Chapter 11 Reaction of Alcohols

Transcription

1 Chapter 11 eaction of Alcohols xidation of alcohols Alcohols are at the same oxidation level as alkenes Therefore alkenes can be converted to alcohols with acidic water PDC or PCC 2 C C X 3 C 3 C X 3 C Cr 3, 2 S 4 Alcohols can be oxidized to carbon-oxygen double bonds (carbonyl compounds) Primary alcohols will be converted to aldehydes under basic oxidation conditions Primary alcohols will be converted to carboxylic acids under nonbasic oxidation conditions

2 Alcohols as Nucleophiles Neutral alcohols can react as nucleophiles (often observe this with carboxylic acid derivatives or inorganic analogs) To make alcohols more nucleophilic, need to abstract the acidic hydrogen (remember pka s!) With this method, can make nucleophilic oxygen that can react through any S N 2 type reaction already studied

3 NUC Alcohols as Electrophiles In these reactions the alcohol is the leaving group (the C- bond is broken during the reaction) NUC Usually the hydroxide, or alkoxide, is a BAD leaving group, therefore we need to convert the alcohol into a GD leaving group 1) The tosylate, which was seen earlier, is commonly used as a way to make the alcoholic oxygen a good leaving group NUC Ts NUC 2) Another method we have already observed is protonation to form water as the leaving group + 2 X Ts X

4 Conversion of Alcohols into alides The methods to convert alcohols into electrophiles are used to transform alcohols into alkyl halides Can occur with either S N 1 or S N 2 conditions depending upon alcohol used Type of alcohol chloride bromide iodide primary secondary tertiary Best reagents for interconversions: SCl 2 SCl 2 PBr 3 PBr 3 P/I 2 P/I 2 Cl Br I Stereochemistry, and possibility of rearrangements, depends on mechanism for each reaction

5 Chapter 12 Infrared Spectroscopy I is used for Functional Group Identification Position of peaks can be used to differentiate all possible carbonyl compounds in addition to distinguishing common functional groups including nitriles, alkynes and aromatic rings C=C double bond CC triple bond Factors to be considered for peaks: Position of Absorbance (related to energy needed for absorbance)

6 C=C intensity C= intensity Factors to be considered for peaks: Intensity of Absorbance (related to dipole of bond undergoing absorbance) Shape of Absorbance (sharp or broad peaks related to type of bond)

7 Chapter 12 Mass Spectrometry In addition to determining the parent molecular weight for a sample, a MS can also be used to characterize what atoms are present and to differentiate isomers Isotopic Patterns for natural abundance: Fragmentation patterns can also be different for isomers

8 Predicted Mass Spectrometry Differences Isotope Differences Used to Distinguish alogen Substituents I Br m/z = 204 no m+2 for iodine m+1 = 6.4% of m m/z = 156 m+2 ~ equal to m Cl F m/z = 112 m+2 ~ 1/3 of m m/z = 96 no m+2 for fluorine

9 Fragmentation Pattern to Determine Structure e-beam m/z 102!-cleavage C 3 or or loss of water C 3 57 emember: nly charged forms are observed in a MS

10 Chapter 13 NM Spectroscopy Any nucleus with either an odd atomic number or odd mass has a nuclear spin A charge species that is spinning creates a current loop, which in turn creates magnetic field lines In solution, however, there are many hydrogens present and the spinning direction is random In presence of large external magnetic field the spin directions are quantized

11 Shielding Need to remember the structure of a compound (consider only an isolated C- bond) C B 0 B net = B 0 - B electron To reach the nucleus the magnetic field must past through the electron cloud surrounding the nucleus The electrons surrounding the nucleus are charged species that can rotate in the presence of the external magnetic field What this means is that the external magnetic field (B 0 ) is effectively reduced by the time it reaches the nucleus (B 0 minus the field of the electron cloud)

12 Splitting In addition to the electron density surrounding the hydrogen causing shielding, each hydrogen acts like its own magnetic field If one magnet is close to another, it will feel the effect of that magnetic field This occurs in a 1 NM a hydrogen will feel the effect of neighboring hydrogens In the field of one additional hydrogen therefore we would observe two signals N+1 rule: can predict the splitting that will be observed by counting the number of hydrogens on adjacent carbons (N) and adding one

13 1 NM Chemical Shift Scale B molecular - C 3 TMS (standard) C 2 C Aromatic- C=C- C-, C-X, C-N alkane B applied B effective ppm (!) Due to empirically observed effects, chemists can predict the position for functional groups, and the predicted splitting pattern for each signal Applied Magnetic Field: omogeneous for 1 NM therefore spin sample Molecular Magnetic Field: two effects will change the magnetic field experienced by nucleus 1) Density of electron density around nucleus shields nucleus (range ~12 ppm for 1 NM, ~200 ppm for 13 C NM) 2) Nearby magnetic nuclei (spin-spin splitting) The effective magnetic field at the nucleus is thus B applied -B molecular

14 13 C NM Spectroscopy Because a 13 C atom has an odd mass, it also has inherent magnetic field lines and will display NM spectroscopy in the presence of a large external magnetic field The downfield shift is dependent upon the shielding caused by the electrons around the carbon, due to the extra electron density around carbon compared to hydrogen there is a greater amount of shielding in a 13 C NM Instead of ~11 ppm range for 1 NM, 13 C NM is typically in a ~200 ppm range Due to the low probability of having two 13 C isotopes adjacent, there is no splitting observed from the possible spin states of adjacent carbons Typically observe a spin decoupled 13 C NM spectrum which has only singlets for each carbon bserve all carbons though, do not need to have a hydrogen attached as with a 1 NM

15 Amount of Downfield Shift is Comparable carboxylic acid 1 NM aldehyde aromatic alkene ether alkyl halide alkanes ppm (!) carbonyl carbons 13 C NM aromatic alkene alkyne C- C X alkanes ppm (!)

16 Chapter 14 Ethers Ethers are generally synthesized through a nucleophilic method Ethers are often used as solvents for organic reactions because the functional group is relatively unreactive ne of the few reactions that they can undergo is alkyl cleavage with I or Br + Br Br + Br Br Very similar to alcohol reactions observed in chapter 11 I > Br >> Cl

17 Epoxides ne type of ethers that are reactive is a cyclic ether in a 3-membered ring called epoxides Epoxides can be synthesized in one of two ways: 1) eacting alkenes with a peracid 2) eacting halohydrins with a weak base

18 egiochemistry in eaction of Epoxides The base catalyzed opening of epoxides goes through a common S N 2 mechanism, therefore the nucleophile attacks the least hindered carbon of the epoxide C 3 MgBr In the acid catalyzed opening of epoxides, the reaction first protonates the oxygen This protonated oxygen can equilibrate to an open form that places more partial positive charge on more substituted carbon, therefore the more substituted carbon is the preferred reaction site for the nucleophile + C 3 C 3

19 Chapter 15 Conjugated Systems Conjugated systems occur anytime there are p orbitals on adjacent atoms in conjugation Whenever there are p orbitals in conjugations, molecular orbitals result by the mixing of orbitals The difference in energy is due to the number of nodes (different phases overlap), more nodes means higher in energy and electrons are filled in lowest energy orbitals first = E 4 p orbitals = 4 Ms

20 Addition to Conjugated Dienes As we have already seen, alkenes can react with electrophiles to create a carbocation With conjugated dienes this reaction will create an allylic carbocation The nucleophile can then react with either resonance form in the second step

21 Kinetic versus Thermodynamic Control What forms faster (kinetic product) and what is more stable (thermodynamic product) need not be the same Consider the addition to conjugated dienes 2!+ E 2 2!+!+ eaction at 2 cation site has a more stable transition state +!+ Generate allylic cation in first step Allylic cation can have water react at two sites eaction at 2 site eaction at 1 site Thus the kinetic product has water reacting at 2 site eaction a 1 site, though, generates more stable product (more substituted double bond) The thermodynamic product has water reacting at 1 site

22 Diels-Alder eaction The reaction between butadiene and ethylene is called a Diels-Alder reaction btain cyclohexene functional units after a Diels-Alder reaction Always try to find the cyclohexene unit in the product, this will indicate what was the initial butadiene and ethylene parts

23 Stereochemistry of Addition Products on previous page did not indicate stereochemistry, but Diels-Alder reaction typically only yields one diastereomer preferentially (does not differentiate enantiomers) Whenever there is a p orbital on the atom attached to the dienophile, the endo product is favored due to orbital interaction between p orbital on dienophile and p orbitals on diene Endo position Interaction of p orbitals NC Exo position N C In endo position, orbitals on alkene substituents can interact with p orbitals of butadiene In exo orientation this interaction is not present

24 egiochemistry of Unsymmetrically Substituted Diels-Alder Products When a monosubstituted butadiene and a monosubstituted alkene react, different regioproducts can be obtained C 3 N 2! C 3 N 2 C 3 or N 2 Can predict favored product by understanding location of charge in molecules 2 3 C 3 C 3 C Consider resonance forms Negative charge is located on C2 and C4 1 2 N N Consider resonance forms Positive charge located on C2 The negative charge will react preferentially with the positive charge to obtain one regioproduct

25 Using this analysis we can predict regioproducts A Diels-Alder reaction can therefore control both regio- and stereochemistry

26 Ultraviolet-Visible (UV-Vis) Spectroscopy Instead of causing molecular vibrations, UV-VIS light causes electronic excitations An electron is excited from the M to the LUM Ethylene LUM Ethylene M E h! If the correct amount of energy is applied (i.e. the correct wavelength of light), the excitation of one electron from the M to the LUM will occur As the amount of conjugation increases, the energy gap between the M and LUM decreases With a lower energy gap, the λmax shifts to a longer wavelength of light to cause excitations

27 Chapter 16 Aromatic Systems When p orbitals are in conjugation in a ring, stability is sometimes much greater than acyclic = = Cyclic systems are thus different than acyclic as seen by how electrons can resonate, -is this difference always better? Depends also on the placement of molecular orbitals (not only due to cyclic) ückels rule: 4n+2 electrons in conjugation = aromatic (more stable) 4n electrons in conjugation = antiaromatic (less stable)

28 Aromatic Ions If p orbitals are in full conjugation in a cyclic system and the number of electrons in conjugation is equal to 4n+2, the compound is more stable regardless of whether the compound is neutral, negatively charged or positively charged = After rehybridization, system has 6 electrons in conjugation in a ring, therefore aromatic pka is ~16 Cyclopentadiene anion is very stable Cyclopentadiene cation is very unstable (will not form) With all cyclic ions, see if p orbitals are conjugated in a ring and then count the number of electrons in conjugation, if 4n+2 then stable, if 4n then unstable

29 Chapter 17 Aromatic eactions Electrophilic Aromatic Substitution Aromatic compounds react through a unique substitution type reaction Initially an electrophile reacts with the aromatic compound to generate an arenium ion (also called sigma complex) The arenium ion has lost aromatic stabilization (one of the carbons of the ring no longer has a conjugated p orbital) In a second step, the arenium ion loses a proton to regenerate the aromatic stabilization The product is thus a substitution (the electrophile has substituted for a hydrogen) and is called an Electrophilic Aromatic Substitution

30 A Variety of Electrophiles Can Be Used The key is generating an electrophilic reagent that can react with the aromatic ring ortho/para director meta director C 3 N 2 C 3 Br 2 FeBr 3 Cl 2 AlCl 3 N 3 2 S 4 Cl AlCl 3 Br C 3 2 N N 2 Electrophile:!+!- Br Br FeBr 3 Cl!+!- Cl Cl AlCl 3 N 2

31 eactions on Aromatic Substituents A variety of reactions can be performed on the aromatic substituents N 2 Sn, Fe, or Zn N 2 Cl deactivating activating Carbon side chains: Friedel-Crafts alkylation Friedel-Crafts acylation Cl Cl AlCl 3 AlCl 3 KMn 4 K NBS h! Zn Cl N 2 N 2 K C 2 Br Clemmensen Wolf-Kishner

32 Nucleophilic Aromatic Substitution Mechanism N 2 Cl NaCN N 2 Cl CN N 2 Cl CN N 2 Cl CN 2 N 2 N 2 N 2 N The anion is stabilized by electron withdrawing groups ortho/para to leaving group N 2 Cl CN N 2 CN 2 N 2 N To regain aromatic stabilization, the chloride leaves to give the substituted product 1) Must have EWG s ortho/para to leaving group -the more EWG s present the faster the reaction rate (intermediate is stabilized) 2) The leaving group ability does not parallel S N 2 reactions -follows electronegativity trend (F > Cl > Br > I)

33 Benzyne Mechanism A second nucleophilic aromatic substitution reaction is a benzyne mechanism Benzyne is an extremely unstable intermediate which will react with any nucleophile present N 2 Br NaN 2, N 3 N2 benzyne Need strong base at moderate temperatures, but do not need EWG s on ring

34 Chapter 18 Ketones and Aldehydes New routes to synthesize ketones and aldehydes From carboxylic acids: Li SCl 2 LiAl(tBu) 3 (2 equiv.) Cl 2 CuLi From nitriles: 1) MgBr 2) +, 2 C N 1) DIBAL 2) +, 2 1) DIBAL 2) +, 2 From dithianes: BuLi S S S S X S S +, gcl 2 2

35 eactions of Ketones and Aldehydes Base mechanism Acid mechanism NUC NUC NUC NUC Types of NUC : MgBr LA ylide cyanide Types of neutral NUC: 2 N 2 eactivity As electrophilicity of carbonyl carbon increases, the reactivity increases < < < Cl 3 C

36 Wittig eaction The carbanion of the ylide is nucleophilic and will react with the carbonyl (Ph) 3 P 3 C C 3 (Ph) 3 P 3 C C C 3 3 betaine The betaine structure will form 4-membered ring between phosporous and oxygen (Ph) 3 P (Ph) 3 P 3 C C C C C 3 C 3 oxyphosphetane The oxyphosphetane will collapse to form a second phosphorous-oxygen bond (Ph) 3 P 3 C C 3 C 3 C 3 3 C C 3 (Ph)3P verall an alkene is formed from the initial carbonyl compound

37 Acetals Acetals are related to hydrates, Instead of geminal dialcohols have geminal ethers 3 C C C C 3 This process is once again an equilibrium process Aldehydes (which are more reactive than ketones) typically favor acetals When both alcohols to form an acetal are intramolecular (on same molecule) then a cyclic acetal is formed 3 C + 3 C Cyclic acetals and ketals are often used because they have a higher equilibrium for the acetal form

38 Baeyer-Villiger Allows conversion of ketone to ester C 3 Mechanism of oxygen insertion? Weak oxygen-oxygen single bond Mechanism is not an insertion, but rather a reaction at carbonyl followed by a migration

39 Chapter 19 Amines The lone pair of electrons on nitrogen can act as an acceptor (hence Brønsted-Lowry base) N 2 K b N The basicity, and hence pk b, is determined by the stability of the amine after protonation 3 C N 3 C 3 C sp 3 hybridization pk b = 4.26 N sp 2 hybridization pk b = C C N sp hybridization pk b = 24 As the percent s character increases for the orbital holding the lone pair of electrons, the electrons are held more closely to the positively charged nucleus ther effects, such as whether lone pair is in resonance or involved in aromatic system, also will affect the pk b for the amine

40 Synthesis of Amines Nucleophilic: N 2 N C 3 I N C 3 I N problem is overalkylation 1) K 2) C 3 I N C 3 N 2 N 2 3 C N 2 eduction: oxime N LA N 2 Gabriel allows only 1 addition amide azide N N 3 LA LA N N 2 nitrile CN LA N 2

41 offman Elimination Elimination of Amines F N F (C 3 ) 3 N anti-elimination With quaternary ammonium salts, E2 reaction occurs to eliminate trimethylamine Cope Elimination F N F ( 3 C) 2 N syn-elimination With N-oxide, syn elimination occurs to eliminate dimethylhydroxy amine Both eliminations favor the less substituted alkene to be formed

42 Arenediazonium Salts Arenediazonium salts can be generated from aniline derivatives N 2 NaN 2 Cl N N The diazonium salt can then be converted into a number of different functional groups N N 2 S 4 BF 4 KI CuCN 3 P 2 F I CN Unique phenol derivatives Unique F substitution Easier I substitution Versatile CN (Sandmeyer) educe to

43 Chapters 20&21 Carboxylic Acids & Derivatives eactions of Acyl Compounds There is a commonality amongst carbonyl reactions, they have a nucleophile react at the carbonyl carbon X X NUC NUC X NUC Generate a tetrahedral intermediate that can expel a leaving group

44 Interconversion of Carboxylic Acid Derivatives Cl Acid chloride Anhydride Ester N 2 Amide Carboxylate The carboxylic acid can thus be converted into any other carboxylic acid derivative, In addition each carboxylic acid derivative can be converted to a carboxylic acid

45 eactivity of Carboxylic Acid Derivatives Cl Acid chloride Anhydride reactivity Ester N 2 Amide Carboxylate All carboxylic acid derivatives can also be converted back to the carboxylic acid (by either acidic or basic hydrolysis) or the derivatives can be directly interconverted to a less reactive form But cannot interconvert a less reactive acyl derivative into a more reactive

46 Predicting eactivity Patterns for Carboxylic Acid Derivatives All of the carboxylic acid derivatives can react with a nucleophile to generate the same carbonyl product the difference is the leaving group Cl NUC NUC Cl pka of conjugate for leaving group -7 NUC NUC ~4-5 NUC NUC 16 N NUC NUC N 35 The stability of the leaving group affects the reactivity pattern for the acid derivatives

47 Chapter 22 eactions at α-carbon A type of reaction with carbonyl compounds is an α-substitution (an electrophile adds to the α carbon of a carbonyl) E+ E In the preceding chapters, we primarily studied nucleophiles reacting at the electrophilic carbonyl carbon NUC NUC

48 eactions of Enols The enol form can react with electrophiles A common reaction is halogenation Na Br Br Br Under basic conditions it is hard to stop at one addition due to hydrogen abstraction of product is more favored than starting material Na Br 2 Br Br Br Br

49 Enolates Enolates are similar to enols but they are far more nucleophilic In order to generate an enolate, need a base to abstract an α-hydrogen LDA will quantitatively form enolate 3 C C 3 LDA 3 C C 2 Using LDA the enolate will be formed quantitatively, with weaker bases will only form the enolate in a small fraction

50 Enolate as a Nucleophile ave already observed many reactions with a negatively charged nucleophile (most S N 2 reactions) An enolate is simply another type of nucleophile, it can react in similar manner as other nucleophiles 3 C C 2 E+ 3 C C 2 E ne common reaction is to alkylate the enolate C 3 Br 3 C C 2 3 C C 2 C 3 This reaction will place an alkyl substituent at the α-position of a carbonyl Any electrophile that will react in a S N 2 reaction can be used

51 Thermodynamic vs. Kinetic Control With unsymmetrical ketones, different enolates can be generated The enolate can be preferentially generated at either site depending upon conditions LDA Kinetic enolate easier hydrogen to abstract Thermodynamic enolate more stable double bond Lower temperature favors kinetic product igher temperatures (in this case usually room temperature and above) favors thermodynamic product

52 Aldol Condensation Instead of reacting the enolate with an alkyl halide, we can also react the enolate with a carbonyl compound The carbonyl can react as an electrophile - 2 Greater the conjugation, the easier for loss of water Upon work-up obtain a β-hydroxy ketone The β-hydroxy ketone that is formed can also lose water to form an α,β-unsaturated ketone

53 Claisen Condensation There are many Name reactions that are modifications of the aldol condensation, A Claisen condensation is an aldol where one carbonyl compound is an ester By using an ester, the chemistry is changed due to the presence of a leaving group C 3 Na Can run reaction with both carbonyls present with weak base due to differences in pka (ketones ~20, esters ~24) With ester leaving group, obtain diketone product

54 Dieckmann A Dieckmann condensation is an intramolecular Claisen condensation C 3 C 3 Convenient method to form 5- or 6-membered rings

55 Michael Addition If we add stabilized enolates to α,β-unsaturated system, the reaction can occur with 1,4-addition NUC NUC Michael product (1,4 addition) Whether a reaction occurs with 1,2- or 1,4-addition, selectively often depends on the stability of the nucleophilic anion. A more stable anion occurs with 1,4 selectivity while a less stable anion occurs with 1,2 selectivity. N C 3 MgBr (C 3 ) 2 CuLi 1,2 1,4 1,4 1,2 1,4 Enolate anions prefer 1,2 but β-diketone or enamines favor 1,4 Grignard reagents prefer 1,2 but Gilman reagents prefer 1,4