chem 352 - exam three

amines

non-bonding electron pair makes it a base and nucleophile, reacts with electrophiles to form ammonium salts; sp3 hybridized and trigonal planar

amine stereocenters

amine nitrogen bonded to three different alkyl groups is technically a stereocenter but interconverts rapidly and can be ignored

nitrogen with four groups CANNOT be ignored

primary amines

systematic name: longest chain bonded to amine, then change suffix to -amine

common: alkyl group + amine

secondary + tertiary amines

identical alkyl groups use prefix di and tri + name of primary amine

different alkyl groups designate systematic name with longest alkyl, then name other alkyls with prefix N

aromatic amines

derivatives of aniline, follows benzyllic naming rules

amine physical properties

primary and secondary amines can H bond which increases their boiling points; higher than esters but lower than alcohols

spectroscopic

IR: N-H 3300-3500, one or two peaks depending on number of alkyls

H NMR: N-H 0.5-5.0; C-H adjacent to N 2.5-3.0

13 C: C bonded to N 30-50

direct nucleophilic substitution

nucleophilic attack of nitrogen nucleophile forms ammonium salt, deprotonation (using other amine nucleophile) forms amine; alkyl halide must be unhindered

avoid quaternary salt by using amine with one R as an H

primary amines: formed with excess NH3

quaternary amines: formed with excess alkyl halide

gabriel synthesis

phthalimide reacts with -OH to form nucleophilic anion, which then reacts with unhindered alkyl halide in an Sn2 reaction, then hydrolyzed with aqueous base to form primary amine and dicarboxylate

reduce nitrogen compounds to primary amines

R-NO2 → H2/Pd-C, Fe HCl, OR Sn, HCl → R-NH2

reduce nitriles to primary amines

R-CN → LiAlH4, H2O → R-CH2-NH2

CN can Sn2 on alkyl halide and lengthen carbon chain

reduce primary, secondary, and tertiary amides to amines

RCONR2 → LiAlH4, H2O → R-CH2-NR2

azides

R-N3 → H2/Pd-C, OR PPh3, H2O → R-NH2

can Sn2 and replace halogens

reductive amination of aldehydes and ketones

converts aldehydes and ketones into primary, secondary, and tertiary amines; nucleophilic attack of NH3 on carbonyl group to form imine, then reduction into amine using NABH3CN

no preference on substitution with retrosynthesis

cyanoborohydride

NaBH3CN

CN withdraws the most, less reactive than BH4 because H- is less powerful

does not reduce aldehydes, ketones, or imine, ONLY IMINIUM IONS

amines as bases

pka of starting acid must be less than 10 for equilibrium to favor products

readily protanated by HCl, H2SO4 and COOH

stronger bases have higher pKa and increased electron density on N

extraction of amines

both compounds readily dissolve in organic solvent CH2Cl2; add 10% HCl to form two layers because amine is protonated to form salt; cyclohexanol remains in bottom layer and can then be separated

alkyl groups and basicity

donate electrons, making alkylamines more basic than NH3

arylamines and basicity

less basic than alkylamines because electron pair on N is delocalized

amides and basicity

less basic than amines because lone pairs delocalize to stabilize C=O

amides in acid are protonated at C=O first because it forms resonance stabilized carbocations

heterocyclic aromatic amines and basicity

more basic if lone pair is in sp2 because it is localized on nitrogen

lone pairs that contribute to aromaticity are NOT basic

hybridization and basicity

weaker bases have higher percentages of s character

amines as nucleophiles

attach carbonyls to form products of nucleophilic addition or substitution

1* + 2* amines with aldehydes and ketones → imines and emanines

NH3, 1*, 2* amines with acid chlorides and anhydrides → amides

DCC + carboxylic acid → amides

substituted analines

1. convert amine (aniline) to amide (acetanilide) using CH3COCl

2. Friedel-Crafts reaction, O+P products

3. hydrolize amide with -OH, H2O or H3O+ → free amino

amines with nitrous acid

H2NO2 = weak, unstable acid; decomposes to +NO group in presence of acid

diazonium salts

formed from 1* and 2* amines using +NO

can explode if dry, useful as synthetic intermediates but rarely isolated

forms “worlds best leaving group”, used with a variety of reactions

substitutions of aryl diazonium salts

Ph-N2+-Cl + H2O → Ph-OH

Ph-N2+-Cl + Cu-X (Br or Cl) → Ph-X

Ph-N2+-Cl + HBF4 → Ph-F

Ph-N2+-Cl + NaI or KI → Ph-I

Ph-N2+-Cl + CuCN → Ph-CN

Ph-N2+-Cl + H3PO2 → benzene

coupled reactions of aryl diazonium salts

diazonium salt + aromatic compound with strong electron donor; highly conjugated and colored

typically forms only para due to large electrophile, but can form ortho if para is blocked

conjugated compounds

absorbs and reflects light; highly conjugated gap between HOMO and LUMO, absorbs specific wavelength

azo dyes

typically charged, colored, adheres to fabric via IMFs (noncovalent)

proteins: use charged dyes → electrostatic interactions

carbohydrate: use H-bonds

amino acids

20, differ in identity of R groups, naturally occur as L (s configuration) except cysteine

zwitterion salt

pH ~ 6

neutral form does not exist, ammonium cation + carboxylate anion

inductive effect of C=O makes +NH3 less basic than alkyl amines

water soluble, high melting points

pI

overall neutral compounds; pH where concentration of amino acid is at a max, average pH of ammonium and carboxylate ions, usually 6-7

basic R groups: higher pI

acidic R groups: lower pI

resolution

separation of racemic mixture; converts pair of enantiomers into diastereomers, separate diastereomers, reconverts to original enantiomer

acetic anhydrite + racemic mixture → N-acetyl amino acids → (R)-a-methylbenzylamine → diastereomer salts → separation and regenerate via hydrolysis

recrystallization

less soluble diastereomer crystallizes/precipitates first

kinetic resolution with enzymes

chemical reaction selectively occurs for one enantiomer; amylases hydrolize amide bonds of L amine-amino acids, then separate

faster reaction due to chiral enzymes

enantioselective hydrogenation

use chiral reagent to synthesize desired enantiomer, mainly contains rhodium, abbreviated Rh*

BINAP: chiral with no tetrahedral stereogenic centers due to shape

alkene → enantioselective hydrogenation → hydrolysis (AcNH → NH2)

peptides

amino acids joined by amide bonds

N terminus left, C terminus right

resonance of amide constricts C-N bond; s-trans more stable due to two R groups on opposite sides of C-N

amino acids with sulfur form disulfide bonds with exposed to oxidizing reagents

peptide synthesis

avoid multiple products due to two functional groups on amino acid by protecting functional groups you do not want to react

2 peptides can form 4 different dipeptides

form amide bond with DCC which makes -OH a better leaving group, then remove protecting groups

protecting NH2 group

forms carbamate

BOC: tert-butoxycarbonyl, removed with trifluoroacetic acid (CF3CO2H), HCl or HBr

Fmoc: 9-fluorenylmethoxycarbonyl → removed with base (NH3 or amine)

Cbz: carbobenzyloxy → removed with H2/Pd-C or HBr, elimination does not need heat

protecting COOH

react with alcohol and acid to form ester, remove using base

CH3OH, H+, cleaved with H2O, -OH

PhCH2OH, H+, removed with H2 Pd-C OR HBr in acetic acid

tert-butyl ester + H2SO4, removed with TFA (F3CCOOH), HCl or HBr

protecting group removal conditions

acid: Boc/otBU; HCl, TFA or HBr

base: Fmoc/OCH3; base

hydrogenation: CBz/OBn; H2/Pd-C or HBr

primary structure

peptide bonds

rotation around amide C-N bond restricted due to electron delocalization

N-H and C=O 180* from each other, restriction around other sigma bonds not restricted

S-trans and s-cis possible, but s-trans most stable

secondary structure

3D conformations of localized regions

alpha helix

twist in clockwise spiral; each turn has 3.6 amino acids, N-H and C=O bonds point along helix axis in opposite directions, H bonding occurs between amino acids in same chain, R groups extend outwards

only possible if bonds around alpha carbon can rotate - no proline

beta sheet

two or more beta sheets lined up side by side, C=O and N-H bonds lie in plane, H bonds between nearby amino acid residues, R groups oriented in alternating above and below sheet

mostly with small R groups (alanine and glycine) because large groups sterically hinder proximity of sheets

tertiary structure

3D shape of entire peptide chain; maximizes stability with polar and charged groups on exterior to minimize dipole-dipole and H-bonding with water or amino acids

covalent disulfide bonds can form

quaternary structure

2+ folded polypeptide chains aggregate into one protein complex where each polypeptide is a subunit

denaturation

process of altering protein shape without breaking amide bonds that form primary structure; high temp, acid, base, agitation

protein type

fibrous: long strand-like proteins that are water insoluble

globular: spherical, water-soluble

serine proteases

catalytic triad consisting of acid, base, and nucleophile; acid and base activate nucleophile with attracts substrate to form covalent intermediate which is then hydrolyzed to regenerate enzyme

organocuprate reagents

R2CuLi

react with organic halides R-X to form coupling products R-R’ that contain a new C-C bond; coupling with vinyl halides are stereospecific and form one stereoisomer

use methyl and primary alkyl halides, and vinyl and aryl halides containing X bonded to an sp2

some cyclic 2* alkyls, no 3* alkyls

suzuki reactions

palladium catalyzed coupling of organic halide with organoborane to form R-R’ with new C-C

palladium catalysts

palladium coordinated to ligands, which donate e- density to metal

dominated by oxidative addition (increases # groups around metal by 2) OR reductive elimination (eliminates 2 groups surrounding metal forming new C-C or C-H bonds)

heck reaction

palladium catalyzed coupling of a vinyl or aryl halide with an alkene to form a more highly substituted alkene with a new C-C bond

typically formed with an ethylene or monosubstituted alkene with Br or I, if Z is Ph, COOR, or CN, the new C-C bond is formed on least substituted carbon to form a trans alkene

vinyl halides are stereospecific

carbene synthesis

Carbene: R-C, neutral reactive intermediate that contains a divalent carbon surrounded by six electrons from lone pair and from two R groups; highly reactive due to unfull octet and acts as an electrophile

cyclopropane synthesis

trihalomethenes (CHX3) with strong base react with double bonds to for cyclopropanes

syn reaction, retains configuration of R groups

simmons smith reaction

formation of nonhalogenated cyclopropanes

I-CH2-I → ZnCu → cyclopropane + ZnI2

metathesis

reaction between two alkene molecules that results in the interchange of Carbons of double bonds;

Equilibrium process, avoid unwanted products by using terminal alkenes because CHCH is a gas, driving reaction right

Align like carbons of starting alkene, break double bonds and form two new bonds using carbons that were not previously bonded to each other (joining two unlike Cs results in starting material)

ring closing metathesis

diene is used as starting material; highly diluted to favor intramolecular metathesis

organoboranes

vinylboranes: catecholeboranes + terminal alkyne add H and Bto alkyne in syn, forming E vinylborane

arylborane: Ph-Li + B(OCH3)3