are examples of simple sugars.  The suffix –ose is used to signify carbohydrate.  Monosaccharides are known and generally classified as an aldose or ketose o Aldoses contain an aldehyde at the top (only) o Ketoses contain a ketone in the center, can be constitutional isomers  Aldoses and ketoses are based off the # of carbon atoms in the molecules as well. o This is done by inserting tri-, tetr-, pent-, ect. Before the – ose. 24.3 Configuration of Aldoses  Aldotetroses o Have 2 chirality centers and there are only four possible aldotetroses  Aldopentoses o Have 3 chirality centers o 8 possible aldopentoses (4 are enantiomers – 4 are L sugars)  Aldohexoses o Have 4 chirality centers o There are 8 D-sugars in this category o D-Glucose is the most common and most important. 24.4 Configuration of Ketoses  Have one less chirality center than aldoses  Naming is similar, Keto replaces aldo 24.5 Cyclic Structures of Monosaccharides  6 membered rings are relatively strain free o equilibrium favors the formation of the cyclic hemi-acetal. PYRANOSE FORMS OF MONOSACCHARIDES  A compound containing both an OH group and an aldehyde group moiety, it will undergo an intramolecular process to form a cyclic hemi-acetal  In the cyclic form – the ring is called a pyranose ring  Pyran – A simple compound that processes a six membered ring with an oxygen atom incorporated in the ring.  In the Haworth - The C1 position is called the anomeric carbon, and the sterisomers are called anomers.  In the (alpha) anomer, the hydroxyl group at the anomeric position is trans to the CH2OH.  In the (Beta) anomer, the hydroxyl group at the anomeric carbon is cis to the CH2OH.  Mutorotation: o Commonly used to describe the fact that A & B (alpha and Beta) anomers can equilibrate via the open chain form. o Occurs more rapidly in the presence of a catalytic acid or base.  3-D Representations of Pyranose Rings o A cyclic form of D-Glucose will spend the majority of its time in a chair conformation.  Chair Conformation o Convention is to place the Oxygen in the upper-rear-right. o The next carbon on the right in the front is the anomeric carbon, this is where the OH that determines the D or L of sugar is placed. If it is on the right, the OH is placed down, if it is on the left, it is placed up on the Haworth projection, from here the OH groups can be labeled Up, Down, and put onto a chair conformation. o After the anomeric carbon has its OH placed, C2’s OH group is placed on the carbon to the left of the anomeric carbon, it goes this way around the ring until the CH2OH is added in C5. o If the sugar is L, the CH2OH is placed down. o If the sugar is D, the CH2OH is placed up. o In regards to cis and trans, it does not always have to be OH CH2OH up to be cis, it can be down in both instances. (Beta cis) (alpha trans)  Tollens Test o In the tollens test, you are oxidizing the sugar from 2-3. Sugars – Reactions  Reduction o Aldehydes in aldoses can be reduced to form alcohols  Oxidation o Reducing Sugars are able to be oxidized. o There is two types of oxidation, a Mild and a Strong. o Mild  Br2 / H2O (Tollens Reagent, Benedicts) o Strong  HNO3 / Heat (Nitric Acid)  Primary alcohol AND aldehyde turn into a carboxylic acid.  This is known as a diacid.  Reactions at Hydroxyl Groups o Formation of Ethers  Excess CH3I / Ag2O (Methyl Iodide)  All Hydroxyl groups gain a Methyl group (OH  OCH3) o Cyclic Acetals  Under acidic conditions  H2O as by-product  Both diols that are next to one another must be cis for this to work.  It cannot occur if it is trans. Sugars – Disaccharides  Unit 2 – Aromatic Chemistry CHEM 225 Organic Chemistry II Lecture 8 Summary Aromatic Spectroscopy Aromatic Reactions Continued Aromatic Spectroscopy  HNMR – o Aromatic Hydrogen – 6-8 ppm (7-9 ppm in some cases) o Benzylic H – 2-3 ppm  CNMR o Carbon signal shows at 100-150 ppm  Shows where the sp2 hybridized carbon atoms show o Signals and patterns  2 signals = para  3 signals = ortho  IR o Sp3 hybridized – 2900 -300 cm-1 o Sp2 hybridized – 3100 cm-1 o Aromatics generally show right above 300 cm-1  If they are “straddling” or going over it is likely to be an aromatic. o Aromatic and Alkyl Halides: 900-675 cm-1 o AR: 2000 cm-1 o AR C-H :3050 cm-1 Reactions Continued  5 Reactions should be memorized for this lecture o Halogenation o Nitration o Sulfonation o Chlorination o Friedel-Craft Alkylation o Friedel-Craft Acylation  Electrophilic Substitution o Halogenation o First you must recall an orgo I synthesis of vicinal dihalides from alkenes via bromine o Instead of adding bromine across the double bond like in dihalide synthesis, you substitute a hydrogen on the aromatic ring for a bromine atom using a Lewis acid catalyst. o Reagents  Br2 / AlBr3   Electrophilic Substitution o Nitration o Substitute the Hydrogen on the benzene with a NO2 group (nitro group) o Reagents  HNO3 / H2SO4  o Reduction of Nitro Groups to Amino Groups  Nitro group on benzene is reduced to NH2  Change nitro group to NH2 when treated with Fe or Zn metal and HCL. o Reagents  Fe (metal) or Zn (metal) / HCL   Electrophilic Substitution o Friedel-Craft Alkylation o Limitations in Friedel-Craft Alkylation  Carbocation rearrangements CAN and WILL occur  Can alkylate the ring multiple times. The product can be more reactive than the starting material. o Reagents  Alkyl Halide / AlCl3   Electrophilic Substitution o Friedel-Craft Acylation o Ketones with an R group attached are able to react in this way o Reagents  Alcyl group / AlCl3 o If the carbocation can rearrange, it will. o Clemmensen Reduction  Zn [Hg] / HCL Heat   Reduces the ketone in the alcyl group after Friedel craft Acylation occurs Orgo 225 Lecture 13 21.12 Preparation and Reactions of Amides Preparation of amides  Amides can be prepared from any of the carboxylic acid derivatives  Most efficiently prepared from acid chlorides Reactions Acid Catalyzed Hydrolysis of Amides Amides can be hydrolyzed to give carboxylic acids Base catalyzed Hydrolysis of Amides Amides can also be hydrolyzed when heated in basic aqueous conditions (this process is very slow) Reduction of Amides When treated with LAH, amides are converted to amides  The carbonyl group is completely removed 21.13 Preparation and Reactions of Nitriles Preparation of nitriles via SN2 reaction Nitriles can be prepared by treating an alkyl halide with a cyanide ion Preparation of nitriles from amides  Nitriles can be prepared via dehydration of an amide Hydrolysis of nitriles Occurs in aqueous acid conditions Nitriles are hydrolyzed to amides then further hydrolyzed to carboxylic acids Reactions between nitriles and Grignard reagents A ketone is obtained when a nitrile is treated with a Grignard reagent Grignard attacks the nitrile – the resulting anion is treated with aqueous acid to give an imine then hydrolyzed to a ketone Reduction of nitriles Nitriles are reduced to amines when treated with LAH 21.14 Synthesis Strategies C-C bond forming reactions c-c bond forming reactions in which the F.G remains the same: 1) Xs RMgBr 2) H2O R2CuLi 1) RMgBr 2) H3O+ In class lecture 13 summary: o Nucleophiles (Nu) – frequently negative, but sometimes not. o Pyridine is not a nucleophile because it wont attack an electrophilic carbon due to sterics since N is in the Ring.  New Rxn: o Hydrolysis of amides  Saponification – hydrolysis of amides in basic conditions  1) NaOH 2) H3O+  Under Acidic Conditions –  H3O+ o Reduction of Amide  LAH  Knocks out the carbonyl group. o Nitriles SN2 rxn  NaCN o Dehydration  SOCl2  Gives you the product + H2O o Reduction with LAH  From oxidation level 3  1 because LAH is a strong reducer  Reduces nitriles down to amines Carboxylic acids are the only acid derivative that don’t get attacked at the carbonyl.  Anytime you start with a carboxylic acids, react with SOCl2 to make an acid chloride  It will never be wrong to go to an acid chloride then down to a lower reactivity. LIPIDS 26.1 Introduction to Lipids and Lipid Chemistry Lipids – defined by the physical property, solubility. Complex lipids – lipids that are readily able to undergo hydrolysis in aqueous acid Lipids are either: Complex Lipids (can be hydrolyzed) o Waxes o Phospholipids o Triglycerides Simple Lipids (cannot be hydrolyzed) o Steroids o Prostaglandins o Terpenes All three of the complex lipids contain ester moieties – rendering them easily hydrolyzed. They also contain long hydro carbon chains – making them soluble in organic solvents. 26.3 Triglycerides o Triglycerides are triesters formed from glycerol and 3 long chain carboxylic acids (commonly known as fatty acids) o A triglyceride is said to contain 3 fatty acid residues o (They are used by mammals and plants for longer term energy storage) Lecture 14 In Class summary Lipids – be able to distinguish between saturated and unsaturated fats, soaps, steroids, waxes, phospholipids, recognize fat vs H2O soluble vitamins. Be able to draw a typical triglyceride Know how to make a soap, and how soap works. Know triacyl glycerides Hydrolysis under basic and acidic conditions: Under basic conditions = saponification Know how to draw amino acids with the side chain given, be able to classify them as nonpolar, polar neutral, polar basic, or polar acidic. PI – isoelectric point  when the zwitter ion exists (neutral overall – but has charges)  Be able to draw an amino acid in varying pH’s  At a lower pH, the N has a + charge and is NH3  Neutral but still charged – N has a + charge, CO- charge  At pH higher than the PI (NH2) and CO has a – charge CHEM 225 Organic Chemistry II UNIT III – Carboxylic Acids and Carboxylic Acid Derivatives Lectures 11-12 Chapter 21 – carboxylic acids and their derivatives 21.1 – Introduction to carboxylic acids - Carboxylic Acids – compounds with a R-COOH moiety.  These compounds are abundant in nature and are responsible for some familiar odors. o CH3COOH – acetic Acid – responsible for the smell of vinegar  Found in a wide range of pharmaceutical products that are used to treat a variety of conditions. o For example – acetylsalicylic acid is found in aspirin.  Vinyl acetate is a derivative of acetic acid, therefore said to be a carboxylic acid derivative 21.2 – Nomenclature of Carboxylic Acids -Monocarboxylic Acids  Contain only one carboxylic acid moiety.  Named with the suffic -–ic acid.  The parent is the longest chain that includes the carbon atom of the carboxylic acid moiety.  When a carboxylic acid moiety is connected to a ring, the compound will be named as an alkane carboxylic acid. Common carboxylic acids to memorize  Formic acid  Acetic Acid  Propionic acid  Butyric acid  Benzoic acid -Diacids  Compounds containing 2 carboxylic acid moieties  Named with the suffix –dioic acid 21.3 – Structure and Properties of –COOH -Structure  Carbon atom of the carboxylic acid moiety is sp2 hybridized and exhibits trigonal planar geometry.  Bond angles are ~120 degrees  Carboxylic acids can form 2 hydrogen bonding interactions allowing molecules to associate with each other in pairs.  The hydrogen bonding interactions explain why carboxylic acids have high boiling points. -Acidity of Carboxylic Acids  Carboxylic acids exhibit mildly acidic protons. Treatment of a carboxylic acid with a strong base yields a carboxylate salt.  Carboxylate salts are ionic, therefore more soluble in water than their corresponding carboxylic acids.  Carboxylate ions are named by replacing the suffix –ic acid with the suffix -ate.  When dissolved in H2O an equilibrium is established in which both the carboxylic acid and the carboxylate ion are both present. In most cases, the equilibrium favors the carboxylic acid 21.4 Preparation of Carboxylic Acids Review of carboxylic acid preparation (Table 21.1 in Klein) 1. Oxidative Cleavage of Alkynes a. Reagents  1) O3 2) H2O b. Cleaves the triple bond and forms 2 carboxylic acids 2. Oxidation of Primary Alcohols a. Reagents  Na2Cr2O7 / H2SO4, H2O b. Other strong oxidizing agents can be used as well c. Oxidizes from Oxidation level of [1] to [3] 3. Oxidation of Alkyl benzenes a. Reagents  Na2Cr2O7 / H2SO4, H2O b. Any alkyl group on an aromatic ring WILL be completely oxidized ti give benzoic acid (benzylic position much have atleast 1 H proton) Hydrolysis of Nitriles  When treated with aqueous acid, a nitrile (a compound with a cyano group) can be converted to a carboxylic acic.  This process of called Hydrolysis  It is a 2 step RXN for converting an alkyl halide into a carboxylic acid. Carboxylation of Grignard Reagents  Carboxylic acids can also be prepared by treating a Grignard reagent with CO2. 21.5 – Reactions of Carboxylic Acids  Carboxylic acids are reduced to alcohols upon treatment with LAH (Lithium Aluminum hydride) They can also be reduced with Borane (BH3)  Borane reacts selectively with the carboxylic acid moiety in the presence of another carbonyl group.  BH3 * TFH  Primary alcohol. 21.7 Introduction to carboxylic acid derivatives Classes of carboxylic acid derivatives 1. Reduction – those that change the oxidation state of the compound 2. No [o] level change – those that do not change the oxidation state of the compound.  Replacement of the OH groups with a different group (Z – which is a heteroatom) does not involve a change in the oxidation state if Z is a heteroatom (Cl, O, N, F, ect. Anything but C and H)  Compounds of this type are carboxylic acid derivatives Types of Carboxylic Acid derivatives 1. Acid Halides 2. Acid Anhydride 3. Ester 4. Amide 5. Nitrile ( 1 is the most reactive, 5 being least reactive) Carboxylic acid derivatives in Nature  Acid halides and anhydrides DO NOT occur (commonly) naturally in nature due to their high reactivity.  In contrast, Esters, are more stable and are abundant in nature.  Amides are abundant in living organisms (proteins are comprised of repeating amide linkages) Naming Acid Halides  Acid halides are named as derivatives of carboxylic acids by replacing the suffix –ic acid with the suffix –yl halide.  When an acid halide moiety is connected to a ring, the suffic “carboxylic acid” is replaced with “carbonyl Halide” Naming Anhydrides  Anhydrides are named as derivatives of carboxylic acids by replacing the suffix –acid with –anhydride  Unsymmetrical anhydrides are prepared from 2 different carboxylic acids o They are named by indicating both acid alphabetically followed by the suffix anhydride Naming Esters  Esters are named as derivatives of carboxylic acids by replacing the suffix –oic acid with the suffix –ate.  What is attached to the C-O- is named first (the R group attached to O). CHEM 225 Organic Chemistry II Chapter 22 – Alpha Carbon Chemistry Enols and Enolates 22.1 Introduction to alpha carbon chemistry – enols and enolates  For compounds containing a carbonyl group, greek letters are used to describe the proximity of each carbon atom to the carbonyl group.  The carbonyl itself does not have a greek letter associated with it.  1 away is known as alpha  2 away is known as beta  3 away is known as gamma  The hydrogen atoms at the positions also adopt the greek letter naming for example, the alpha carbon has alpha protons.  This chapter will explore reactions occurring at the alpha position. Enols  In the presence of a catalytic acid or base, a ketone will exist in equilibrium with an enol.  Tautomers – rapidly interconverting constitutional isomers that differ from each other in the placement of a proton and the position of a double bond.  Tautomers are not resonance structures  In general, the position of equilibrium will significantly favor the ketone.  In some cases, the tautomer is stabilized and exhibits a more substantial presence at equilibrium.  In the case of phenol, it has aromaticity and is more stable than the ketone form.  Tauomerization is catalyzed by trace amounts of either acid or base. Enolates  When treated with a strong base, the alpha proton at the alpha position of a ketone is deprotonated to give a resonance stabilized intermediate called an enolate.  Called ambident nucleophiles because they possess two nucleophilic sites, each of which can attach the electrophile.  When oxygen attacks the electrophile, it is known as an O Attack  When the Carbon attacks the electrophile, it is known as a C attack  Ca attack is more common then O-attack.  Enolates are more useful than enols because 1. Enolates possess a full negative charge and are therefore more reactive 2. Enolates can be stored for a short period of time, enols cannot be isolated nor stored.  The vast majority of the reactions in this chapter occur via enolate intermediates.  Alpha protons of an aldehyde or ketone are acidic Choosing base for enolate formation  Aldehydes and ketones generally have a pka of 16-20  When an alkoxide ion is used as the base, an equilibrium is established in which the alkoxide ion and enolate ion are both present.  In contrast, many other bases such as sodium hydride can irreversibly and completely convert an aldehyde to an enolate  When sodium hydride is used as a base, hydrogen gas is formed and bubbled out of solution as all of the aldehyde molecules are converted to enolate ions. 22.2 Alpha Halogenation of Enols and Enolates  Alpha halogenation in acidic conditions o Under acid catalyzed conditions, ketones and aldehydes will under go halogenation at the alpha position. o When an unsymmetrical ketone is used, bromination occurs primarily at the more substituted side of the ketone  The halogenated product can undergo elimination when treated with a base Alpha bromination of –COOH: Hell-Volhard Zelinski Reaction  Regular alpha bromination occurs with aldehydes and ketones, but not with –COOH, esters or amides.  This is because they are not readily converted to their corresponding enols.  Carboxylic acids undergo bromination when treated with 1. Br2, PBr3 2. H2O CHEM  225   Organic  Chemistry  II     Lecture  19  &  Lecture  20  In  Class  Summary       Lecture  19  –  Enols  and  Enolates     • Enolates  and  enols  can  form  c-­‐c  bonds     • The  carbonyl  species  act  as  both  the  electrophil  and  nucleophile.   o They  must  have  alpha  protons  available.     • Enol  –  Neutral  at  equilibrium  with  its  keto  tautomer   • Enolate  –  negative  charge,  loses  the  proton   o Keto  +  Strong  base  =  enolate   • When  you  have  a  choice  of  alpha  protons,  you  can  have  a  kinetic  or  a   thermodynamic  enolate   o Kinetic  Enolate  –  occurs  on  the  less  substituted  side,  less  stable  and   easiest  to  grab.   o Thermodynamic  Enolate  –  Most  stable,  occurs  on  the  more   substituted  side,  given  time  to  equilibrate     Lecture  20  –  Aldol  Reactions  &  Claisen  Reactions       • Aldol     o Has  a  beta  hydroxyl   o The  starting  materials  are  and  aldehyde  with  an  alpha  proton   o Gives  you  an  aldehyde-­‐alcohol  product   • Mixed  Aldols   o Gives  a  variety  of  products.   o Also  called  crossed  aldols   o Has  2  different  starting  materials   • Claisen  Reactions   o Starts  with  an  ester   o Carbonyl  is  the  E+  and  the  Nu-­‐  is  the  alpha  proton   o Similar  to  the  acyl  substitution       Aldol  and  Claisen   • Important  in  synthetic  chemistry  because  they’re  c-­‐c  bond  forming  reactions   Chapter 23 Amines Lecture 18 Chem 225 23.1 Introduction to Amines Classification of Amines:  Amines are derivatives of ammonia, in which one or more of the protons has been  replaced with alkyl or aryl groups.  Amines are classified as primary, secondary, and tertiary, this is in regards to how many  R groups are attached to the Nitorgen atom.  Amines are abundant in nature, naturally occurring amines isolated from plants are called alkaloids.  Many pharmaceuticals also contain amine moieties. Reactivity of Amines:  The nitrogen atom of an amine possess a lone pair that represents a region of high  electron density. o The presence of this lone pair is responsible for most of the reactions exhibited by amines.  o Specifically, the lone pair can function as a base or nucleophile. 23.2 Nomenclature of Amines Nomenclature of Primary Amines:  A primary amine is a compound containing an NH2 group connected to an alkyl group.  If the R group is generally simple, they tend to be named as alkyl amines.  Ex: (Draw the Structures) Ethyl Amine                                  Isopropyl Amine                              Cyclohexyl Amine  Primary amines that contain more complex alkyl groups are generally named as  alkanamines, with the suffix –amine.  If there are other functional groups present (of higher priority), the amine is often named  as a substituent (Amino) Ex:  4­aminobutanol Para­animobenzoic acid  Aromatic Amines are also called aryl amines – generally named as derivatives of  aniline. Ex: Aniline  Meta­chloroaniline Nomenclature of Secondary and Tertiary Amines:  Can also be named as alkyl amines or as alkanamines  Naming will depend on the complexity of the molecule Ex: (Draw the Structures) Ethyl methyl propyl amine Diethyl amine  Complex structures are named as follows: (s) 2,2­dichloro­N­Ethyl­N­Methyl­3­hexanamine   The N represents that the substituent is attached to the Nitrogen rather than a carbon atom on the structure. 23.3 Properties of Amines Geometry:  The nitrogen atom of an amine is typically sp3 hybridized with the lone pair occupying  an sp3 hybridized orbital.  All 4 orbitals are arranged in the shape that approximates a tetrahedron with bond angles  of 108 degrees.  Amines containing three different alkyl groups are chiral compounds. o Compounds of this type are generally not optically active at room temperature  because pyramidal inversion occurs rapidly creating racemic mixtures. Colligative Properties  Amines exhibit solubility trends that are similar to the trends exhibited by alcohols. o Amines with fewer than 5 carbons per amino group will typically be soluble in  water.   Primary and secondary amines can form intermolecular Hydrogen bonds and typically  have higher Boiling Points than alkanes but lower boiling points than alcohols.  The boiling points increase as a function of their capacity to form hydrogen bonds. Ex: Propane ­42C                                      Ethyl Amine 17C                                      Ethanol 78C  Primary Amines will typically exhibit higher boiling points than tertiary amines. Ex:  Propylamine 50C                     Ethyl methyl Amine 34C                     Trimethyl amine 3C Basicity of Amines:  One of the most important properties of amines is their basicity.  Amines are generally stronger bases than alcohols or ethers, and they can effectively be  protonated by weak acids. Delocalization Effects:  The ammonium ions of most alkyl amines are characterized by a PKa value between 10­ 11, but aryl amines are very different.  Ammonium ions of aryl amines are more acidic than the ammonium ions of alkyl amines. o Aryl amines are less basic.   The lone pair occupies a p orbital and is delocalized by the aromatic system. o The resonance stabilization is lost if the lone pair is protonated.  EDG – such as methoxy will slightly increase the basicity of aryl amines.  EWG – such as nitro will significantly decrease the basicity of aryl amines. Amines at Physiological pH:  An amine moiety also exists primarily as a charged ammonium ion at physiological pH.  +  ­­­­­     + R3N + H R3NH <­­ 23.4 Preparation of Amines – A Review  Preparing an amine from an alkyl halide:  Amines can be prepared from alkyl halides in a 2 step process in which the alkyl halide is converted to a nitrile, which then undergoes reduction. 1) Cyanide ion functions as a nucleophile, displacing the halide leaving group.  2) involves reduction of the resulting nitrile. This reduction can be accomplished with a strong  reducing agent such as LAH.  Preparing an Amine from carboxylic acids CH3 (CH2)4 COOH ­­­ 1) SOCl2 / 2) H2O  CH3(CH2)4 CONH2  ­­­ 1) Xs LAH / 2) H2O  CH3(CH2)5 NH2 1. The carboxylic acid is first converted into an amide, which is then reduced with a strong  reducing agent such as LAH to give the amine. Preparing aniline and its derivatives from Benzene: Benzen + HNO3/ H2SO4  Nitro Benzene  Nitrobenzene +  H2/Pt or Fe, Zn, Sn, or SnCl2 / H30+  Aniline  23.5 Preparation of amines Via substitution Reactions Alkylation of Ammonia:  Ammonia is a very good nucleophile and will readily undergo alkylation when treated  with alkyl halides.  As a primary amine is formed, it can further undergo alkylation to produce a secondary  amine which can then undergo even further alkylation to produce a tertiary amine.  The tertiary amine is able to undergo even further alkylation to produce a quaternary  ammonium salt.  o If the quaternary ammonium salt is the desired product then an excess of the alkyl halide is used and ammonium is said to undergo exhaustive alkylation.  Monoalkylation is difficult to achieve because each successive alkylation renders the  nitrogen atom more nucleophilic. The Azide Synthesis:  A better method for preparing primary amines than alkylation of ammonia because it  avoids the formation of secondary and tertiary amines. CX + NAN3  CN3 CN3 + H2/Pt or 1) LAH / 2) H2O  CNH2 23.12 Nitrogen Heterocycles  A heterocycle is a ring that contains atoms of more than one element.  Common organic heterocycles are comprised of carbon and either, nitrogen, oxygen or  sulfur. Pyrrole and Imidazole:  Pyrrole­ o 5 membered aromatic ring containing one Nitrogen. o The lone pair participates in its aromaticity.  Imidazole –  o Similar to pyrrole, but has a second Nitrogen at the 3  position. o Hisamine, a imidazole is an important biological compound. Pyridine and Pyrimidine:  Pyridine –  o 6 membered aromatic ring containing 1 Nitrogen atom o The lone pair of the nitrogen occupies an sp2 hybridized orbital, as a result  pyridine is a stronger base than pyrrole.  Pyrimidine – o Similar to pyridine, but has an extra Nitrogen atom at the 3  position.  o Pyrimidine is less basic than Pyridine due to the inductive effects of the second  nitrogen.  CHEM 225 Organic Chemistry II Professor Richard Gurney Simmons College UNIT 1 – Carbonyl Chemistry : Chemistry of Aldehydes,  Ketones, and Carbohydrates Lecture 1 – Aldehydes & Ketones Reading from Klein Chapter 20 Sections: 20.1­20.4, 20.9, 20.10, 20.13   Introduction  Nomenclature  Nucleophilic Addition   Oxidation Reduction  Wittig Reagents and Reactions IMPORTANT: The following notes are in order according to the Simmons College CHEM 225  syllabus for reading, and lecture videos. Some portions of material is continued in different  sections and labeled according to section and chapter in the two books used during this unit of  the course. 20.1 Introduction to Aldehydes and Ketones Aldehyde: (RCHO) Ketone: (R C2)    Both aldehydes and ketones are similar in structure. Each contain a C = O, which is  called a carbonyl group.  Aldehydes and ketones are responsible for many flavors and smells that we experience. Ex. Vanillin – Responsible for the vanilla flavor  Many important biological compounds also exhibit carbonyl moiety. (Progesterone &  Testosterone, the female and male sex hormones.  Simple Aldehydes and Ketones are industrially important as well.  Formaldehyde Acetone  Compounds containing a carbonyl react with a large variety of nucleophiles,  affording a wide range of products.  Klein CH. 20.4 Introduction to Nucleophilic addition reactions  The electrophilicity of a carbonyl group derives from resonance as well as inductive effects. RESONANCE  One of the resonance structures shows carbon with a positive charge, this indicates that the carbon atom is deficient in electron density (delta positive)  The carbon atom is originally sp2, making it trigonal planar, but after the nucleophilic attack, the carbon becomes sp3 hybridized and then has a tetrahedral geometry. o In recognition of this geometric change, the resulting alkoxide ion is often called a tetrahedral intermediate. o In general, aldehydes are more reactive than ketons toward nucleophilic attack, this can be explained by both steric and electronic effects. Steric Effects: A ketone has 2 alkyl groups (one on either side of the carbonyl group) that contribute to steric hindrance in the transition state of a nucleophilc attack. In contrast, an aldehyde only has one alkyl group, so the transition state is less crowded and lower in energy. Electronic Effects:  We must recall that alkyl groups are electron donating – a ketone has 2 electron donating alkyl groups that can stabilize the delta + on the carbon atom of the carbonyl group. In contrast, aldehydes have only one electron donating group. Ketone: Has 2 Electron donating alkyl groups that stabilize the partial positive charge. Aldehydes: Only has 1 electron donating alkyl group to stabilize the partial positive charge.  The delta + of an aldehyde is less stabilized than a ketone. As a result, aldehydes are more electrophilic than ketones and therefore are more reactive. 20.3 Preparing Aldehydes and Ketones (summary of preparation methods and reagents) Summary of Aldehyde Preparation Summary of Ketone Preparation 20.2 Nomenclature  Recall that there are 4 discrete steps in naming organic compounds. 1. Identify and name the parent 2. Identify and name the substituents 3. Assign a locant to each substituent 4. Assemble the substituents alphabetically  Aldehydes and ketones may also be named using the same 4 step procedure  When naming the parent, the suffix – al indicates the presence of an aldehyde group. The suffix –one indicates the presence of a ketone.  When choosing the parent chain, identify the longest change that includes the carbon of the aldehydic group.  When numbering, the aldehydic carbon is assigned #1.  When chirality is present, S & R is necessary at the beginning of the name.  A cyclic compound containing an aldehyde group immediately adjacent to the ring is named a carbaldehyde. Ketone Nomenclature:  All steps are the same for ketones (not a carbaldehyde however)  Suffix – one  IUPAC recognizes the common names of many simple ketones, including:  Although it is barely used, IUPAC rules allow simple ketones to be name as “alkyl, alkyl ketones” Ex: 20.13 Spectroscopic analysis of aldehydes and ketones  Aldehydes and Ketones exhibit several characteristic signals in their IR & NNR Spectra. IR Signals: The carbonyl group produces a strong signal in an IR spectra around 1750 – 1720 cm-1. A conjugated carbonyl may have a lower wavelength however. Ring strain however has the opposite effect on a carbonyl group. Ring strain will increase where the IR signal appears. Aldehydes generally exhibit two signals C – H between 2700 – 2850 cm -1 and a C = O stretch. HNMR Signals:  The carbonyl itself does not create a signal, HNMR is commonly known as proton NMR.  Aldehydic protons generally produce signals around 10 ppm. CNMR Signals: The carbonyl of a ketone or aldehyde will generally produce a weak signal around 200 ppm. 20.4 Intro to nucleophilic addition reactions (continued & review) Resonance and induction play an important role. O is delta negative C is delta positive Carbon of the carbonyl is the electrophile Aldehydes are more reactive because the (C) delta positive end is less stabilized than that of a ketone which has two electron stabilizing alkyl groups. Grignard Reagent: The Grignard reagent itself provides for strongly basic conditions o This is because Grignard reagents are both strong nucleophiles and strong bases. o This reaction can not take place under acidic conditions because Grignard reagents are destroyed when presented with an acid. ** Grignard Reagents are very strong nucleophiles and will attack aldehydes and ketones to PRODUCE Alcohols. The Grignard reagent follows a general mechanism for the reaction between a nucleophile and a carbonyl group under basic conditions. The general mechanism has 2 steps. o Nucleophilic attack o Proton transfer NUCLEOPHILIC ADDITION UNDER BASIC CONDITIONS INSERT FROM BOOK Aldehydes and Ketones also react with a wide variety of other nucleophiles under acidic conditions. Under acidic conditions 1. The carbonyl is first protonated 2. Undergoes a nucleophilic attack (The steps appear in the opposite order when under acidic conditions) NUCLEOPHILIC ADDITION UNDER ACID CONDITIONS 20.2 pg 922 Mechanism  In acidic conditions, the protonating of the carbonyl group generate a very powerful electrophile The ability of the nucleophile being able to function as a leaving group is important. The Grignard reagent is a strong nucleophile, but does NOT act as a leaving group o As a result, the equilibrium greatly favors the products, the reaction only occurs one way. Halides: Halides however are good nucleophiles and good leaving groups.  When a halide functions as a nucleophile, the equilibrium favors the starting ketone. 20.10 Carbon Nucleophiles Grignard Reagents: When trated with a Grignard reagent, aldehydes and ketones are converted to alcohols, accompanied by a formation of a new C – C bond. Carbohydrin Formation: When trated with hydrogen cyanide (HCN), aldehydes and ketones are converted into Cyanohydrins, which are categorized by the presence of a cyano group and a hydroxyl group that are connected to the same atom Wittig Reaction (Vittig): Georg Wittig, a german chemist awarded the nobel prize in chemistry in 1979.  This reaction can be used to convert a ketone into an alkene by forming a new C –C bond at the location of the carbonyl moiety.  The Phosphorus (P) containing reagent is called a Phosphorane, it belongs to a larger class called ylides  Ylide: A compound with two oppositely charged atoms adjacent to one another. This phosphorane exhibits a negative charge on the carbon, and a positive charge on the phosphorus.  The wittig reagent is a carbanion and can attack the carbonyl group in the first step of the mechanism. o This generates an intermediate called a betaine.  Betaine – neutral compound with two oppositely charged atoms that are not adjacent to each other. Wittig reagent preparation Easily prepared by treating triphenylphosphaline with an alkyl halide followed by a strong base. Insert image from notes*** The mechanism for the formation of a wittig reagent involves an Sn2 reaction, is a then followed by a deprotonation with a strong base. 20.9 Hydrogen Nucleophiles  When reduced, aldehydes and ketones go to alcohols  When trated with a hydride reducing agent (LAH or NaBH4) aldehydes and ketones are reduced to alcohols. The reduction of ketones or aldehydes with hydride agents: Klein – Organic Chemistry Second Language, Second Semester Topics (OCSL 2S) Chapter 5 – Ketones and Aldehydes 5.1 Preparation of ketones and aldehydes  Ketones and Aldehydes are made in many ways.  The most useful type of transformation is forming a C= O bond from an alcohol.  There are three types of alcohols.  Primary, secondary, and tertiary. Primary Alcohols: Can be oxidized to form aldehydes Secondary Alcohols:   Can be oxidized to form Ketones Tertiary Alcohols:  CANNOT be oxidized because carbon can not form five bonds. Alcohols & Reagents Primary Alcohols:   Oxidize to aldehyde, but NOT further.  With a strong reagent, it can go from alcohol to a carboxylic acid, with a  milder reagent, it can go from alcohol to aldehyde.   This can be accomplished with a reagent called PYRIDINUM CHLOROCHROMATE, or PCC. PCC Structure 1 This reagent provides milder oxidizing conditions – therefore, the reaction stops at the aldehyde and does not  continue to the carboxylic acid.  Secondary Alcohols: Can be converted into a ketone upon treatment with sodium dichromate and sulfuric acid. Na 2r 2 7 H 2O ,4H O2 * Alternatively * The JONES reagent can be used, this is formed from CrO3 in aqueous acetone.   Whether or not you’re planning to use Na Cr 2  2r 7 e jones reagent, you are performing an oxidation that involves a chromium oxidizing agent.   The alcohol is being oxidized, and the chromium is being reduced.   Chromium oxidations work well for secondary alcohols, but not for primary alcohols. This is because the  conditions are too strong, and oxidize it too far to a carboxylic acid.  Ozonolysis:   Ozonolysis is another way to form C = O (other than oxidation)  The ozonolysis reaction essentially takes every C = C bond in the compound and breaks it to form a C = O.  5.2 Stability and Reactivity of C = O Bonds  Ketones and aldehydes are very similar to one another in their structure, however there are differences in their stability and reactivity.  Since they are structurally similar to one another, they also react similarly. Basics of C = O C = O is a carbonyl group.  It is important to not confuse the term carbonyl with the term acyl. The term “acyl” is used to refer to a carbonyl group together with an alkyl group.  When we want to know how a carbonyl will react, we must first look at the electronic effects – where the delta positive and negative areas are on the compound.  There are always two factors to explore, induction and resonance.  First start with induction: O is more electronegative than Carbon and therefore the oxygen will withdraw electron density.  Next we must look as resonance, we still see that the carbon is electro positive, and the oxygen is electro negative, this time because of resonance. IMAGE F  This means that the carbon atom is very electrophilic and the oxygen atom is very nucleophilic.  The geometry of a carbonyl group facilitates the carbon atom functioning as an electrophile. o SP2 hybridized carbon atoms have a trigonal planar geometry. o This makes is easy for a nucleophile to attack the carbonyl group since there is NO steric hindrance  Different nucleophiles are also able to attack carbonyl groups.  Carbonyl Groups are Thermodynamically very stable o Generally forming C = O is a process of downhill energy o But converting C = O to C – O is generally a process of uphill energy o The formation of carbonyl groups are generally the driving force in a reaction. Summary of 5.1 & 5.2 Klein OCSL 2 nd Semester  The carbon atom of the carbonyl group is the electrophile.  The electrophilic C is attacked by the nucleophile.  Carbonyl groups are very stable, the carbonyl formation can serve as a driving force GUIDING PRINCIPLES 1. A carbonyl can be attacked by a nucleophile (many different ones) 2. After a carbonyl group is attacked, it will try to reform IF possible. (But it is not always possible. 5.3 H- Nucleophiles  Exploration of nucleophiles that can attack ketones and aldehydes  Focusing on hydrogen nucleophiles. “Hydrogen” nucleophiles are a source of a negatively charged hydrogen atom that can attack a ketone or aldehyde. (Negatively charged hydrogen atom is called a hydride).  The simplest way to get a hydride is from sodium hydride (NaH).  Sodium hydride is an ionic compound so it is made up of Na+ and H-  NaH is a strong base, therefore you will not see it serve as a hydride nucleophile.  The strength of the base is determined by the stability of the negative charge.  An unstable negative charge corresponds to a strong base while a stabilized negative charge corresponds to a weak base.  Nucleophilicity is not based on stability, but rather on polarizability.  Polarizability: the ability of an atom or molecule to distribute its electron density unevenly in response to external influences.  Larger atoms are more polarizable = better nucleophiles  Smaller atoms are less polarizable = not as strong of nucleophiles.  H- is a strong base, but not such a strong nucleophile, this is because hydrogen does not stabilize a charge well.  We DO NOT use NaH as a nucleophile source.  Although H- itself cannot be used as a nucleophile, ther are many reagents that can serve as a “delivering agent” Sodium borohydride  NaBH4, is somewhat selective with what it will react with, it will not react with all carbonyl groups, like esters. BUT it will react with both aldehydes and Ketones. Lithium Aluminum Hydride (LiAlH4)  Lithium Aluminum Hydride is more reactive than sodium borohydride. Aluminum is larger than boron, this ma


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